BioMed Research International: Immunology http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. Inhibition of Hydrogen Sulfide Production by Gene Silencing Attenuates Inflammatory Activity by Downregulation of NF-κB and MAP Kinase Activity in LPS-Activated RAW 264.7 Cells Tue, 19 Aug 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/848570/ Hydrogen sulfide is an endogenous inflammatory mediator produced by the activity of cystathionine γ-lyase (CSE) in macrophages. The objective of this study was to explore the mechanism by which hydrogen sulfide acts as an inflammatory mediator in lipopolysaccharide- (LPS-) induced macrophages. In this study, we used small interfering RNA (siRNA) to inhibit CSE expression in macrophages. We found that CSE silencing siRNA could reduce the LPS-induced activation of transcription factor nuclear factor-κB (NF-κB) significantly. Phosphorylation and activation of extra cellular signal-regulated kinase 1/2 (ERK1/2) increased in LPS-induced macrophages. We showed that phosphorylation of ERK in LPS-induced RAW 264.7 cells reached a peak 30 min after activation. Our findings show that silencing CSE gene by siRNA reduces phosphorylation and activation of ERK1/2 in LPS-induced RAW 264.7 cells. These findings suggest that siRNA reduces the inflammatory effects of hydrogen sulfide through the ERK-NF-κB signalling pathway and hydrogen sulfide plays its inflammatory role through ERK-NF-κB pathway in these cells. Alireza Badiei, Nethaji Muniraj, Stephen Chambers, and Madhav Bhatia Copyright © 2014 Alireza Badiei et al. All rights reserved. NK Cells in Mucosal Defense against Infection Thu, 14 Aug 2014 11:28:32 +0000 http://www.hindawi.com/journals/bmri/2014/413982/ Conventional natural killer cells (NK cells) provide continual surveillance for cancer and rapid responses to infection. They develop in the bone marrow, emerge as either NK precursor cells, immature, or mature cells, and disperse throughout the body. In the periphery NK cells provide critical defense against pathogens and cancer and are noted to develop features of adaptive immune responses. In the tightly regulated and dynamic mucosal tissues, they set up residency via unknown mechanisms and from sources that are yet to be defined. Once resident, they appear to have the ability to functionally mature dependent on the mucosal tissue microenvironment. Mucosal NK cells play a pivotal role in early protection through their cytolytic function and IFNγ production against bacteria, fungi, viruses, and parasitic infections. This review presents what is known about NK cell development and phenotypes of mucosal tissue resident conventional NK cells. The question of how they come to reside in their tissues and published data on their function against pathogens during mucosal infection are discussed. Dissecting major questions highlighted in this review will be important to the further understanding of NK cell homing and functional diversity and improve rational design of NK cell based therapies against mucosal infection. Daria Ivanova, Ryan Krempels, Jennyfer Ryfe, Kaitlyn Weitzman, David Stephenson, and Jason P. Gigley Copyright © 2014 Daria Ivanova et al. All rights reserved. Immune Mechanisms in Vascular Disease and Stroke Thu, 14 Aug 2014 05:53:46 +0000 http://www.hindawi.com/journals/bmri/2014/730691/ Ban-Hock Toh, Alexander Bobik, Tin S. Kyaw, Grant R. Drummond, Christopher G. Sobey, and Tomasz J. Guzik Copyright © 2014 Ban-Hock Toh et al. All rights reserved. Myeloid-Derived microRNAs, miR-223, miR27a, and miR-652, Are Dominant Players in Myeloid Regulation Mon, 11 Aug 2014 06:43:49 +0000 http://www.hindawi.com/journals/bmri/2014/870267/ In the past few years expanding knowledge has been accumulated about the role of microRNAs (miRNAs) not only in hematopoiesis and cancer, but also in inflammatory and infectious diseases. Regarding myeloid cells, our knowledge is relatively insufficient, therefore we intended to collect the available data of miRNA profiles of myeloid cells. In addition to a rather general myeloid regulator miR-223, two other miRNAs seem to be useful subjects in understanding of myeloid miRNA biology: miR-27a and miR-652. We review functions of these three miRNAs and other myeloid miRNAs focusing on their roles in monocytes, neutrophils, eosinophils, basophils and mast cells. Anna B. Gilicze, Zoltán Wiener, Sára Tóth, Edit Buzás, Éva Pállinger, Franco H. Falcone, and András Falus Copyright © 2014 Anna B. Gilicze et al. All rights reserved. Biotechnological Drugs: The Breakthrough in Autoimmune Rheumatic Conditions Sun, 10 Aug 2014 08:27:17 +0000 http://www.hindawi.com/journals/bmri/2014/481973/ Lorenzo Cavagna, Lesley-Ann Saketkoo, Andreas Schwarting, and Roberto Caporali Copyright © 2014 Lorenzo Cavagna et al. All rights reserved. Vagus Nerve through 7 nAChR Modulates Lung Infection and Inflammation: Models, Cells, and Signals Sun, 20 Jul 2014 11:12:04 +0000 http://www.hindawi.com/journals/bmri/2014/283525/ Cholinergic anti-inflammatory pathway (CAP) bridges immune and nervous systems and plays pleiotropic roles in modulating inflammation in animal models by targeting different immune, proinflammatory, epithelial, endothelial, stem, and progenitor cells and signaling pathways. Acute lung injury (ALI) is a devastating inflammatory disease. It is pathogenically heterogeneous and involves many cells and signaling pathways. Here, we emphasized the research regarding the modulatory effects of CAP on animal models, cell population, and signaling pathways that involved in the pathogenesis of ALI. By comparing the differential effects of CAP on systemic and pulmonary inflammation, we postulated that a pulmonary parasympathetic inflammatory reflex is formed to sense and respond to pathogens in the lung. Work targeting the formation and function of pulmonary parasympathetic inflammatory reflex would extend our understanding of how vagus nerve senses, recognizes, and fights with pathogens and inflammatory responses. Haiya Wu, Ling Li, and Xiao Su Copyright © 2014 Haiya Wu et al. All rights reserved. Murine Aortic Smooth Muscle Cells Acquire, Though Fail to Present Exogenous Protein Antigens on Major Histocompatibility Complex Class II Molecules Sun, 20 Jul 2014 08:56:35 +0000 http://www.hindawi.com/journals/bmri/2014/949845/ In the present study aortic murine smooth muscle cell (SMC) antigen presentation capacity was evaluated using the Eα-GFP/Y-Ae system to visualize antigen uptake through a GFP tag and tracking of Eα peptide/MHCII presentation using the Y-Ae Ab. Stimulation with IFN-γ (100 ng/mL) for 72 h caused a significant increase in the percentage of MHC class II positive SMCs, compared with unstimulated cells. Treatment with Eα-GFP (100 μg/mL) for 48 h induced a significant increase in the percentage of GFP positive SMCs while it did not affect the percentage of Y-Ae positive cells, being indicative of antigen uptake without its presentation in the context of MHC class II. After IFN-γ-stimulation, ovalbumin- (OVA, 1 mg/mL) or OVA323–339 peptide-(0.5 μg/mL) treated SMCs failed to induce OT-II CD4+ T cell activation/proliferation; this was also accompanied by a lack of expression of key costimulatory molecules (OX40L, CD40, CD70, and CD86) on SMCs. Finally, OVA-treated SMCs failed to induce DO11.10-GFP hybridoma activation, a process independent of costimulation. Our results demonstrate that while murine primary aortic SMCs express MHC class II and can acquire exogenous antigens, they fail to activate T cells through a failure in antigen presentation and a lack of costimulatory molecule expression. Marcella Maddaluno, Neil MacRitchie, Gianluca Grassia, Armando Ialenti, John P. Butcher, Paul Garside, James M. Brewer, and Pasquale Maffia Copyright © 2014 Marcella Maddaluno et al. All rights reserved. Roles of Inflammation, Oxidative Stress, and Vascular Dysfunction in Hypertension Sun, 20 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/406960/ Hypertension is a complex condition and is the most common cardiovascular risk factor, contributing to widespread morbidity and mortality. Approximately 90% of hypertension cases are classified as essential hypertension, where the precise cause is unknown. Hypertension is associated with inflammation; however, whether inflammation is a cause or effect of hypertension is not well understood. The purpose of this review is to describe evidence from human and animal studies that inflammation leads to the development of hypertension, as well as the evidence for involvement of oxidative stress and endothelial dysfunction—both thought to be key steps in the development of hypertension. Other potential proinflammatory conditions that contribute to hypertension—such as activation of the sympathetic nervous system, aging, and elevated aldosterone—are also discussed. Finally, we consider the potential benefit of anti-inflammatory drugs and statins for antihypertensive therapy. The evidence reviewed suggests that inflammation can lead to the development of hypertension and that oxidative stress and endothelial dysfunction are involved in the inflammatory cascade. Aging and aldosterone may also both be involved in inflammation and hypertension. Hence, in the absence of serious side effects, anti-inflammatory drugs could potentially be used to treat hypertension in the future. Quynh N. Dinh, Grant R. Drummond, Christopher G. Sobey, and Sophocles Chrissobolis Copyright © 2014 Quynh N. Dinh et al. All rights reserved. Blood Monocyte Subsets and Selected Cardiovascular Risk Markers in Rheumatoid Arthritis of Short Duration in relation to Disease Activity Mon, 14 Jul 2014 12:48:55 +0000 http://www.hindawi.com/journals/bmri/2014/736853/ Objectives. To evaluate blood monocyte subsets and functional monocyte properties in patients with rheumatoid arthritis (RA) of short duration in the context of cardiovascular (CV) risk and disease activity. Methods. We studied conventional markers of CV risk, intima media thickness (IMT), and blood monocyte subsets in 27 patients aged 41 ± 10 years with RA of short duration (median 12 months) and 22 healthy controls. The RA subjects were divided into low (DAS28: 2.6–5.1) and high (DAS28 > 5.1) disease activity. Results. RA patients exhibited increased levels of intermediate (CD14++CD16+) monocytes with decreased CD45RA expression compared to controls, increased counts of classical (CD14++CD16−) monocytes, and decreased percentages of nonclassical (CD14+CD16++) monocytes. Patients with high disease activity had lower HLA DR expression on classical monocytes compared to low disease activity patients. There were no differences in monocyte subsets between subjects with DAS > 5.1 and DAS ≤ 5.1. There were no significant intergroup differences in IMT and the majority of classical CV risk factors. Conclusions. Patients with RA of short duration show alteration in peripheral blood monocyte subsets despite the fact that there is no evidence of subclinical atherosclerosis. Disease activity assessed with DAS28 was associated with impaired functional properties but not with a shift in monocyte subpopulations. Ewa Klimek, Tomasz Mikołajczyk, Joanna Sulicka, Beata Kwaśny-Krochin, Mariusz Korkosz, Grzegorz Osmenda, Barbara Wizner, Andrzej Surdacki, Tomasz Guzik, Tomasz K. Grodzicki, and Anna Skalska Copyright © 2014 Ewa Klimek et al. All rights reserved. Modulation of TLR 3, 7 and 8 Expressions in HCV Genotype 3 Infected Individuals: Potential Correlations of Pathogenesis and Spontaneous Clearance Sun, 13 Jul 2014 13:58:22 +0000 http://www.hindawi.com/journals/bmri/2014/491064/ Background. Hepatitis C virus is the major cause of chronic hepatitis worldwide which finally leads to the development of hepatocellular carcinoma. Toll like receptors (TLRs) play an important role in the course of many viral infections, but the role of TLRs in HCV pathogenesis has not been well elucidated so far. Objective. The aim of this study was to analyse the mRNA expression of TLRs 3, 7, and 8 in different stages of HCV infection including chronic, cirrhosis, interferon treated resolved, and relapsed cases. Methodology. Total RNA from whole blood was extracted and mRNA expression of TLRs 3, 7, and 8 genes was analyzed by quantitative real-time RT-PCR using β-Actin gene as an internal control. Results. This study consisted of 100 HCV infected individuals and twenty healthy controls. TLR 3 expression was found to be significantly elevated in individuals who had spontaneously cleared the virus , whereas TLR 7 was found to be 3.26 times more elevated in patients with cirrhosis of liver. In IFN induced individuals, TLR 8 expression levels were found to be 2.28-fold elevated as compared to control population. Conclusion. TLRs 3, 7, and 8 are prime biomarker candidates for HCV infection mRNA expression analysis which might improve current therapeutic approaches. Rushna Firdaus, Aritra Biswas, Kallol Saha, Anirban Mukherjee, Falguni Pal, Sujit Chaudhuri, Alok Chandra, Asokananda Konar, and Provash Chandra Sadhukhan Copyright © 2014 Rushna Firdaus et al. All rights reserved. The Effect of Citrus Peel Extracts on Cytokines Levels and T Regulatory Cells in Acute Liver Injury Sun, 13 Jul 2014 08:44:35 +0000 http://www.hindawi.com/journals/bmri/2014/127879/ Background. T cell-mediated immune responses contribute to the hepatocellular injury during autoimmune hepatitis, viral infection, and hepatotoxins. Pharmacological compounds regulating immune responses are suitable candidates for prevention/treatment of this pathology. Therefore, the main aim of this study was to define the effects of antioxidant, anti-inflammatory mixture of citrus peel extract (CPE) on the immune-mediated liver injury. Methods. The influence of CPE on liver injury was determined by the activity of transaminases in plasma and the histological changes. Anti-inflammatory and antioxidant effects were studied by measuring frequency of T regulatory cells (Tregs), cytokines (TNF-α, IL-10, and IFN-γ), and nitric oxide levels. Results. The CPE application notably prevents development of liver injury through decreasing levels of both cytokines (TNF-alpha, INF) and regulatory T cells and increasing levels of IL-10. CPE injection also diminished the serum NO, which in turn resulted in evident reduction of the liver damage. Conclusion. Our findings represent the primary preclinical data indicating that the CPE in vivo could ameliorate Con A induced hepatitis. The low dose of CPE most likely can be used for the treatment of the T cell-mediated liver injury as in autoimmune hepatitis, alcoholic hepatitis, and chronic viral hepatitis. Ia Pantsulaia, Manana Iobadze, Nato Pantsulaia, and Tinatin Chikovani Copyright © 2014 Ia Pantsulaia et al. All rights reserved. Expression of Acetylcholine Receptors by Experimental Rat Renal Allografts Wed, 09 Jul 2014 11:05:16 +0000 http://www.hindawi.com/journals/bmri/2014/289656/ Chronic allograft injury (CAI) is a major cause for renal allograft dysfunction and characterized by vasculopathies, tubular atrophy, and fibrosis. We demonstrated that numerous leukocytes interact with vascular endothelial cells of allografts and produce acetylcholine, which contributes to vascular remodeling. The cholinergic system might be a promising target for the development of novel therapies. However, neither the cellular mechanisms nor the acetylcholine receptors involved in CAI are known. Kidney transplantation was performed in the Lewis to Lewis and in the Fischer-334 to Lewis rat strain combination, which is an established experimental model for CAI. Expression of nicotinic and muscarinic acetylcholine receptors mRNA was quantified in renal tissue by real-time RT-PCR on days 9 and 42 after surgery. We detected CHRNA2–7, CHRNA10, CHRNB2, CHRNB4, and CHRM1–3 mRNA in normal kidneys and in renal transplants. In contrast, CHRNA9, CHRM4, and CHRM5 mRNA remained below the threshold of detection. In renal allografts, CHRNA3 and CHRNB4 mRNA expression were dramatically reduced compared to isografts. In conclusion, we demonstrated that most acetylcholine receptor subtypes are expressed by normal and transplanted kidneys. Allograft rejection downmodulates CHRNA3 and CHRNB4 mRNA. The role of different acetylcholine receptor subtypes in the development of CAI remains to be established. Marion Meixner, Srebrena Atanasova, Winfried Padberg, and Veronika Grau Copyright © 2014 Marion Meixner et al. All rights reserved. Metoprolol Reduces Proinflammatory Cytokines and Atherosclerosis in ApoE−/− Mice Tue, 08 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/548783/ A few studies in animals and humans suggest that metoprolol (β1-selective adrenoceptor antagonist) may have a direct antiatherosclerotic effect. However, the mechanism behind this protective effect has not been established. The aim of the present study was to evaluate the effect of metoprolol on development of atherosclerosis in ApoE−/− mice and investigate its effect on the release of proinflammatory cytokines. Male ApoE−/− mice were treated with metoprolol (2.5 mg/kg/h) or saline for 11 weeks via osmotic minipumps. Atherosclerosis was assessed in thoracic aorta and aortic root. Total cholesterol levels and Th1/Th2 cytokines were analyzed in serum and macrophage content in lesions by immunohistochemistry. Metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta ( versus Control). Further, metoprolol reduced serum TNFα and the chemokine CXCL1 ( versus Control for both) as well as decreasing the macrophage content in the plaques ( versus Control). Total cholesterol levels were not affected. In this study we found that a moderate dose of metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta of ApoE−/− mice. Metoprolol also decreased serum levels of proinflammatory cytokines TNFα and CXCL1 and macrophage content in the plaques, showing that metoprolol has an anti-inflammatory effect. Marcus A. Ulleryd, Evelina Bernberg, Li Jin Yang, Göran M. L. Bergström, and Maria E. Johansson Copyright © 2014 Marcus A. Ulleryd et al. All rights reserved. Effects of Anti-TNF Alpha Drugs on Disability in Patients with Rheumatoid Arthritis: Long-Term Real-Life Data from the Lorhen Registry Sun, 06 Jul 2014 08:13:51 +0000 http://www.hindawi.com/journals/bmri/2014/416892/ This study involving 1033 patients with RA confirms the effectiveness of etanercept, adalimumab, and infliximab in reducing RA-related disability even in patients with a history of highly active and longstanding RA. Moreover, we found that the improvement in disability was biphasic, with a marked improvement during the first year of anti-TNF therapy, followed by slower but significant recovery over the subsequent four years. Matteo Filippini, Chiara Bazzani, Fabiola Atzeni, Piercarlo Sarzi Puttini, Antonio Marchesoni, Ennio Giulio Favalli, Roberto Caporali, Lorenzo Cavagna, and Roberto Gorla Copyright © 2014 Matteo Filippini et al. All rights reserved. Terminally Differentiated Epithelial Cells of the Thymic Medulla and Skin Express Nicotinic Acetylcholine Receptor Subunit α3 Thu, 03 Jul 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/757502/ In the thymus, T cell maturation is influenced by cholinergic signaling, and the predominantly expressed receptor is the α3-subunit of nicotinic acetylcholine receptors, encoded by the chrna3 gene. We here determined its cellular distribution utilizing an appropriate eGFP-expressing reporter mouse strain. Neither T cells (CD4, CD8) nor mesenchymal cells (desmin-positive) expressed eGFP. In the thymic medulla, eGFP-positive cells either were scattered or, more frequently, formed small clusters resembling Hassall’s corpuscles. Immunolabeling revealed that these cells were indeed terminally differentiated epithelial cells expressing keratin 10 (K10) but neither typical cortical (K8, K18) nor medullary keratins (K5, K14). These labeling patterns reflected those in the epidermis of the skin, where overlap of K10 and eGFP expression was seen in the stratum granulosum, whereas underlying basal cells displayed K5-immunoreactivity. A substantial portion of thymic eGFP-positive cells was also immunoreactive to chromogranin A, a peptide previously reported in epidermal keratinocytes in the stratum granulosum. Its fragment catestatin has multiple biological activities, including suppression of proinflammatory cytokine release from macrophages and inhibition of α3β4 nAChR. The present findings suggest that its thymic production and/or release are under cholinergic control involving nAChR containing the α3-subunit. Aichurek Soultanova, Alexandra R. Panneck, Amir Rafiq, and Wolfgang Kummer Copyright © 2014 Aichurek Soultanova et al. All rights reserved. Antibodies in the Pathogenesis of Hypertension Mon, 23 Jun 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/504045/ It has long been known that circulating levels of IgG and IgM antibodies are elevated in patients with essential and pregnancy-related hypertension. Recent studies indicate these antibodies target, and in many cases activate, G-protein coupled receptors and ion channels. Prominent among these protein targets are AT1 receptors, α1-adrenoceptors, β1-adrenoceptors, and L-type voltage operated Ca2+ channels, all of which are known to play key roles in the regulation of blood pressure through modulation of vascular tone, cardiac output, and/or Na+/water reabsorption in the kidneys. This suggests that elevated antibody production may be a causal mechanism in at least some cases of hypertension. In this brief review, we will further describe the protein targets of the antibodies that are elevated in individuals with essential and pregnancy-related hypertension and the likely pathophysiological consequences of antibody binding to these targets. We will speculate on the potential mechanisms that underlie elevated antibody levels in hypertensive individuals and, finally, we will outline the therapeutic opportunities that could arise with a better understanding of how and why antibodies are produced in hypertension. Christopher T. Chan, Maggie Lieu, Ban-Hock Toh, Tin S. Kyaw, Alexander Bobik, Christopher G. Sobey, and Grant R. Drummond Copyright © 2014 Christopher T. Chan et al. All rights reserved. Adiponectin Levels Are Reduced While Markers of Systemic Inflammation and Aortic Remodelling Are Increased in Intrauterine Growth Restricted Mother-Child Couple Sun, 22 Jun 2014 07:46:52 +0000 http://www.hindawi.com/journals/bmri/2014/401595/ Aim of the Study. To investigate the relationships between the adipocytokine levels, markers of inflammation, and vascular remodelling in pregnancies complicated by intrauterine growth restriction (IUGR). Materials and Methods. This was a retrospective study. One hundred and forty pregnant patients were enrolled. Adiponectin, leptin, tumor necrosis factor α (TNFα), interleukin-6 (IL-6), and C reactive protein (CRP) were assessed in IUGR, small for gestational age (SGA), and appropriate for gestational age (AGA) mother-child couples at delivery. IUGR and SGA fetuses were defined as fetuses whose estimated fetal weight (EFW) was below 10th percentile for gestational age with and without umbilical artery (UA) Doppler abnormalities, respectively. Fetal aorta intima media thickness (aIMT) was evaluated by ultrasound in the same fetal groups. Data were analyzed by R (version 2.15.2). Results. There were 37 IUGR mother-child couples, 33 SGA, and 70 AGA. Leptin, TNFα, IL-6, and CRP serum levels were higher in IUGR pregnant patients (). Adiponectin levels were significantly reduced in IUGR fetuses compared to SGA and AGA, while leptin, TNFα, and IL-6 levels were higher in IUGR group (). Fetal aIMT was significantly higher in IUGR () and in this group there was a negative correlation between aIMT and adiponectin/leptin ratio (A/L ratio) () and between adiponectin and IL-6 levels (). Conclusions. In conclusion, compared to SGA and AGA, IUGR fetuses had reduced circulating levels of adiponectin and elevated measures of aIMT and several inflammatory markers. Moreover, adiponectin levels were negatively correlated with aIMT in IUGR fetuses suggesting a possible causal link between reduced adiponectin and vessel remodelling. Silvia Visentin, Annunziata Lapolla, Ambrogio Pietro Londero, Chiara Cosma, Mariagrazia Dalfrà, Martina Camerin, Diego Faggian, Mario Plebani, and Erich Cosmi Copyright © 2014 Silvia Visentin et al. All rights reserved. Denture-Related Stomatitis Is Associated with Endothelial Dysfunction Sun, 22 Jun 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/474016/ Oral inflammation, such as periodontitis, can lead to endothelial dysfunction, accelerated atherosclerosis, and vascular dysfunction. The relationship between vascular dysfunction and other common forms of oral infections such as denture-related stomatitis (DRS) is unknown. Similar risk factors predispose to both conditions including smoking, diabetes, age, and obesity. Accordingly, we aimed to investigate endothelial function and major vascular disease risk factors in 44 consecutive patients with dentures with clinical and microbiological features of DRS () and without DRS (). While there was a tendency for higher occurrence of diabetes and smoking, groups did not differ significantly in respect to major vascular disease risk factors. Groups did not differ in main ambulatory blood pressure, total cholesterol, or even CRP. Importantly, flow mediated dilatation (FMD) was significantly lower in DRS than in non-DRS subjects, while nitroglycerin induced vasorelaxation (NMD) or intima-media thickness (IMT) was similar. Interestingly, while triglyceride levels were normal in both groups, they were higher in DRS subjects, although they did not correlate with either FMD or NMD. Conclusions. Denture related stomatitis is associated with endothelial dysfunction in elderly patients with dentures. This is in part related to the fact that diabetes and smoking increase risk of both DRS and cardiovascular disease. Joanna Maciąg, Grzegorz Osmenda, Daniel Nowakowski, Grzegorz Wilk, Anna Maciąg, Tomasz Mikołajczyk, Ryszard Nosalski, Agnieszka Sagan, Magdalena Filip, Mirosław Dróżdż, Jolanta Loster, Tomasz J. Guzik, and Marta Cześnikiewicz-Guzik Copyright © 2014 Joanna Maciąg et al. All rights reserved. Low Density Lipoprotein-Containing Circulating Immune Complexes: Role in Atherosclerosis and Diagnostic Value Wed, 18 Jun 2014 09:19:02 +0000 http://www.hindawi.com/journals/bmri/2014/205697/ It has been suggested that low density lipoprotein-containing circulating immune complexes (LDL-CIC) play a role in atherogenesis and are involved in the formation of early atherosclerotic lesion. These complexes, as well as anti-LDL autoantibodies, have been found in the blood and in the atherosclerotic lesions of patients with different cardiovascular diseases, as well as in the blood of animals with experimental atherosclerosis. It can be suggested that the presence of anti-LDL antibodies in the blood is a result of immune response induced by lipoprotein modification. LDL-CIC differs from native LDL in many aspects. It has much lower sialic acid content, smaller diameter, and higher density and is more electronegative than native LDL. Fraction of LDL-CICs is fundamental to the serum atherogenicity manifested at the cellular level. LDL-CIC, unlike native LDL, is able to induce intracellular accumulation of neutral lipids, especially esterified cholesterol, in cells cultured from uninvolved human aortic intima and in macrophage cultures. After removal of LDL-CIC, the CHD patient’s sera lose their atherogenic properties. Titer of LDL-CIC in blood serum significantly correlates with progression of atherosclerosis in human in vivo and has the highest diagnostic value among other measured serum lipid parameters. Elevated CIC-cholesterol might well be a possible risk factor of coronary atherosclerosis. Igor A. Sobenin, Jukka T. Salonen, Andrey V. Zhelankin, Alexandra A. Melnichenko, Jari Kaikkonen, Yuri V. Bobryshev, and Alexander N. Orekhov Copyright © 2014 Igor A. Sobenin et al. All rights reserved. Role of IL-33 and Its Receptor in T Cell-Mediated Autoimmune Diseases Mon, 16 Jun 2014 11:05:12 +0000 http://www.hindawi.com/journals/bmri/2014/587376/ Interleukin-33 (IL-33) is a new cytokine of interleukin-1 family, whose specific receptor is ST2. IL-33 exerts its functions via its target cells and plays different roles in diseases. ST2 deletion and exclusion of IL-33/ST2 axis are accompanied by enhanced susceptibility to dominantly T cell-mediated organ-specific autoimmune diseases. It has been reported that IL-33/ST2 pathway plays a key role in host defense and immune regulation in inflammatory and infectious diseases. This review focuses on new findings in the roles of IL-33 and ST2 in several kinds of T cell-mediated autoimmune diseases. Qing Zhao and Guangjie Chen Copyright © 2014 Qing Zhao and Guangjie Chen. All rights reserved. MicroRNAs in Autoimmune Diseases Wed, 04 Jun 2014 08:59:27 +0000 http://www.hindawi.com/journals/bmri/2014/527895/ Autoimmune diseases (ADs) are featured by body's immune responses being directed towards its own specific target organs or multiple organ systems, causing persistent inflammation and consequent tissue damage. miRNAs are small noncoding RNAs in a size of approximately 22 nt that play important regulatory roles in many organisms by cleavage or translational inhibition of targeted mRNAs. Many miRNAs are reported to be differentially expressed in ADs and may play a pivotal role in regulating immune responses and autoimmunity. In this review, current research progress in the miRNAs in ADs was elucidated. Zigang Qu, Wenhui Li, and Baoquan Fu Copyright © 2014 Zigang Qu et al. All rights reserved. The Role of CTLA-4 Exon-1 49 A/G Polymorphism and Soluble CTLA-4 Protein Level in Egyptian Patients with Behçet's Disease Mon, 02 Jun 2014 13:04:00 +0000 http://www.hindawi.com/journals/bmri/2014/513915/ This study analyzed the association of the A/G SNP at position +49 of exon-1 in the CTLA-4 gene to the susceptibility and clinical manifestations of Behcet’s disease (BD). It was performed on 60 Egyptian BD patients and 95 age- and sex-matched healthy controls. The genotypes for the +49 A/G polymorphism of the CTLA-4 gene were determined by PCR-RFLP, while the serum level of CTLA-4 protein was measured by ELISA. CTLA-4 +49 A allele (, , and CI (95%) = 1.90–4.99) and A/A genotype (, , and CI (95%) = 2.58–17.10) frequency distribution was significantly more increased in patients than in the controls, with no significant differences between males and females with regard to the genotype or allele frequency distribution. A/A genotype was associated with a more reduced expression of sCTLA-4 protein in patients than in the controls ( versus , resp; ). In addition, it is associated with the occurrence of ocular and vasculitic manifestations of BD in the patient group. The CTLA-4 gene could be considered as a susceptibility and a disease-modifying gene to BD in Egyptian population that needs further confirmatory studies on larger cohorts. Sahar M. Abdel Galil and Hoda A. Hagrass Copyright © 2014 Sahar M. Abdel Galil and Hoda A. Hagrass. All rights reserved. CB2 Receptor Activation Ameliorates the Proinflammatory Activity in Acute Lung Injury Induced by Paraquat Thu, 22 May 2014 09:36:08 +0000 http://www.hindawi.com/journals/bmri/2014/971750/ Paraquat, a widely used herbicide, is well known to exhibit oxidative stress and lung injury. In the present study, we investigated the possible underlying mechanisms of cannabinoid receptor-2 (CB2) activation to ameliorate the proinflammatory activity induced by PQ in rats. JWH133, a CB2 agonist, was administered by intraperitoneal injection 1 h prior to PQ exposure. After PQ exposure for 4, 8, 24, and 72 h, the bronchoalveolar lavage fluid was collected to determine levels of TNF-α and IL-1β, and the arterial blood samples were collected for detection of PaO2 level. At 72 h after PQ exposure, lung tissues were collected to determine the lung wet-to-dry weight ratios, myeloperoxidase activity, lung histopathology, the protein expression level of CB2, MAPKs (ERK1/2, p38MAPK, and JNK1/2), and NF-κBp65. After rats were pretreated with JWH133, PQ-induced lung edema and lung histopathological changes were significantly attenuated. PQ-induced TNF-α and IL-1β secretion in BALF, increases of PaO2 in arterial blood, and MPO levels in the lung tissue were significantly reduced. JWH133 could efficiently activate CB2, while inhibiting MAPKs and NF-κB activation. The results suggested that activating CB2 receptor exerted protective activity against PQ-induced ALI, and it potentially contributed to the suppression of the activation of MAPKs and NF-κB pathways. Zhenning Liu, Yu Wang, Hongyu Zhao, Qiang Zheng, Li Xiao, and Min Zhao Copyright © 2014 Zhenning Liu et al. All rights reserved. Are Proteinase 3 and Cathepsin C Enzymes Related to Pathogenesis of Periodontitis? Mon, 19 May 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/420830/ Aim. Cathepsin C is the activator of the polymorphonuclear leukocyte-derived proteinase 3, which contributes to inflammatory processes. The aim of the present study was to investigate gingival crevicular fluid (GCF) proteinase 3 and cathepsin C levels in periodontal diseases. Design. Eighteen patients with chronic periodontitis (CP), 20 patients with generalized aggressive periodontitis (G-AgP), 20 patients with gingivitis, and 18 healthy subjects were included in the study. Periodontal parameters including probing depth, clinical attachment level, papilla bleeding index, and plaque index were assessed in all study subjects. GCF proteinase 3 and cathepsin C levels were analyzed by ELISA. Results. GCF proteinase 3 total amount was significantly higher in diseased groups compared to control group, after adjusting age . No differences were found in GCF cathepsin C levels among the study groups . Periodontal parameters of sampling sites were positively correlated with GCF proteinase 3 total amounts but not with cathepsin C total amounts . Conclusions. Elevated levels of GCF proteinase 3 in CP, G-AgP, and gingivitis might suggest that proteinase 3 plays a role during inflammatory periodontal events in host response. However, cathepsin C in GCF does not seem to have an effect on the pathogenesis of periodontal diseases. Oya Türkoğlu, Elif Azarsız, Gülnur Emingil, Necil Kütükçüler, and Gül Atilla Copyright © 2014 Oya Türkoğlu et al. All rights reserved. Periodontal Pathogens and Atherosclerosis: Implications of Inflammation and Oxidative Modification of LDL Sun, 18 May 2014 09:35:55 +0000 http://www.hindawi.com/journals/bmri/2014/595981/ Inflammation is well accepted to play a crucial role in the development of atherosclerotic lesions, and recent studies have demonstrated an association between periodontal disease and cardiovascular disease. Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, causative agents of destructive chronic inflammation in the periodontium, can accelerate atheroma deposition in animal models. Emerging evidence suggests that vaccination against virulence factors of these pathogens and anti-inflammatory therapy may confer disease resistance. In this review, we focus on the role of inflammatory mechanisms and oxidative modification in the formation and activation of atherosclerotic plaques accelerated by P. gingivalis or A. actinomycetemcomitans in an ApoE-deficient mouse model and high-fat-diet-fed mice. Furthermore, we examine whether mucosal vaccination with a periodontal pathogen or the anti-inflammatory activity of catechins can reduce periodontal pathogen-accelerated atherosclerosis. Tomoko Kurita-Ochiai and Masafumi Yamamoto Copyright © 2014 Tomoko Kurita-Ochiai and Masafumi Yamamoto. All rights reserved. Anti-Inflammatory Effects of the Nicotinergic Peptides SLURP-1 and SLURP-2 on Human Intestinal Epithelial Cells and Immunocytes Sun, 04 May 2014 07:13:10 +0000 http://www.hindawi.com/journals/bmri/2014/609086/ A search for novel and more efficient therapeutic modalities of inflammatory bowel disease (IBD) is one of the most important tasks of contemporary medicine. The anti-inflammatory action of nicotine in IBD might be therapeutic, but its toxicity due to off-target and nonreceptor effects limited its use and prompted a search for nontoxic nicotinergic drugs. We tested the hypothesis that SLURP-1 and -2—the physiological nicotinergic substances produced by the human intestinal epithelial cells (IEC) and immunocytes—can mimic the anti-inflammatory effects of nicotine. We used human CCL-241 enterocytes, CCL-248 colonocytes, CCRF-CEM T-cells, and U937 macrophages. SLURP-1 diminished the TLR9-dependent secretion of IL-8 by CCL-241, and IFNγ-induced upregulation of ICAM-1 in both IEC types. rSLURP-2 inhibited IL-1β-induced secretion of IL-6 and TLR4- and TLR9-dependent induction of CXCL10 and IL-8, respectively, in CCL-241. rSLURP-1 decreased production of TNFα by T-cells, downregulated IL-1β and IL-6 secretion by macrophages, and moderately upregulated IL-10 production by both types of immunocytes. SLURP-2 downregulated TNFα and IFNγR in T-cells and reduced IL-6 production by macrophages. Combining both SLURPs amplified their anti-inflammatory effects. Learning the pharmacology of SLURP-1 and -2 actions on enterocytes, colonocytes, T cells, and macrophages may help develop novel effective treatments of IBD. Alex I. Chernyavsky, Valentin Galitovskiy, Igor B. Shchepotin, and Sergei A. Grando Copyright © 2014 Alex I. Chernyavsky et al. All rights reserved. Mannan-Binding Lectin in Cardiovascular Disease Wed, 30 Apr 2014 09:10:38 +0000 http://www.hindawi.com/journals/bmri/2014/616817/ Cardiovascular disease remains the leading cause of mortality and morbidity worldwide so research continues into underlying mechanisms. Since innate immunity and its potent component mannan-binding lectin have been proven to play an important role in the inflammatory response during infection and ischaemia-reperfusion injury, attention has been paid to its role in the development of cardiovascular complications as well. This review provides a general outline of the structure and genetic polymorphism of MBL and its role in inflammation/tissue injury with emphasis on associations with cardiovascular disease. MBL appears to be involved in the pathogenesis of atherosclerosis and, in consequence, coronary artery disease and also inflammation and tissue injury after myocardial infarction and heart transplantation. The relationship between MBL and disease is rather complex and depends on different genetic and environmental factors. That could be why the data obtained from animal and clinical studies are sometimes contradictory proving not for the first time that innate immunity is a “double-edge sword,” sometimes beneficial and, at other times disastrous for the host. Izabela Pągowska-Klimek and Maciej Cedzyński Copyright © 2014 Izabela Pągowska-Klimek and Maciej Cedzyński. All rights reserved. The Yin and Yang of Innate Immunity in Stroke Wed, 30 Apr 2014 07:27:59 +0000 http://www.hindawi.com/journals/bmri/2014/807978/ Immune system plays an elementary role in the pathophysiological progress of ischemic stroke. It consists of innate and adaptive immune system. Activated within minutes after ischemic onset, innate immunity is responsible for the elimination of necrotic cells and tissue repair, while it is critically involved in the initiation and amplification of poststroke inflammation that amplifies ischemic damage to the brain tissue. Innate immune response requires days to be fully developed, providing a considerable time window for therapeutic intervention, suggesting prospect of novel immunomodulatory therapies against poststroke inflammation-induced brain injury. However, obstacles still exist and a comprehensive understanding of ischemic stroke and innate immune reaction is essential. In this review, we highlighted the current experimental and clinical data depicting the innate immune response following ischemic stroke, mainly focusing on the recognition of damage-associated molecular patterns, activation and recruitment of innate immune cells, and involvement of various cytokines. In addition, clinical trials targeting innate immunity were also documented regardless of the outcome, stressing the requirements for further investigation. Xiaomeng Xu and Yongjun Jiang Copyright © 2014 Xiaomeng Xu and Yongjun Jiang. All rights reserved. The Emerging Role of Biotechnological Drugs in the Treatment of Gout Wed, 16 Apr 2014 15:55:21 +0000 http://www.hindawi.com/journals/bmri/2014/264859/ One of the most important therapeutic advances obtained in the field of rheumatology is the availability of the so-called bio(techno)logical drugs, which have deeply changed treatment perspectives in diseases such as rheumatoid arthritis and ankylosing spondylitis. According to the steadily increasing attention on gout, due to well-established prognostic and epidemiology implications, in the last 5 years, the same change of perspective has been observed also for this disease. In fact, several bio(techno)logical agents have been investigated both for the management of the articular gout symptoms, targeting mainly interleukin-1β, as well as urate-lowering therapies such as recombinant uricases. Among the IL-1β inhibitors, the majority of studies involve drugs such as anakinra, canakinumab, and rilonacept, but other compounds are under development. Moreover, other potential targets have been suggested, as, for example, the TNF alpha and IL-6, even if data obtained are less robust than those of IL-1β inhibitors. Regarding urate-lowering therapies, the recombinant uricases pegloticase and rasburicase clearly showed their effectiveness in gout patients. Also in this case, new compounds are under development. The aim of this review is to focus on the various aspects of different bio(techno)logical drugs in gouty patients. L. Cavagna and W. J. Taylor Copyright © 2014 L. Cavagna and W. J. Taylor. All rights reserved. Treatment Comparison in Rheumatoid Arthritis: Head-to-Head Trials and Innovative Study Designs Wed, 16 Apr 2014 07:30:13 +0000 http://www.hindawi.com/journals/bmri/2014/831603/ Over the last decades, the increasing knowledge in the area of rheumatoid arthritis has progressively expanded the arsenal of available drugs, especially with the introduction of novel targeted therapies such as biological disease modifying antirheumatic drugs (DMARDs). In this situation, rheumatologists are offered a wide range of treatment options, but on the other side the need for comparisons between available drugs becomes more and more crucial in order to better define the strategies for the choice and the optimal sequencing. Indirect comparisons or meta-analyses of data coming from different randomised controlled trials (RCTs) are not immune to conceptual and technical challenges and often provide inconsistent results. In this review we examine some of the possible evolutions of traditional RCTs, such as the inclusion of active comparators, aimed at individualising treatments in real-life conditions. Although head-to-head RCTs may be considered the best tool to directly compare the efficacy and safety of two different DMARDs, surprisingly only 20 studies with such design have been published in the last 25 years. Given the recent advent of the first RCTs truly comparing biological DMARDs, we also review the state of the art of head-to-head trials in RA. Ennio Giulio Favalli, Serena Bugatti, Martina Biggioggero, and Roberto Caporali Copyright © 2014 Ennio Giulio Favalli et al. All rights reserved. Correlated Inflammatory Responses and Neurodegeneration in Peptide-Injected Animal Models of Alzheimer’s Disease Sun, 13 Apr 2014 15:37:44 +0000 http://www.hindawi.com/journals/bmri/2014/923670/ Animal models of Alzheimer’s disease (AD) which emphasize activation of microglia may have particular utility in correlating proinflammatory activity with neurodegeneration. This paper reviews injection of amyloid-β (Aβ) into rat brain as an alternative AD animal model to the use of transgenic animals. In particular, intrahippocampal injection of peptide demonstrates prominent microglial mobilization and activation accompanied by a significant loss of granule cell neurons. Furthermore, pharmacological inhibition of inflammatory reactivity is demonstrated by a broad spectrum of drugs with a common endpoint in conferring neuroprotection in peptide-injected animals. Peptide-injection models provide a focus on glial cell responses to direct peptide injection in rat brain and offer advantages in the study of the mechanisms underlying neuroinflammation in AD brain. James G. McLarnon Copyright © 2014 James G. McLarnon. All rights reserved. Determinants of Disability in Multiple Sclerosis: An Immunological and MRI Study Wed, 09 Apr 2014 12:11:21 +0000 http://www.hindawi.com/journals/bmri/2014/875768/ Multiple sclerosis (MS) is characterized by a wide interpatient clinical variability and available biomarkers of disease severity still have suboptimal reliability. We aimed to assess immunological and MRI-derived measures of brain tissue damage in patients with different motor impairment degrees, for in vivo investigating the pathogenesis of MS-related disability. Twenty-two benign (B), 26 secondary progressive (SP), and 11 early, nondisabled relapsing-remitting (RR) MS patients and 37 healthy controls (HC) underwent conventional and diffusion tensor brain MRI and, as regards MS patients, immunophenotypic and functional analysis of stimulated peripheral blood mononuclear cells (PBMC). Corticospinal tract (CST) fractional anisotropy and grey matter volume were lower and CST diffusivity was higher in SPMS compared to RRMS and BMS patients. CD14+IL6+ and CD4+IL25+ cell percentages were higher in BMS than in SPMS patients. A multivariable model having EDSS as the dependent variable retained the following independent predictors: grey matter volume, CD14+IL6+ and CD4+IL25+ cell percentages. In patients without motor impairment after long-lasting MS, the grey matter and CST damage degree seem to remain as low as in the earlier disease stages and an immunological pattern suggestive of balanced pro- and anti-inflammatory activity is observed. MRI-derived and immunological measures might be used as complementary biomarkers of MS severity. Paola Tortorella, Maria Marcella Laganà, Marina Saresella, Eleonora Tavazzi, Maria Giulia Preti, Cristian Ricci, Francesca Baglio, Ivana Marventano, Federica Piancone, Giuseppe Baselli, Pietro Cecconi, Domenico Caputo, Mario Clerici, and Marco Rovaris Copyright © 2014 Paola Tortorella et al. All rights reserved. MicroRNA Roles in the NF-κB Signaling Pathway during Viral Infections Wed, 02 Apr 2014 12:25:23 +0000 http://www.hindawi.com/journals/bmri/2014/436097/ NF-κB signaling network is a crucial component of innate immunity. miRNAs are a subtype of small noncoding RNAs, involved in regulation of gene expression at the posttranscriptional level. Increasing evidence has emerged that miRNAs play an important role in regulation of NF-κB signaling pathway during viral infections. Both host and viral miRNAs are attributed to modulation of NF-κB activity, thus affecting viral infection and clearance. Understandings of the mechanisms of these miRNAs will open a direction for development of novel antivirus drugs. Zeqian Gao, Yongxi Dou, Yixia Chen, and Yadong Zheng Copyright © 2014 Zeqian Gao et al. All rights reserved. Combined Cytolytic Effects of a Vaccinia Virus Encoding a Single Chain Trimer of MHC-I with a Tax-Epitope and Tax-Specific CTLs on HTLV-I-Infected Cells in a Rat Model Thu, 27 Mar 2014 09:18:49 +0000 http://www.hindawi.com/journals/bmri/2014/902478/ Adult T cell leukemia (ATL) is a malignant lymphoproliferative disease caused by human T cell leukemia virus type I (HTLV-I). To develop an effective therapy against the disease, we have examined the oncolytic ability of an attenuated vaccinia virus (VV), LC16m8Δ (m8Δ), and an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) line, 4O1/C8, against an HTLV-I-infected rat T cell line, FPM1. Our results demonstrated that m8Δ was able to replicate in and lyse tumorigenic FPM1 cells but was incompetent to injure 4O1/C8 cells, suggesting the preferential cytolytic activity toward tumor cells. To further enhance the cytolysis of HTLV-I-infected cells, we modified m8Δ and obtained m8Δ/RT1AlSCTax180L, which can express a single chain trimer (SCT) of rat major histocompatibility complex class I with a Tax-epitope. Combined treatment with m8Δ/RT1AlSCTax180L and 4O1/C8 increased the cytolysis of FPM1V.EFGFP/8R cells, a CTL-resistant subclone of FPM1, compared with that using 4O1/C8 and m8Δ presenting an unrelated peptide, suggesting that the activation of 4O1/C8 by m8Δ/RT1AlSCTax180L further enhanced the killing of the tumorigenic HTLV-I-infected cells. Our results indicate that combined therapy of oncolytic VVs with SCTs and HTLV-I-specific CTLs may be effective for eradication of HTLV-I-infected cells, which evade from CTL lysis and potentially develop ATL. Takashi Ohashi, Takafumi Nakamura, Minoru Kidokoro, Xianfeng Zhang, and Hisatoshi Shida Copyright © 2014 Takashi Ohashi et al. All rights reserved. Ankylosing Spondylitis and Rheumatoid Arthritis: Serum Levels of TNF- and Its Soluble Receptors during the Course of Therapy with Etanercept and Infliximab Mon, 24 Mar 2014 16:35:26 +0000 http://www.hindawi.com/journals/bmri/2014/675108/ The effects of the TNF-α blockers infliximab or etanercept on the levels of TNF-α, TNF-receptor 1 (TNF-R1), and TNF-receptor 2 (TNF-R2), as well as the levels of the inflammation markers CRP and IL-6, were measured in ankylosing spondylitis (AS) and rheumatoid arthritis (RA) patients receiving treatment with either compound. We found that RA patients tend to have higher levels of TNF-α than both healthy individuals and AS patients prior to treatment (). We measured greatly increased levels of TNF-α in both the AS and RA etanercept patient groups during the course of treatment, while in the infliximab treated patients, the amount of TNF-α measured remained unchanged. Elevated TNF-α in the etanercept treated patients does not appear to be a significant risk factor for the spontaneous development of further autoimmune diseases in our study group. Increased levels of TNF-R1 were determined in both AS () and RA () patients when compared to healthy controls. In AS patients, the levels of TNF-R1 dropped significantly when treated with either infliximab () or etanercept (). In contrast, the levels of this receptor remained unchanged in RA patients treated with either compound. Martin Schulz, Helmut Dotzlaw, and Gunther Neeck Copyright © 2014 Martin Schulz et al. All rights reserved. MicroRNAs: New Regulators of Toll-Like Receptor Signalling Pathways Thu, 20 Mar 2014 06:07:32 +0000 http://www.hindawi.com/journals/bmri/2014/945169/ Toll-like receptors (TLRs), a critical family of pattern recognition receptors (PRRs), are responsible for the innate immune responses via signalling pathways to provide effective host defence against pathogen infections. However, TLR-signalling pathways are also likely to stringently regulate tissue maintenance and homeostasis by elaborate modulatory mechanisms. MicroRNAs (miRNAs) have emerged as key regulators and as an essential part of the networks involved in regulating TLR-signalling pathways. In this review, we highlight our understanding of the regulation of miRNA expression profiles by TLR-signalling pathways and the regulation of TLR-signalling pathways by miRNAs. We focus on the roles of miRNAs in regulating TLR-signalling pathways by targeting multiple molecules, including TLRs themselves, their associated signalling proteins and regulatory molecules, and transcription factors and functional cytokines induced by them, at multiple levels. Xiaobing He, Zhizhong Jing, and Guofeng Cheng Copyright © 2014 Xiaobing He et al. All rights reserved. Adipokines, Biomarkers of Endothelial Activation, and Metabolic Syndrome in Patients with Ankylosing Spondylitis Tue, 18 Mar 2014 00:00:00 +0000 http://www.hindawi.com/journals/bmri/2014/860651/ Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. AS patients also display a high prevalence of features clustered under the name of metabolic syndrome (MeS). Anti-TNF-α therapy was found to be effective to treat AS patients by suppressing inflammation and also improving endothelial function. Previously, it was demonstrated that a short infusion of anti-TNF-α monoclonal antibodyinfliximab induced a rapid and dramatic reduction in serum insulin levels and insulin resistance along with a rapid improvement of insulin sensitivity in nondiabetic AS patients. The role of adipokines, MeS-related biomarkers and biomarkers of endothelial cell activation and inflammation seem to be relevant in different chronic inflammatory diseases. However, its implication in AS has not been fully established. Therefore, in this review we summarize the recent advances in the study of the involvement of these molecules in CV disease or MeS in AS. The assessment of adipokines and biomarkers of endothelial cell activation and MeS may be of potential relevance in the stratification of the CV risk of patients with AS. Fernanda Genre, Raquel López-Mejías, José A. Miranda-Filloy, Begoña Ubilla, Beatriz Carnero-López, Ricardo Blanco, Trinitario Pina, Carlos González-Juanatey, Javier Llorca, and Miguel A. González-Gay Copyright © 2014 Fernanda Genre et al. All rights reserved. Potent Anti-Inflammatory Activity of Carbohydrate Polymer with Oxide of Zinc Wed, 12 Mar 2014 10:51:01 +0000 http://www.hindawi.com/journals/bmri/2014/712312/ Pebisut is a biological adhesive composed of naturally occurring carbohydrates combined with zinc oxide (ZnO) initially used as a coadjutant for healing of anastomoses. Likewise some works demonstrated that carbohydrate complexes exerts anti-inflammatory activity and it is widely known that ZnO modulate inflammation. However, the direct effects of Pebisut on isolated cells and acute inflammatory responses remained to be investigated. The present study evaluated anti-inflammatory effect of Pebisut using lipopolysaccharide (LPS) stimulated human mononuclear cells, chemotaxis, and cell infiltration in vivo in a murine model of peritonitis. Our data show that human cells treated with different dilutions of Pebisut release less IL-6, IL-1β, and IL-8 after LPS stimuli compared with the control treated cells. In addition, Pebisut lacked chemotactic activity in human mononuclear cells but was able to reduce chemotaxis towards CCL2, CCL5, and CXCL12 that are representative mononuclear cells chemoattractants. Finally, in a murine model of peritonitis, we found less number of macrophages (F4/80+) and T lymphocytes (CD3+) in peritoneal lavages from animals treated with Pebisut. Our results suggest that Pebisut has anti-inflammatory activity, which might have a beneficial effect during anastomoses healing or wounds associated with excessive inflammation. Mario Adan Moreno-Eutimio, Nayeli Goreti Nieto-Velázquez, Lorena Espinosa-Monroy, Yessica Torres-Ramos, Araceli Montoya-Estrada, Jorge Cueto, Juan Jose Hicks, and Gustavo Acosta-Altamirano Copyright © 2014 Mario Adan Moreno-Eutimio et al. All rights reserved. A Novel Strategy for Inducing the Antitumor Effects of Triterpenoid Compounds: Blocking the Protumoral Functions of Tumor-Associated Macrophages via STAT3 Inhibition Tue, 11 Mar 2014 08:52:18 +0000 http://www.hindawi.com/journals/bmri/2014/348539/ There are many types of nontumor cells, including leukocytes, fibroblasts, and endothelial cells, in the tumor microenvironment. Among these cells, infiltrating macrophages have recently received attention as novel target cells due to their protumoral functions. Infiltrating macrophages are called tumor-associated macrophages (TAMs). TAMs polarized to the M2 phenotype are involved in tumor development and are associated with a poor clinical prognosis. Therefore, the regulation of TAM activation or M2 polarization is a new strategy for antitumor therapy. We screened natural compounds possessing an inhibitory effect on the M2 polarization of human macrophages. Among 200 purified natural compounds examined, corosolic acid (CA) and oleanolic acid (OA), both are categorized in triterpenoid compounds, inhibited macrophage polarization to M2 phenotype by suppressing STAT3 activation. CA and OA also directly inhibited tumor cell proliferation and sensitized tumor cells to anticancer drugs, such as adriamycin and cisplatin. The in vivo experiments showed that CA significantly suppressed subcutaneous tumor development and lung metastasis in a murine sarcoma model. The application of triterpenoid compounds, such as CA and OA, is a potential new anticancer therapy targeting macrophage activation, with synergistic effects with anticancer agents. Yukio Fujiwara, Motohiro Takeya, and Yoshihiro Komohara Copyright © 2014 Yukio Fujiwara et al. All rights reserved. Attenuation of Collagen-Induced Arthritis in Rat by Nicotinic Alpha7 Receptor Partial Agonist GTS-21 Thu, 27 Feb 2014 13:50:21 +0000 http://www.hindawi.com/journals/bmri/2014/325875/ This research was performed to observe the effect of GTS-21 on Collagen Induced Arthritis (CIA). CIA model was used and after the onset of arthritis, the rats were divided into three groups based on their clinical symptoms score. Two groups were intraperitoneally (IP) injected daily with GTS-21 (1 mg/kg, 2.5 mg/kg) for a week, whereas phosphate buffered saline (PBS) was used for the control group. Cytokine titers, radiological, and histological examinations were performed at different time points after treatment with GTS-21. Compared with those of the control, the levels of TNF-α, IL-1, and IL-6 in the serum were significantly reduced after GTS-21 management. In addition, radiological results show that bone degradation was inhibited as well. Moreover, the hematoxylin and eosin (H&E) staining indicated that the histological score was significantly alleviated in the therapeutic group. Tartrate-resistant acid phosphatase (TRAP) stain-positive cells were also detected in the destruction of the articular cartilage, which was significantly reduced compared with the control group. This study provides the first evidence on the effect of GTS-21 as a potential treatment for RA. Yiping Hu, Ruoxi Liu, Jinchao Li, Ye Yue, Wenxiang Cheng, and Peng Zhang Copyright © 2014 Yiping Hu et al. All rights reserved. Helminth Infection Increases the Probability of Indeterminate QuantiFERON Gold in Tube Results in Pregnant Women Wed, 19 Feb 2014 13:39:59 +0000 http://www.hindawi.com/journals/bmri/2014/364137/ Background. Approximately one-third of the world population is infected with M. tuberculosis and helminths (Kariminia et al. (2009), Walson et al. (2010)). Pregnancy and Helminth infection are known to suppress the response (Kariminia et al. (2009), Elias et al. (2006)) on which the QuantiFERON Gold in Tube (QFT-GIT) assay, that measures the released IFN- upon in vitro stimulation with mycobacterial antigens, relies on (Thomas et al. (2010)). Objective. To determine whether QFT-GIT indeterminate result is significantly associated with helminth infection or not. Methods. In this cross-sectional study, eighty-five pregnant mothers were screened for parasitic and LTBI using Kato-Katz and QFT-GIT test-respectively, Result. The prevalence of helminth infection in pregnant mothers was 23 (27%) of this 17 (20%) was due to Schistosoma mansoni. Among the total of 85 study participants 26.8% were QFT-GIT positive and 14 (17%) had indeterminate results. Three samples (21.4%) were randomly selected from the indeterminate QFT-GIT results and retested to check the reproducibility of the assay and remained indeterminate. QFT-GIT indeterminate result showed significant association with helminth infection. Conclusion. Helminth infections were significantly associated with indeterminate QFT-GIT results in pregnant mothers. Therefore further study is important to evaluate the possible effect of helminth infection by excluding the effect of pregnancy, as pregnancy also downregulates cellular immunity. Dawit Gebreegziabiher, Kassu Desta, Rawleigh Howe, and Markos Abebe Copyright © 2014 Dawit Gebreegziabiher et al. All rights reserved. FC-98 Regulates TLR9-Mediated of CXCL-10 Expression in Dendritic Cells via MAPK and STAT1 Signaling Pathway Mon, 17 Feb 2014 11:13:49 +0000 http://www.hindawi.com/journals/bmri/2014/926130/ Dendritic cells (DCs), as the most potent professional antigen presenting cells, play a crucial role in both innate and adaptive immune systems. Genomic bacterial DNA mimicked by unmethylated CpG motifs is discovered to possess immunostimulatory effects. CpG-DNA recognized by Toll-like receptor 9 (TLR9) on DCs arouses many immune diseases (such as cancer, viral infection, and autoimmune disorders). In this study we investigated the effects of FC-98 on CpG-induced bone marrow-derived DCs (BMDCs). The results showed that FC-98 significantly inhibited the CpG-induced BMDCs maturation and function by suppressing the expression of surface markers (CD40, CD80, CD86, and MHCII). Moreover, FC-98 downregulated the expression of C-X-C motif chemokine 10 (CXCL-10) both at the mRNA and protein level after CpG induction. Meanwhile, FC-98 markedly affected the migration of BMDCs to T cells without affecting their endocytosis capacity. Furthermore, FC-98 was confirmed to decrease CXCL-10 expression by inhibiting CpG-induced activation of MAPKs (ERK, JNK, and p38) and STAT1 signaling. Overall, these results suggested that FC-98 was a potential molecule in the treatment of CXCL-10-mediated immune diseases. Yonghong Yang, Huan Dou, Xiaoqin Li, Yuxian Song, Wei Gong, Renxiang Tan, and Yayi Hou Copyright © 2014 Yonghong Yang et al. All rights reserved. Establishment and Evaluation of Stable Cell Lines Inhibiting Foot-and-Mouth Disease Virus by RNA Interference Mon, 10 Feb 2014 11:52:10 +0000 http://www.hindawi.com/journals/bmri/2014/109428/ RNA interference (RNAi) has been proved to be a powerful tool for foot-and-mouth disease virus FMDV inhibition in vitro and in vivo. We established five stable baby hamster kidney 21 cell lines (BHK-21) containing five short hairpin RNAs (shRNAs) expression plasmids (p3D1shRNA, p3D2shRNA, p3D3shRNA, p3D4shRNA, and p3D5shRNA) targeting 3D gene of FMDV. Immunofluorescent assay, virus titration, and real-time quantitative reverse transcription polymerase chain reaction (Q-RT-PCR) were conducted to detect the effect of shRNAs on FMDV replication. After challenged with FMDV of O/CHA/99, two cell lines (p3D1shRNA and p3D4shRNA) showed a significant reduction in the synthesis of viral protein and RNA, accompanied by a sharp decrease in viral yield, and the inhibition could last for at least thirty passages. We developed an efficient procedure for the establishment and evaluation of stable cell lines for anti-FMDV research based on RNAi technology, which can be a candidate method for anti-FMDV research. Yuan-xing Gu, Zong-liang Gao, Jian-hua Zhou, Jie Zhang, and Yong-sheng Liu Copyright © 2014 Yuan-xing Gu et al. All rights reserved. Flow Cytometry Assessment of In Vitro Generated CD138+ Human Plasma Cells Sun, 09 Feb 2014 13:08:20 +0000 http://www.hindawi.com/journals/bmri/2014/536482/ The in vitro CD40-CD154 interaction promotes human B lymphocytes differentiation into plasma cells. Currently, CD138 is the hallmark marker enabling the detection of human plasma cells, both in vitro and in vivo; its presence can be monitored by flow cytometry using a specific antibody. We have developed a culture system allowing for the differentiation of memory B lymphocytes. In order to detect the newly formed plasma cells, we have compared their staining using five anti-CD138 monoclonal antibodies (mAbs). As a reference, we also tested human cell lines, peripheral blood mononuclear cells, and bone marrow samples. The five anti-CD138 mAbs stained RPMI-8226 cells (>98%) with variable stain index (SI). The highest SI was obtained with B-A38 mAb while the lowest SI was obtained with DL-101 and 1D4 mAbs. However, the anti-CD138 mAbs were not showing equivalent CD138+ cells frequencies within the generated plasma cells. B-A38, B-B4, and MI-15 were similar (15–25%) while DL-101 mAb stained a higher proportion of CD138-positive cells (38–42%). DL-101 and B-A38 mAbs stained similar populations in bone marrow samples but differed in their capacity to bind to and cell lines. In conclusion, such cellular fluctuations suggest heterogeneity in human plasma cell populations and/or in CD138 molecules. Rayelle Itoua Maïga, Jennifer Lemieux, Annie Roy, Carl Simard, and Sonia Néron Copyright © 2014 Rayelle Itoua Maïga et al. All rights reserved. Thymic Epithelial Cell Development and Its Dysfunction in Human Diseases Mon, 03 Feb 2014 06:55:59 +0000 http://www.hindawi.com/journals/bmri/2014/206929/ Thymic epithelial cells (TECs) are the key components in thymic microenvironment for T cells development. TECs, composed of cortical and medullary TECs, are derived from a common bipotent progenitor and undergo a stepwise development controlled by multiple levels of signals to be functionally mature for supporting thymocyte development. Tumor necrosis factor receptor (TNFR) family members including the receptor activator for NFκB (RANK), CD40, and lymphotoxin β receptor (LTβR) cooperatively control the thymic medullary microenvironment and self-tolerance establishment. In addition, fibroblast growth factors (FGFs), Wnt, and Notch signals are essential for establishment of functional thymic microenvironment. Transcription factors Foxn1 and autoimmune regulator (Aire) are powerful modulators of TEC development, differentiation, and self-tolerance. Dysfunction in thymic microenvironment including defects of TEC and thymocyte development would cause physiological disorders such as tumor, infectious diseases, and autoimmune diseases. In the present review, we will summarize our current understanding on TEC development and the underlying molecular signals pathways and the involvement of thymus dysfunction in human diseases. Lina Sun, Hongran Li, Haiying Luo, and Yong Zhao Copyright © 2014 Lina Sun et al. All rights reserved. The Soluble Form of CTLA-4 from Serum of Patients with Autoimmune Diseases Regulates T-Cell Responses Wed, 29 Jan 2014 14:46:04 +0000 http://www.hindawi.com/journals/bmri/2014/215763/ Cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is a costimulatory receptor transducing a potent inhibitory signal. Increasing evidence showed that CTLA-4 gene is an important susceptibility locus for autoimmune disorders. Alternatively spliced mRNA generates a soluble form, called sCTLA-4. Whereas low levels of sCTLA-4 are detected in normal human serum, increased/high serum levels are observed in several autoimmune diseases. The biological significance of increased sCTLA-4 serum level is not fully clarified yet. It can be envisaged that sCTLA-4 specifically inhibits the early T-cell activation by blocking the interaction of CD80/CD86 with the costimulatory receptor CD28. On the other hand, higher levels of sCTLA-4 could contend the binding of the membrane form of CTLA-4 with CD80/CD86, in later activation phase, causing a reduction of inhibitory signalling. We showed that sCTLA-4 from sera of patients with different autoimmune diseases is able to display functional activities on an in vitro system acting on the proliferation capability and modulating the secretion of cytokines. We observed a dual effect of sCTLA-4: inhibiting the secretion of IFN-γ, IL-2, IL-7, and IL-13 and activating the secretion of TGF-β and IL-10. This study underlines the role of sCTLA-4 in modulating the immune response and its relevance in autoimmune disease pathogenesis. Rita Simone, Giampaola Pesce, Princey Antola, Margarita Rumbullaku, Marcello Bagnasco, Nicola Bizzaro, and Daniele Saverino Copyright © 2014 Rita Simone et al. All rights reserved. Infliximab Reverses Suppression of Cholesterol Efflux Proteins by TNF-α: A Possible Mechanism for Modulation of Atherogenesis Thu, 23 Jan 2014 13:28:42 +0000 http://www.hindawi.com/journals/bmri/2014/312647/ Tumor necrosis factor- (TNF-) α is a proinflammatory proatherogenic cytokine. Infliximab, an anti-TNF-α monoclonal antibody, is effective in treating rheumatoid arthritis. However, its impact on cardiovascular burden and lipid transport is unclear. The present study investigates the effect of TNF-α and infliximab on reverse cholesterol transport (RCT) proteins. Uptake of modified lipoproteins by macrophages in the vasculature leads to atherogenic foam cell formation. RCT is mediated by proteins including ATP binding cassette transporters A1 (ABCA1), G1 (ABCG1), liver X receptor- (LXR-) α, and 27-hydroxylase. RCT counteracts lipid overload by ridding cells of excess cholesterol. THP-1 human monocytes were incubated with either TNF-α alone or TNF-α with infliximab. Expression of proteins involved in cholesterol efflux was analyzed. TNF-α significantly reduced both ABCA1 and LXR-α mRNA (to , , and , , versus control set as 100%, resp.). Infliximab nullified the TNF-α effect. Results were confirmed by Western blot. Infliximab abolished the increase in foam cells induced by TNF-α. TNF-α treatment significantly reduces ABCA1 and LXR-α expression in monocytes, thus bringing about a proatherogenic state. The anti-TNF drug infliximab, commonly used in rheumatology, restored RCT proteins. This is the first report of an atheroprotective effect of infliximab on RCT in monocytes. Iryna Voloshyna, Sangeetha Seshadri, Kamran Anwar, Michael J. Littlefield, Elise Belilos, Steven E. Carsons, and Allison B. Reiss Copyright © 2014 Iryna Voloshyna et al. All rights reserved. Immunomodulation in Human Dendritic Cells Leads to Induction of Interferon-Gamma Production by Leishmania donovani Derived KMP-11 Antigen via Activation of NF-B in Indian Kala-Azar Patients Wed, 22 Jan 2014 14:05:21 +0000 http://www.hindawi.com/journals/bmri/2014/947606/ Dendritic cells (DCs) and macrophages (Ms) are well-known antigen presenting cells with an ability to produce IL-12 which indicates that they have potential of directing acquired immunity toward a Th1-biased response. The aim of this study was to examine the effect of Leishmania specific KMP-11 antigen through comparison of immune responses after presentation by DCs and Ms to T cells in Indian patients with VL. Patients with DCS and Ms were directed against a purified Leishmania donovani antigen (KMP-11) and phytohaemagglutinin (PHA). The cytokines (IL-12, IL-10, and TGF-) producing abilities of the DCs and Ms against these antigens were determined by flow cytometry. The transcription factor (NF-B) and T-cell cytokine support (IFN-, IL-10), which could be significant in effector immune function, were also determined. Severe hindrance in the immune protection due to Leishmania parasites, as revealed by decreased expression of IL-12 and upregulation of IL-10 and TGF- expression in the Ms compared to DCs, occurred in VL patients. The production of IL-12 in response to L. donovani KMP-11 antigen was increased in DCs which was reduced in Ms of VL patients. In contrast, the presentation of KMP-11 antigen by DCs to T-lymphocytes in VL patients significantly increased the IFN- produced by these immune cells, whereas the levels of IL-10 were significantly elevated after presentation of KMP-11antigen by Ms. The VL patients were observed with severely dysfunctional Ms in terms of NF-B activity that could be recovered only after stimulation of DCs with L. donovani KMP-11 antigen. Immunologically the better competitiveness of KMP-11 antigen through a dendritic cell delivery system may be used to revert T-cell anergy, and control strategy can be designed accordingly against kala-azar. Rajesh Chaudhary, Ajay Amit, Anupam Yadav, Anurag Singh, Vikash Kumar, S. K. Singh, Shyam Narayan, Vidyanand Rabidas, K. Pandey, Anil Kumar, Pradeep Das, and Sanjiva Bimal Copyright © 2014 Rajesh Chaudhary et al. All rights reserved. Toward Understanding the Role of Aryl Hydrocarbon Receptor in the Immune System: Current Progress and Future Trends Mon, 06 Jan 2014 14:17:23 +0000 http://www.hindawi.com/journals/bmri/2014/520763/ The immune system is regulated by distinct signaling pathways that control the development and function of the immune cells. Accumulating evidence suggest that ligation of aryl hydrocarbon receptor (Ahr), an environmentally responsive transcription factor, results in multiple cross talks that are capable of modulating these pathways and their downstream responsive genes. Most of the immune cells respond to such modulation, and many inflammatory response-related genes contain multiple xenobiotic-responsive elements (XREs) boxes upstream. Active research efforts have investigated the physiological role of Ahr in inflammation and autoimmunity using different animal models. Recently formed paradigm has shown that activation of Ahr by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3′-diindolylmethane (DIM) prompts the differentiation of CD4+Foxp3+ regulatory T cells (Tregs) and inhibits T helper (Th)-17 suggesting that Ahr is an innovative therapeutic strategy for autoimmune inflammation. These promising findings generate a basis for future clinical practices in humans. This review addresses the current knowledge on the role of Ahr in different immune cell compartments, with a particular focus on inflammation and autoimmunity. Hamza Hanieh Copyright © 2014 Hamza Hanieh. All rights reserved. SEA Antagonizes the Imatinib-Meditated Inhibitory Effects on T Cell Activation via the TCR Signaling Pathway Thu, 02 Jan 2014 11:45:44 +0000 http://www.hindawi.com/journals/bmri/2014/682010/ The BCR-ABL kinase inhibitor imatinib is highly effective in the treatment of chronic myeloid leukemia (CML). However, long-term imatinib treatment induces immunosuppression, which is mainly due to T cell dysfunction. Imatinib can reduce TCR-triggered T cell activation by inhibiting the phosphorylation of tyrosine kinases such as Lck, ZAP70, LAT, and PLCγ1 early in the TCR signaling pathway. The purpose of this study was to investigate whether the superantigen SEA, a potent T cell stimulator, can block the immunosuppressive effects of imatinib on T cells. Our data show that the exposure of primary human T cells and Jurkat cells to SEA for 24 h leads to the upregulation of the Lck and ZAP70 proteins in a dose-dependent manner. T cells treated with SEA prior to TCR binding had increased the tyrosine phosphorylation of Lck, ZAP70, and PLCγ1. Pretreatment with SEA prevents the inhibitory effects of imatinib on TCR signaling, which leads to T cell proliferation and IL-2 production. It is conceivable that SEA antagonizes the imatinib-mediated inhibition of T cell activation and proliferation through the TCR signaling pathway. Guanming Wang, Yuhui Yan, Xiaohua Chen, Chen Lin, and Yangqiu Li Copyright © 2014 Guanming Wang et al. All rights reserved. Lactobacilli Reduce Chemokine IL-8 Production in Response to TNF-α and Salmonella Challenge of Caco-2 Cells Sat, 28 Dec 2013 13:32:11 +0000 http://www.hindawi.com/journals/bmri/2013/925219/ The probiotic properties of two selected lactobacilli strains were assessed. L. salivarius and L. plantarum displayed higher hydrophobicity (48% and 54%, resp.) and coaggregation ability with four pathogens (from 7.9% to 57.5%). L. salivarius and L. plantarum had good inhibitory effects on S. aureus (38.2% and 49.5%, resp.) attachment to Caco-2 cells. Live lactobacilli strains and their conditioned media effectively inhibited IL-8 production (<14.6 pg/mL) in TNF-α-induced Caco-2 cells. Antibiotic-treated and the sonicated lactobacilli also maintained inhibitory effects (IL-8 production from 5.0 to 36.3 pg/mL); however, the heat-treated lactobacilli lost their inhibitory effects (IL-8 production from 130.2 to 161.0 pg/mL). These results suggest that both the structural components and the soluble cellular content of lactobacilli have anti-inflammatory effects. We also found that pretreatment of Caco-2 cells with lactobacilli inhibited S. typhimurium-induced IL-8 production (<27.3 pg/mL). However, lactobacilli did not inhibit IL-8 production in Caco-2 cells pretreated with S. typhimurium. These results suggest that the tested lactobacilli strains are appropriate for preventing inflammatory diseases caused by enteric pathogens but not for therapy. In short, L. salivarius and L. plantarum are potential candidates for the development of microbial ecological agents and functional foods. Da-Yong Ren, Chang Li, Yan-Qing Qin, Rong-Lan Yin, Shou-Wen Du, Fei Ye, Hong-Feng Liu, Mao-Peng Wang, Yang Sun, Xiao Li, Ming-Yao Tian, and Ning-Yi Jin Copyright © 2013 Da-Yong Ren et al. All rights reserved. Role of Omega-3 Polyunsaturated Fatty Acids in the Production of Prostaglandin E2 and Nitric Oxide during Experimental Murine Paracoccidioidomycosis Wed, 25 Dec 2013 08:27:36 +0000 http://www.hindawi.com/journals/bmri/2013/947687/ There has recently been increased interest in the potential health effects of omega-3 polyunsaturated fatty acids on the immune system. Paracoccidioidomycosis is the most important endemic mycosis in Latin America. Macrophages have a fundamental role and act as first line of organism defense. The purpose of this study was to analyze the effect of n-3 fatty acids on the production of PGE2 and NO by mice infected with Pb18 and fed a diet enriched with LNA for 8 weeks. To study the effect of omega-3 fatty acids on macrophage activity during experimental paracoccidioidomycosis, mice were infected with Pb18 and fed a diet supplemented with LNA. PGE2 in the serum of animals was analyzed and NO in the supernatants of macrophages cultured and challenged in vitro with Pb18 was measured. Omega-3 fatty acids seemed to decrease the production of PGE2 in vivo in the infected group fed an LNA-supplemented diet during the 4th and 8th weeks of the experiment. At the same time, we observed an increase in synthesis of NO by peritoneal macrophages in this group. Omega-3 fatty acids thus appear to have an immunomodulatory effect in paracoccidioidomycosis. S. C. Sargi, M. M. O. Dalalio, A. G. Moraes, J. E. L. Visentainer, D. R. Morais, and J. V. Visentainer Copyright © 2013 S. C. Sargi et al. All rights reserved. Oral Immunogenicity of Plant-Made Mycobacterium tuberculosis ESAT6 and CFP10 Thu, 19 Dec 2013 11:17:57 +0000 http://www.hindawi.com/journals/bmri/2013/316304/ Two lines of transgenic carrot plants producing Mycobacterium tuberculosis proteins (ESAT6 and CFP10) have been constructed. The target proteins are present in carrot storage roots at a level not less than 0.056% of the total storage protein (TSP) for ESAT6 and 0.002% of TSP for CFP10. As has been shown, oral immunization of mice induces both the cell-mediated and humoral immunities. These data suggest that the proteins in question are appropriate as a candidate edible vaccine against tuberculosis. Elena A. Uvarova, Pavel A. Belavin, Natalya V. Permyakova, Alla A. Zagorskaya, Olesya V. Nosareva, Almagul A. Kakimzhanova, and Elena V. Deineko Copyright © 2013 Elena A. Uvarova et al. All rights reserved. Modulation of Lung Immune Response Thu, 05 Dec 2013 15:46:29 +0000 http://www.hindawi.com/journals/bmri/2013/239020/ Alexandre de Paula Rogerio, Carlo José Freire Oliveira, Edinéia Lemos de Andrade, and Oliver Haworth Copyright © 2013 Alexandre de Paula Rogerio et al. All rights reserved. Perinatal Exposure to Insecticide Methamidophos Suppressed Production of Proinflammatory Cytokines Responding to Virus Infection in Lung Tissues in Mice Tue, 03 Dec 2013 14:37:21 +0000 http://www.hindawi.com/journals/bmri/2013/151807/ Methamidophos, a representative organophosphate insecticide, is regulated because of its severe neurotoxicity, but it is suspected of contaminating agricultural foods in many countries due to illicit use. To reveal unknown effects of methamidophos on human health, we evaluated the developmental immunotoxicity of methamidophos using a respiratory syncytial virus (RSV) infection mouse model. Pregnant mice were exposed to methamidophos (10 or 20 ppm) in their drinking water from gestation day 10 to weaning on postnatal day 21. Offsprings born to these dams were intranasally infected with RSV. The levels of interleukin-6 (IL-6) and interferon-gamma in the bronchoalveolar lavage fluids after infection were significantly decreased in offspring mice exposed to methamidophos. Treatment with methamidophos did not affect the pulmonary viral titers but suppressed moderately the inflammation of lung tissues of RSV-infected offspring, histopathologically. DNA microarray analysis revealed that gene expression of the cytokines in the lungs of offspring mice exposed to 20 ppm of methamidophos was apparently suppressed compared with the control. Methamidophos did not suppress IL-6 production in RSV-infected J774.1 cell cultures. Thus, exposure of the mother to methamidophos during pregnancy and nursing was suggested to cause an irregular immune response in the lung tissues in the offspring mice. Wataru Watanabe, Hiroki Yoshida, Akihiko Hirose, Toshi Akashi, Tomomi Takeshita, Nao Kuroki, Asami Shibata, Satoko Hongo, Seiko Hashiguchi, Katsuhiko Konno, and Masahiko Kurokawa Copyright © 2013 Wataru Watanabe et al. All rights reserved. Ovarian Stimulation Affects the Population of Mouse Uterine NK Cells at Early Pregnancy Sun, 17 Nov 2013 17:09:39 +0000 http://www.hindawi.com/journals/bmri/2013/182531/ The aim of this study was to determine the influence of ovarian stimulation on endometrial mouse NK cell population. For superovulation, the female adult NMRI mice were injected i.p. with 10 IU of the pregnant mare serum gonadotropin followed 48 h later by an i.p. injection of 10 IU human chorionic gonadotropin hormone. Ovarian stimulated and nonstimulated mice were mated with fertile male. The presence of vaginal plug proved natural pregnancy, and this day was considered as day one of pregnancy. Tissue samples were prepared from the uterine horn and spleen of both groups of study on 7th day of pregnancy. Serum estradiol-17 and progesterone were measured at the same time. The tissue cryosections were prepared and double stained for CD 161 and CD3 markers, and NK cells population was analyzed. Relative frequency of NK cells was significantly lower in stroma and myometrium in hyperstimulated mice compared with the control group. However, no difference was seen in percentage of NK cells in spleen. The ovarian stimulation influences the proportion of uterine NK cells and may affect the embryo implantation. Parvin Dorfeshan, Mojdeh Salehnia, and Seyed Mohammad Moazzeni Copyright © 2013 Parvin Dorfeshan et al. All rights reserved. Prevalence of Bronchiectasis in Asthma according to Oral Steroid Requirement: Influence of Immunoglobulin Levels Wed, 13 Nov 2013 13:24:44 +0000 http://www.hindawi.com/journals/bmri/2013/109219/ Purpose. To establish the prevalence of bronchiectasis in asthma in relation to patients’ oral corticosteroid requirements and to explore whether the increased risk is due to blood immunoglobulin (Ig) concentration. Methods. Case-control cross-sectional study, including 100 sex- and age-matched patients, 50 with non-steroid-dependent asthma (NSDA) and 50 with steroid-dependent asthma (SDA). Study protocol: (a) measurement of Ig and gG subclass concentration; (b) forced spirometry; and (c) high-resolution thoracic computed tomography. When bronchiectasis was detected, a specific etiological protocol was applied to establish its etiology. Results. The overall prevalence of bronchiectasis was 12/50 in the SDA group and 6/50 in the NSDA group (). The etiology was documented in six patients (four NSDA and two SDA). After excluding these patients, the prevalence of bronchiectasis was 20% (10/50) in the SDA group and 2/50 (4%) in the NSDA group (). Patients with asthma-associated bronchiectasis presented lower FEV1 values than patients without bronchiectasis, but the levels of Ig and subclasses of IgG did not present differences. Conclusions. Steroid-dependent asthma seems to be associated with a greater risk of developing bronchiectasis than non-steroid-dependent asthma. This is probably due to the disease itself rather than to other influencing factors such as immunoglobulin levels. Manel Luján, Xavier Gallardo, María José Amengual, Montserrat Bosque, Rosa M. Mirapeix, and Christian Domingo Copyright © 2013 Manel Luján et al. All rights reserved. Recent Advances in Genetic Predisposition of Myasthenia Gravis Tue, 05 Nov 2013 11:03:20 +0000 http://www.hindawi.com/journals/bmri/2013/404053/ Myasthenia gravis (MG) is an autoimmune disease mediated by the presence of autoantibodies that bind to components of the neuromuscular junction, causing the symptoms of muscular weakness and fatigability. Like most autoimmune disorders, MG is a multifactorial, noninherited disease, though with an established genetic constituent. The heterogeneity observed in MG perplexes genetic analysis even more, as it occurs in various levels, including diverse autoantigens, thymus histopathology, and age at onset. In this context of distinct subgroups, a plethora of association studies, discussed in this review, have assessed the involvement of various HLA and non-HLA related loci in MG susceptibility, over the past five years. As expected, certain HLA alleles were strongly associated with MG. Many of the non-HLA genes, such as PTPN22 and CTLA-4, have been previously studied in MG and other autoimmune diseases and their association with MG has been reevaluated in more cohesive groups of patients. Moreover, novel risk or protective loci have been revealed, as in the case of TNIP1 and FOXP3. Although the majority of these results have been derived from candidate gene studies, the focal point of all recent genetic studies is the first genome-wide association study (GWAS) conducted on early-onset MG patients. Zoi Zagoriti, Manousos E. Kambouris, George P. Patrinos, Socrates J. Tzartos, and Konstantinos Poulas Copyright © 2013 Zoi Zagoriti et al. All rights reserved. Low pH Environmental Stress Inhibits LPS and LTA-Stimulated Proinflammatory Cytokine Production in Rat Alveolar Macrophages Wed, 30 Oct 2013 13:26:09 +0000 http://www.hindawi.com/journals/bmri/2013/742184/ Gastric aspiration increases the risks for developing secondary bacterial pneumonia. Cytokine elaboration through pathogen recognition receptors (PRRs) is an important mechanism in initiating innate immune host response. Effects of low pH stress, a critical component of aspiration pathogenesis, on the PRR pathways were examined, specifically toll-like receptor-2 (TLR2) and TLR4, using isolated rat alveolar macrophages (aMØs). We assessed the ability of aMØs after brief exposure to acidified saline to elaborate proinflammatory cytokines in response to lipopolysaccharide (LPS) and lipoteichoic acid (LTA) stimulation, known ligands of TLR4 and TLR2, respectively. Low pH stress reduced LPS- and LTA-mediated cytokine release (CINC-1, MIP-2, TNF-, MCP-1, and IFN-). LPS and LTA increased intracellular Ca2+ concentrations while Ca2+ chelation by BAPTA decreased LPS- and LTA-mediated cytokine responses. BAPTA blocked the effects of low pH stress on most of LPS-stimulated cytokines but not of LTA-stimulated responses. In vivo mouse model demonstrates suppressed E. coli and S. pneumoniae clearance following acid aspiration. In conclusion, low pH stress inhibits antibacterial cytokine response of aMØs due to impaired TLR2 (MyD88 pathway) and TLR4 signaling (MyD88 and TRIF pathways). The role of Ca2+ in low pH stress-induced signaling is complex but appears to be distinct between LPS- and LTA-mediated responses. Stanley F. Fernandez, Christopher Fung, Jadwiga D. Helinski, Ravi Alluri, Bruce A. Davidson, and Paul R. Knight III Copyright © 2013 Stanley F. Fernandez et al. All rights reserved. Novel Vaccine Adjuvants Tue, 22 Oct 2013 10:22:11 +0000 http://www.hindawi.com/journals/bmri/2013/835105/ Anshu Agrawal, Mohammad Owais, and Udai P. Singh Copyright © 2013 Anshu Agrawal et al. All rights reserved. Oligomannose-Coated Liposome as a Novel Adjuvant for the Induction of Cellular Immune Responses to Control Disease Status Thu, 10 Oct 2013 12:11:28 +0000 http://www.hindawi.com/journals/bmri/2013/562924/ Professional phagocytic cells, such as dendritic cells, are mainly responsible for phagocytosis, antigen presentation, and cytokine secretion, which induce subsequent activation of T cell-mediated immunity. Thus, strategies that deliver antigens and stimulatory signals to the cells have significant implications for vaccine design. In this paper, we summarize the potential for liposomes coated with the neoglycolipids containing oligomannose residues (OMLs) as a novel adjuvant for induction of Th1 immune responses and CTLs specific for the encased antigen. OMLs preferentially take up peripheral phagocytic cells. In response to OML uptake, the cells secrete IL-12 selectively, enhance the expression of costimulatory molecules, and migrate into lymphoid tissues from peripheral tissues. OMLs also have the ability to deliver encapsulated protein antigens to the MHC class I and class II pathways to generate antigen-specific CTLs and Th1 cells, respectively, and lipid antigen to CD1d to activate NKT cells. Since administration of OML-based vaccines can eliminate an established tumor, inhibit elevation of the serum IgE level, and prevent progression of protozoan infections in several murine, human, and bovine models, OML-based vaccines have revealed their potential for clinical use in vaccination for a variety of diseases in which CTLs and/or Th1 cells act as effector cells. Naoya Kojima, Mariko Ishii, Yoko Kawauchi, and Hideaki Takagi Copyright © 2013 Naoya Kojima et al. All rights reserved. MHC Universal Cells Survive in an Allogeneic Environment after Incompatible Transplantation Wed, 09 Oct 2013 19:13:19 +0000 http://www.hindawi.com/journals/bmri/2013/796046/ Cell, tissue, and organ transplants are commonly performed for the treatment of different diseases. However, major histocompatibility complex (MHC) diversity often prevents complete donor-recipient matching, resulting in graft rejection. This study evaluates in a preclinical model the capacity of MHC class I-silenced cells to engraft and grow upon allogeneic transplantation. Short hairpin RNA targeting β2-microglobulin (RN_shβ2m) was delivered into fibroblasts derived from LEW/Ztm () (RT1-) rats using a lentiviral-based vector. MHC class I (RT1-A-) expressing and -silenced cells were injected subcutaneously in LEW rats () and MHC-congenic LEW.1W rats (), respectively. Cell engraftment and the status of the immune response were monitored for eight weeks after transplantation. In contrast to RT1-A-expressing cells, RT1-A-silenced fibroblasts became engrafted and were still detectable eight weeks after allogeneic transplantation. Plasma levels of proinflammatory cytokines IL-1α, IL-1β, IL-6, TNF-α, and IFN-γ were significantly higher in animals transplanted with RT1-A-expressing cells than in those receiving RT1-A-silenced cells. Furthermore, alloantigen-specific T-cell proliferation rates derived from rats receiving RT1-A-expressing cells were higher than those in rats transplanted with RT1-A-silenced cells. These data suggest that silencing MHC class I expression might overcome the histocompatibility barrier, potentially opening up new avenues in the field of cell transplantation and regenerative medicine. Constança Figueiredo, Dirk Wedekind, Thomas Müller, Stefanie Vahlsing, Peter A. Horn, Axel Seltsam, and Rainer Blasczyk Copyright © 2013 Constança Figueiredo et al. All rights reserved. Internalization of B Cell Receptors in Human EU12 μHC+ Immature B Cells Specifically Alters Downstream Signaling Events Wed, 09 Oct 2013 11:07:25 +0000 http://www.hindawi.com/journals/bmri/2013/807240/ It has been recognized for a long time that engagement of B cell antigen receptors (BCRs) on immature B cells or mature B cells leads to completely opposite cell fate decisions. The underlying mechanism remains unclear. Here, we show that crosslinking of BCRs on human EU12 μHC+ immature B cells resulted in complete internalization of cell surface BCRs. After loss of cell surface BCRs, restimulation of EU12 μHC+ cells showed impaired Ca2+ flux, delayed SYK phosphorylation, and decreased CD19 and FOXO1 phosphorylation, which differ from those in mature Daudi or Ramos B cells with partial internalization of BCRs. In contrast, sustained phosphorylation and reactivation of ERK upon restimulation were observed in the EU12 μHC+ cells after BCR internalization. Taken together, these results show that complete internalization of cell surface BCRs in EU12 μHC+ cells specifically alters the downstream signaling events, which may favor receptor editing versus cell activation. Jing Liu, Wanqin Xie, Miles D. Lange, Sang Yong Hong, Kaihong Su, and Zhixin Zhang Copyright © 2013 Jing Liu et al. All rights reserved. Potential Effects of Medicinal Plants and Secondary Metabolites on Acute Lung Injury Wed, 09 Oct 2013 11:02:38 +0000 http://www.hindawi.com/journals/bmri/2013/576479/ Acute lung injury (ALI) is a life-threatening syndrome that causes high morbidity and mortality worldwide. ALI is characterized by increased permeability of the alveolar-capillary membrane, edema, uncontrolled neutrophils migration to the lung, and diffuse alveolar damage, leading to acute hypoxemic respiratory failure. Although corticosteroids remain the mainstay of ALI treatment, they cause significant side effects. Agents of natural origin, such as medicinal plants and their secondary metabolites, mainly those with very few side effects, could be excellent alternatives for ALI treatment. Several studies, including our own, have demonstrated that plant extracts and/or secondary metabolites isolated from them reduce most ALI phenotypes in experimental animal models, including neutrophil recruitment to the lung, the production of pro-inflammatory cytokines and chemokines, edema, and vascular permeability. In this review, we summarized these studies and described the anti-inflammatory activity of various plant extracts, such as Ginkgo biloba and Punica granatum, and such secondary metabolites as epigallocatechin-3-gallate and ellagic acid. In addition, we highlight the medical potential of these extracts and plant-derived compounds for treating of ALI. Daniely Cornélio Favarin, Jhony Robison de Oliveira, Carlo Jose Freire de Oliveira, and Alexandre de Paula Rogerio Copyright © 2013 Daniely Cornélio Favarin et al. All rights reserved. The Multifaceted Aspects of Interstitial Lung Disease in Rheumatoid Arthritis Wed, 25 Sep 2013 16:33:40 +0000 http://www.hindawi.com/journals/bmri/2013/759760/ Interstitial lung disease (ILD) is a relevant extra-articular manifestation of rheumatoid arthritis (RA) that may occur either in early stages or as a complication of long-standing disease. RA related ILD (RA-ILD) significantly influences the quoad vitam prognosis of these patients. Several histopathological patterns of RA-ILD have been described: usual interstitial pneumonia (UIP) is the most frequent one, followed by nonspecific interstitial pneumonia (NSIP); other patterns are less commonly observed. Several factors have been associated with an increased risk of developing RA-ILD. The genetic background plays a fundamental but not sufficient role; smoking is an independent predictor of ILD, and a correlation with the presence of rheumatoid factor and anti-cyclic citrullinated peptide antibodies has also been reported. Moreover, both exnovo occurrence and progression of ILD have been related to drug therapies that are commonly prescribed in RA, such as methotrexate, leflunomide, anti-TNF alpha agents, and rituximab. A greater understanding of the disease process is necessary in order to improve the therapeutic approach to ILD and RA itself and to reduce the burden of this severe extra-articular manifestation. Lorenzo Cavagna, Sara Monti, Vittorio Grosso, Nicola Boffini, Eva Scorletti, Gloria Crepaldi, and Roberto Caporali Copyright © 2013 Lorenzo Cavagna et al. All rights reserved. Proteinase-Activated Receptor-2 Agonist Activates Anti-Influenza Mechanisms and Modulates IFNγ-Induced Antiviral Pathways in Human Neutrophils Sun, 22 Sep 2013 16:15:58 +0000 http://www.hindawi.com/journals/bmri/2013/879080/ Proteinase-activated receptor-2 (PAR2) is expressed by human leukocytes and participates in the development of inflammatory diseases. Recent studies demonstrated an ability of PAR2 agonist to enhance IFNγ-induced antiviral responses of human leukocytes. However, the precise cellular antiviral defense mechanisms triggered in leukocytes after stimulation with IFNγ and/or PAR2 agonist remain elusive. Therefore, we aimed to identify neutrophil defense mechanisms involved in antiviral resistance. Here we demonstrated that PAR2 agonist enhanced IFNγ-related reduction of influenza A virus (IAV) replication in human neutrophils. PAR2-mediated decrease in IAV replication was associated with reduced NS-1 transcription. Moreover, PAR2-dependent neutrophil activation resulted in enhanced myeloperoxidase degranulation and extracellular myeloperoxidase disrupted IAV. The production of ROS was elevated in response to PAR2 activation. Interestingly, IFNγ did not influence both effects: PAR2 agonist-triggered myeloperoxidase (MPO) release and reactive oxygen species (ROS) production, which are known to limit IAV infections. In contrast, orthomyxovirus resistance gene A (MxA) protein expression was synergistically elevated through PAR2 agonist and IFNγ in neutrophils. Altogether, these findings emphasize two PAR2-controlled antiviral mechanisms that are independent of or modulated by IFNγ. Micha Feld, Victoria Shpacovitch, Christina Ehrhardt, Michaela Fastrich, Tobias Goerge, Stephan Ludwig, and Martin Steinhoff Copyright © 2013 Micha Feld et al. All rights reserved. Modulation of the Effects of Lung Immune Response on Bone Marrow by Oral Antigen Exposure Sun, 22 Sep 2013 14:58:40 +0000 http://www.hindawi.com/journals/bmri/2013/474132/ Allergic airway inflammation is attenuated by oral tolerization (oral exposure to allergen, followed by conventional sensitization and challenge with homologous antigen), which decreases airway allergen challenge-induced eosinophilic infiltration of the lungs and bone marrow eosinophilia. We examined its effects on bone marrow eosinophil and neutrophil production. Mice of wild type (BP-2, BALB/c, and C57BL/6) and mutant strains (lacking iNOS or CD95L) were given ovalbumin (OVA) or water (vehicle) orally and subsequently sensitized and challenged with OVA (OVA/OVA/OVA and H2O/OVA/OVA groups, resp.). Anti-OVA IgG and IgE, bone marrow eosinophil and neutrophil numbers, and eosinophil and neutrophil production ex vivo were evaluated. T lymphocytes from OVA/OVA/OVA or control H2O/OVA/OVA donors were transferred into naïve syngeneic recipients, which were subsequently sensitized/challenged with OVA. Alternatively, T lymphocytes were cocultured with bone marrow eosinophil precursors from histocompatible sensitized/challenged mice. OVA/OVA/OVA mice of the BP-2 and BALB/c strains showed, relative to H2O/OVA/OVA controls, significantly decreased bone marrow eosinophil counts and ex vivo eosinopoiesis/neutropoiesis. Full effectiveness in vivo required sequential oral/subcutaneous/intranasal exposures to the same allergen. Transfer of splenic T lymphocytes from OVA/OVA/OVA donors to naive recipients prevented bone marrow eosinophilia and eosinopoiesis in response to recipient sensitization/challenge and supressed eosinopoiesis upon coculture with syngeneic bone marrow precursors from sensitized/challenged donors. P. Xavier-Elsas, C. L. C. A. Silva, L. Pinto, T. Queto, B. M. Vieira, M. G. Aranha, B. De Luca, D. Masid-de-Brito, R. A. Luz, R. S. Lopes, R. Ferreira, and M. I. Gaspar-Elsas Copyright © 2013 P. Xavier-Elsas et al. All rights reserved. Illuminating the Petite Picture of T Cell Memory Responses to Listeria monocytogenes Sun, 22 Sep 2013 10:37:24 +0000 http://www.hindawi.com/journals/bmri/2013/121684/ The ease to culture, moderately less safety constraints in handling, and above all, hurdle free induction of an anticipated infection in mouse rendered Listeria monocytogenes the rank of a model organism for studying a variety of host immune responses. Listeria monocytogenes being an intracellular pathogen evokes potent CD8 T cell response during which CD8 T cells pass through a massive expansion phase. This is generally followed by contraction phase wherein majority of activated cells undergo apoptosis leaving behind a population of memory CD8 T cells that has potential to confer enhanced protection upon reencounter with the same pathogen. Functional attributes of various cytokines, transcription factors, receptors, adaptors, and effectors pertaining to the generation of robust memory T cell response have begun to be unravelled for better understanding of memory and opening avenues to create superior vaccine strategies. This review is an attempt to unveil related discoveries along with updating recent advances on this issue. Saba Tufail, Khan Farheen Badrealam, Mohammad Owais, and Swaleha Zubair Copyright © 2013 Saba Tufail et al. All rights reserved. Effect of the Plasmid-DNA Vaccination on Macroscopic and Microscopic Damage Caused by the Experimental Chronic Trypanosoma cruzi Infection in the Canine Model Thu, 19 Sep 2013 18:22:30 +0000 http://www.hindawi.com/journals/bmri/2013/826570/ The dog is considered the main domestic reservoir for Trypanosoma cruzi infection and a suitable experimental animal model to study the pathological changes during the course of Chagas disease (CD). Vaccine development is one of CD prevention methods to protect people at risk. Two plasmids containing genes encoding a trans-sialidase protein (TcSP) and an amastigote-specific glycoprotein (TcSSP4) were used as DNA vaccines in a canine model. Splenomegaly was not found in either of the recombinant plasmid-immunized groups; however, cardiomegaly was absent in animals immunized only with the plasmid containing the TcSSP4 gene. The inflammation of subendocardial and myocardial tissues was prevented only with the immunization with TcSSP4 gene. In conclusion, the vaccination with these genes has a partial protective effect on the enlargement of splenic and cardiac tissues during the chronic CD and on microscopic hearth damage, since both plasmids prevented splenomegaly but only one avoided cardiomegaly, and the lesions in heart tissue of dog immunized with plasmid containing the TcSSP4 gene covered only subepicardial tissue. Olivia Rodríguez-Morales, Silvia C. Carrillo-Sánchez, Humberto García-Mendoza, Alberto Aranda-Fraustro, Martha A. Ballinas-Verdugo, Ricardo Alejandre-Aguilar, José Luis Rosales-Encina, Maite Vallejo, and Minerva Arce-Fonseca Copyright © 2013 Olivia Rodríguez-Morales et al. All rights reserved. The Role of Osteoimmunology in Periodontal Disease Tue, 17 Sep 2013 18:18:11 +0000 http://www.hindawi.com/journals/bmri/2013/639368/ Periodontal disease is a pathological condition that involves inflammation of the tooth supporting structures. It occurs in response to the presence of bacterial plaque on the tooth structure. The host defense system, including innate and adaptive immunity, is responsible for combating the pathologic bacteria invading the periodontal tissue. Failure to eradicate the invading pathogens will result in a continuous state of inflammation where inflammatory cells such as lymphocytes, PMNs, and macrophages will continue to produce inflammatory mediators in an effort to destroy the invaders. Unfortunately, these inflammatory mediators have a deleterious effect on the host tissue as well as foreign microbes. One of the effects of these mediators on the host is the induction of matrix degradation and bone resorption through activation of proteases and other inflammatory mediators that activate osteoclasts. Rayyan A. Kayal Copyright © 2013 Rayyan A. Kayal. All rights reserved. Chronic Heat Stress Inhibits Immune Responses to H5N1 Vaccination through Regulating CD4+CD25+Foxp3+ Tregs Tue, 17 Sep 2013 08:48:19 +0000 http://www.hindawi.com/journals/bmri/2013/160859/ Chronic heat stress (CHS) is known to have negative impacts on the immune responses in animals and increases their susceptibility to infections including the highly pathogenic avian influenza virus H5N1. However, the role of regulatory T cells (Tregs) in CHS immunosuppression remains largely undefined. In this study, we demonstrated a novel mechanism by which CHS suppressed both Th1 and Th2 immune responses and dramatically decreased the protective efficacy of the formalin-inactivated H5N1 vaccine against H5N1 influenza virus infection. This suppression was found to be associated with the induced generation of CD4+CD25+FoxP3+ Tregs and the increased secretions of IL-10 and TGF-β in CD4+ T cells. Adoptive transfer of the induced Tregs also suppressed the protective efficacy of formalin-inactivated H5N1 virus immunization. Collectively, this study identifies a novel mechanism of CHS immunosuppression mediated by regulating CD4+CD25+Foxp3+ Tregs. Di Meng, Yanxin Hu, Chong Xiao, Tangting Wei, Qiang Zou, and Ming Wang Copyright © 2013 Di Meng et al. All rights reserved. Antileukotriene Reverts the Early Effects of Inflammatory Response of Distal Parenchyma in Experimental Chronic Allergic Inflammation Sun, 15 Sep 2013 13:59:37 +0000 http://www.hindawi.com/journals/bmri/2013/523761/ Aims. Compare the effects of montelukast or dexamethasone in distal lung parenchyma and airway walls of guinea pigs (GP) with chronic allergic inflammation. Methods. GP have inhaled ovalbumin (OVA group-2x/week/4weeks). After the 4th inhalation, GP were treated with montelukast or dexamethasone. After 72 hours of the 7th inhalation, GP were anesthetised, and lungs were removed and submitted to histopathological evaluation. Results. Montelukast and dexamethasone treatments reduced the number of eosinophils in airway wall and distal lung parenchyma compared to OVA group (). On distal parenchyma, both treatments were effective in reducing RANTES, NF-κB, and fibronectin positive cells compared to OVA group (). Montelukast was more effective in reducing eotaxin positive cells on distal parenchyma compared to dexamethasone treatment (), while there was a more expressive reduction of IGF-I positive cells in OVA-D group (). On airway walls, montelukast and dexamethasone were effective in reducing IGF-I, RANTES, and fibronectin positive cells compared to OVA group (). Dexamethasone was more effective in reducing the number of eotaxin and NF-κB positive cells than Montelukast (). Conclusions. In this animal model, both treatments were effective in modulating allergic inflammation and remodeling distal lung parenchyma and airway wall, contributing to a better control of the inflammatory response. Nathália Brandão Gobbato, Flávia Castro Ribas de Souza, Stella Bruna Napolitano Fumagalli, Fernanda Degobbi Tenório Quirino dos Santos Lopes, Carla Máximo Prado, Milton Arruda Martins, Iolanda de Fátima Lopes Calvo Tibério, and Edna Aparecida Leick Copyright © 2013 Nathália Brandão Gobbato et al. All rights reserved. Immunomodulatory Effects of Adipose-Derived Stem Cells: Fact or Fiction? Tue, 10 Sep 2013 09:58:42 +0000 http://www.hindawi.com/journals/bmri/2013/383685/ Adipose-derived stromal cells (ASCs) are often referred to as adipose-derived stem cells due to their potential to undergo multilineage differentiation. Their promising role in tissue engineering and ability to modulate the immune system are the focus of extensive research. A number of clinical trials using ASCs are currently underway to better understand the role of such cell niche in enhancing or suppressing the immune response. If governable, such immunoregulatory role would find application in several conditions in which an immune response is present (i.e., autoimmune conditions) or feared (i.e., solid organ or reconstructive transplantation). Although allogeneic ASCs have been shown to prevent acute GvHD in both preclinical and clinical studies, their potential warrants further investigation. Well-designed and standardized clinical trials are necessary to prove the role of ASCs in the treatment of immune disorders or prevention of tissue rejection. In this paper we analyze the current literature on the role of ASCs in immunomodulation in vitro and in vivo and discuss their potential in regulating the immune system in the context of transplantation. Angelo A. Leto Barone, Saami Khalifian, W. P. Andrew Lee, and Gerald Brandacher Copyright © 2013 Angelo A. Leto Barone et al. All rights reserved. A Fusion Protein between Streptavidin and the Endogenous TLR4 Ligand EDA Targets Biotinylated Antigens to Dendritic Cells and Induces T Cell Responses In Vivo Thu, 05 Sep 2013 08:04:47 +0000 http://www.hindawi.com/journals/bmri/2013/864720/ The development of tools for efficient targeting of antigens to antigen presenting cells is of great importance for vaccine development. We have previously shown that fusion proteins containing antigens fused to the extra domain A from fibronectin (EDA), an endogenous TLR4 ligand, which targets antigens to TLR4-expressing dendritic cells (DC), are highly immunogenic. To facilitate the procedure of joining EDA to any antigen of choice, we have prepared the fusion protein EDAvidin by linking EDA to the N terminus of streptavidin, allowing its conjugation with biotinylated antigens. We found that EDAvidin, as streptavidin, forms tetramers and binds biotin or biotinylated proteins with a ~ 2.6 × 10−14 mol/L. EDAvidin favours the uptake of biotinylated green fluorescent protein by DC. Moreover, EDAvidin retains the proinflammatory properties of EDA, inducing NF-κβ by TLR4-expressing cells, as well as the production of TNF-α by the human monocyte cell line THP1 and IL-12 by DC. More importantly, immunization of mice with EDAvidin conjugated with the biotinylated nonstructural NS3 protein from hepatitis C virus induces a strong anti-NS3 T cell immune response. These results open a new way to use the EDA-based delivery tool to target any antigen of choice to DC for vaccination against infectious diseases and cancer. Laura Arribillaga, Maika Durantez, Teresa Lozano, Francesc Rudilla, Federico Rehberger, Noelia Casares, Lorea Villanueva, Marta Martinez, Marta Gorraiz, Francisco Borrás-Cuesta, Pablo Sarobe, Jesús Prieto, and Juan José Lasarte Copyright © 2013 Laura Arribillaga et al. All rights reserved. Primary Immunodeficiency Diseases at Reference and High-Specialty Hospitals in the State of Guanajuato, Mexico Sun, 01 Sep 2013 13:57:05 +0000 http://www.hindawi.com/journals/bmri/2013/187254/ Background. In general, primary immunodeficiency diseases (PIDs) are underdiagnosed in most countries. The objective of this study was to describe the frequency and clinical spectrum of PID in the most important tertiary hospitals in our region. Methods. An observational, cross-sectional, with retrospective chart, review study was conducted. A total of 26 patients were included and grouped according to the updated classification of PIDs. Results. PIDs spectra were as follows: predominantly antibody deficiency diseases were the most common category (65.38%), followed by other well-defined immunodeficiency syndromes (11.55%), congenital defects of phagocyte number and/or function (7.69%), complement deficiencies (3.85%), combined T- and B-cell immunodeficiencies (3.85%), and defects in innate immunity (3.85%). The mean time elapsed from the onset of symptoms to the reference and diagnosis by a tertiary hospital was of 4.65 ± 6.95 years. Conclusions. Predominant antibody deficiency disease was the most common group of PIDs, agreeing with international reports. Awareness of underdiagnosis by physicians is crucial for a prompt diagnosis and treatment, which in turn should improve the quality of life among patients with PIDs. Eduardo Guaní-Guerra, Ulises Noel García-Ramírez, Ana Isabel Jiménez-Romero, José Manuel Velázquez-Ávalos, Gabriela Gallardo-Martínez, and Francisco-Javier Mendoza-Espinoza Copyright © 2013 Eduardo Guaní-Guerra et al. All rights reserved. Synthesis of a Novel Thiazolidinedione and Evaluation of Its Modulatory Effect on IFN-γ, IL-6, IL-17A, and IL-22 Production in PBMCs from Rheumatoid Arthritis Patients Sun, 01 Sep 2013 08:54:36 +0000 http://www.hindawi.com/journals/bmri/2013/926060/ Rheumatoid arthritis (RA) is an autoimmune disease frequently characterized by chronic synovitis of multiple joints. The pathogenesis of RA is complex and involves many proinflammatory cytokines as Th17 related ones. PPARγ is a nuclear receptor activator that represses proinflammatory gene expression. Thus, this work aimed to synthetize a new thiazolidinedione (TZD) analogue based on a well-known anti-inflammatory and PPARγ agonist activity of this ring and evaluate its anti-inflammatory activity. After chemical structure confirmation, the compound named 5-(5-bromo-2-methoxy-benzylidene)-3-(2-nitro-benzyl)-thiazolidine-2,4-dione TM17 was submitted to cytokine releasing inhibition and PPARγ genetic modulation assays. The new compound showed no toxicity on human and murine cells, decreasing IL-6 secretion by murine splenocytes and reducing IL-17A, IL-22, and IFN-γ expression in peripheral blood mononuclear cells from patients with RA. TM17 was more efficient in modulating the mRNA expression of PPARγ than its well-used TZD agonist rosiglitazone. Surprisingly, TM17 was efficient on IL-17A and IFN-γ reduction, like the positive control methylprednisolone, and presented a better effect on IL-22 levels. In conclusion, PBMCs obtained from RA patients under TM17 treatment present a significant reduction in IL-17A, IL-22, and IFN-γ levels, but not IL-6 when compared with nontreated cells, as well as increase PPARγ mRNA expression in absence of stimulus addressing it as a promising molecule in RA treatment. Laurindo Ferreira da Rocha Junior, Moacyr Jesus Barreto de Melo Rêgo, Mariana Brayner Cavalcanti, Michelly Cristiny Pereira, Marina Galdino da Rocha Pitta, Priscilla Stela Santana de Oliveira, Sayonara Maria Calado Gonçalves, Angela Luzia Branco Pinto Duarte, Maria do Carmo Alves de Lima, Ivan da Rocha Pitta, and Maira Galdino da Rocha Pitta Copyright © 2013 Laurindo Ferreira da Rocha Junior et al. All rights reserved. Intracellular Secretory Leukoprotease Inhibitor Modulates Inositol 1,4,5-Triphosphate Generation and Exerts an Anti-Inflammatory Effect on Neutrophils of Individuals with Cystic Fibrosis and Chronic Obstructive Pulmonary Disease Thu, 29 Aug 2013 14:11:37 +0000 http://www.hindawi.com/journals/bmri/2013/560141/ Secretory leukoprotease inhibitor (SLPI) is an anti-inflammatory protein present in respiratory secretions. Whilst epithelial cell SLPI is extensively studied, neutrophil associated SLPI is poorly characterised. Neutrophil function including chemotaxis and degranulation of proteolytic enzymes involves changes in cytosolic calcium (Ca2+) levels which is mediated by production of inositol 1,4,5-triphosphate (IP3) in response to G-protein-coupled receptor (GPCR) stimuli. The aim of this study was to investigate the intracellular function of SLPI and the mechanism-based modulation of neutrophil function by this antiprotease. Neutrophils were isolated from healthy controls (), individuals with cystic fibrosis (CF) () or chronic obstructive pulmonary disease (COPD) (). Recombinant human SLPI significantly inhibited fMet-Leu-Phe (fMLP) and interleukin(IL)-8 induced neutrophil chemotaxis () and decreased degranulation of matrix metalloprotease-9 (MMP-9), hCAP-18, and myeloperoxidase (MPO) (). The mechanism of inhibition involved modulation of cytosolic IP3 production and downstream Ca2+ flux. The described attenuation of Ca2+ flux was overcome by inclusion of exogenous IP3 in electropermeabilized cells. Inhibition of IP3 generation and Ca2+ flux by SLPI may represent a novel anti-inflammatory mechanism, thus strengthening the attractiveness of SLPI as a potential therapeutic molecule in inflammatory airway disease associated with excessive neutrophil influx including CF, non-CF bronchiectasis, and COPD. Emer P. Reeves, Nessa Banville, Dorothy M. Ryan, Niamh O’Reilly, David A. Bergin, Kerstin Pohl, Kevin Molloy, Oliver J. McElvaney, Khalifah Alsaleh, Ahmed Aljorfi, Osama Kandalaft, Eimear O'Flynn, Patrick Geraghty, Shane J. O’Neill, and Noel G. McElvaney Copyright © 2013 Emer P. Reeves et al. All rights reserved. Aminopeptidase N (CD13) Is Involved in Phagocytic Processes in Human Dendritic Cells and Macrophages Mon, 26 Aug 2013 08:37:49 +0000 http://www.hindawi.com/journals/bmri/2013/562984/ Aminopeptidase N (APN or CD13) is a membrane ectopeptidase expressed by many cell types, including myelomonocytic lineage cells: monocytes, macrophages, and dendritic cells. CD13 is known to regulate the biological activity of various peptides by proteolysis, and it has been proposed that CD13 also participates in several functions such as angiogenesis, cell adhesion, metastasis, and tumor invasion. We had previously reported that, in human monocytes and macrophages, CD13 modulates the phagocytosis mediated by receptors for the Fc portion of IgG antibodies (FcγRs). In this work, we analyzed the possible interaction of CD13 with other phagocytic receptors. We found out that the cross-linking of CD13 positively modulates the phagocytosis mediated by receptors of the innate immune system, since a significant increase in the phagocytosis of zymosan particles or heat-killed E. coli was observed when CD13 was cross-linked using anti-CD13 antibodies, in both macrophages and dendritic cells. Also, we observed that, during the phagocytosis of zymosan, CD13 redistributes and is internalized into the phagosome. These findings suggest that, besides its known functions, CD13 participates in phagocytic processes in dendritic cells and macrophages. Mónica I. Villaseñor-Cardoso, Dulce A. Frausto-Del-Río, and Enrique Ortega Copyright © 2013 Mónica I. Villaseñor-Cardoso et al. All rights reserved. The Immunobiology of Prostanoid Receptor Signaling in Connecting Innate and Adaptive Immunity Tue, 20 Aug 2013 13:47:05 +0000 http://www.hindawi.com/journals/bmri/2013/683405/ Prostanoids, including prostaglandins (PGs), thromboxanes (TXs), and prostacyclins, are synthesized from arachidonic acid (AA) by the action of Cyclooxygenase (COX) enzymes. They are bioactive inflammatory lipid mediators that play a key role in immunity and immunopathology. Prostanoids exert their effects on immune and inflammatory cells by binding to membrane receptors that are widely expressed throughout the immune system and act at multiple levels in innate and adaptive immunity. The immunoregulatory role of prostanoids results from their ability to regulate cell-cell interaction, antigen presentation, cytokine production, cytokine receptor expression, differentiation, survival, apoptosis, cell-surface molecule levels, and cell migration in both autocrine and paracrine manners. By acting on immune cells of both systems, prostanoids and their receptors have great impact on immune regulation and play a pivotal role in connecting innate and adaptive immunity. This paper focuses on the immunobiology of prostanoid receptor signaling because of their potential clinical relevance for various disorders including inflammation, autoimmunity, and tumorigenesis. We mainly discuss the effects of major COX metabolites, PGD2, PGE2, their signaling during dendritic cell (DC)-natural killer (NK) reciprocal crosstalk, DC-T cell interaction, and subsequent consequences on determining crucial aspects of innate and adaptive immunity in normal and pathological settings. Hedi Harizi Copyright © 2013 Hedi Harizi. All rights reserved. The SDF-1α3′ A Genetic Variation Is Correlated with Susceptibility of Asthma in Iranian Patients Tue, 20 Aug 2013 10:32:40 +0000 http://www.hindawi.com/journals/bmri/2013/759361/ Background and Aim. Chemokine/receptor axis is a predominant actor of clinical disorders. They are key factors of pathogenesis of almost all clinical situations including asthma. Correspondingly, CXCL12 is involved in the immune responses. Therefore, this study was designed to explore the association between gene polymorphism at position +801 of CXCL12, known as , and susceptibility to asthma in Iranian patients. Material and Methods. In this experimental study, samples were taken from 162 asthma patients and 189 healthy controls on EDTA. DNA was extracted and analyzed for CXCL12 polymorphisms using PCR-RLFP. The demographic information was also collected in parallel with the experimental part of the study by a questionnaire which was designed specifically for this study. Findings. Our results indicated a significant difference () between the A/A, A/G, and G/G genotypes and A and G alleles of polymorphisms at position +801 of CXCL12. We also showed an elevated level of CXCL12 circulating level in Iranian asthma patients. Conclusion. Our findings suggest that (CXCL12) polymorphism plays a role in pathogenesis of asthma. It can also be concluded that circulatory level of CXCL12 presumably can be used as one of the pivotal biological markers in diagnosis of asthma. Houshang Rafatpanah, Masoud Amin, Mohsen Ghasemshirazi, Mohammad Kazemiarababadi, Hossein Khorramdelazad, Hamid Abousaidi, Ziba Shabani, Ahmadreza Sayadi, Gholamhossein Hassanshahi, and Jamile Samadi Copyright © 2013 Houshang Rafatpanah et al. All rights reserved. Carbon Nanofibers Have IgE Adjuvant Capacity but Are Less Potent Than Nanotubes in Promoting Allergic Airway Responses Mon, 19 Aug 2013 10:08:32 +0000 http://www.hindawi.com/journals/bmri/2013/476010/ There is a growing concern for the possible health impact of nanoparticles. The main objective of this study was to investigate the allergy-promoting capacity of four different carbon nanofiber (CNF) samples in an injection and an airway mouse model of allergy. Secondly, the potency of the CNF was compared to the previously reported allergy-promoting capacity of carbon nanotubes (CNT) in the airway model. Ultrafine carbon black particles (ufCBP) were used as a positive control. Particles were given together with the allergen ovalbumin (OVA) either by subcutaneous injection into the footpad or intranasally to BALB/cA mice. After allergen booster, OVA-specific IgE, IgG1, and IgG2a in serum were measured. In the airway model, inflammation was determined as influx of inflammatory cells (eosinophils, neutrophils, lymphocytes, and macrophages) and by mediators (MCP-1 and TNF- present in bronchoalveolar fluid (BALF)). CNF and CNT both increased OVA-specific IgE levels in the two models, but in the airway model, the CNT gave a significantly stronger IgE response than the CNF. Furthermore, the CNT and not the CNF promoted eosinophil lung inflammation. Our data therefore suggest that nanotube-associated properties are particularly potent in promoting allergic responses. Unni Cecilie Nygaard, Mari Samuelsen, Calin Daniel Marioara, and Martinus Løvik Copyright © 2013 Unni Cecilie Nygaard et al. All rights reserved. Role of Campylobacter jejuni Infection in the Pathogenesis of Guillain-Barré Syndrome: An Update Tue, 13 Aug 2013 13:10:54 +0000 http://www.hindawi.com/journals/bmri/2013/852195/ Our current knowledge on Campylobacter jejuni infections in humans has progressively increased over the past few decades. Infection with C. jejuni is the most common cause of bacterial gastroenteritis, sometimes surpassing other infections due to Salmonella, Shigella, and Escherichia coli. Most infections are acquired due to consumption of raw or undercooked poultry, unpasteurized milk, and contaminated water. After developing the diagnostic methods to detect C. jejuni, the possibility to identify the association of its infection with new diseases has been increased. After the successful isolation of C. jejuni, reports have been published citing the occurrence of GBS following C. jejuni infection. Thus, C. jejuni is now considered as a major triggering agent of GBS. Molecular mimicry between sialylated lipooligosaccharide structures on the cell envelope of these bacteria and ganglioside epitopes on the human nerves that generates cross-reactive immune response results in autoimmune-driven nerve damage. Though C. jejuni is associated with several pathologic forms of GBS, axonal subtypes following C. jejuni infection may be more severe. Ample amount of existing data covers a large spectrum of GBS; however, the studies on C. jejuni-associated GBS are still inconclusive. Therefore, this review provides an update on the C. jejuni infections engaged in the pathogenesis of GBS. Kishan Kumar Nyati and Roopanshi Nyati Copyright © 2013 Kishan Kumar Nyati and Roopanshi Nyati. All rights reserved. The Immune Interplay between the Host and the Pathogen in Aspergillus fumigatus Lung Infection Tue, 30 Jul 2013 11:30:00 +0000 http://www.hindawi.com/journals/bmri/2013/693023/ The interplay between Aspergillus fumigatus and the host immune response in lung infection has been subject of studies over the last years due to its importance in immunocompromised patients. The multifactorial virulence factors of A. fumigatus are related to the fungus biological characteristics, for example, structure, ability to grow and adapt to high temperatures and stress conditions, besides capability of evading the immune system and causing damage to the host. In this context, the fungus recognition by the host innate immunity occurs when the pathogen disrupts the natural and chemical barriers followed by the activation of acquired immunity. It seems clear that a Th1 response has a protective role, whereas Th2 reactions are often associated with higher fungal burden, and Th17 response is still controversial. Furthermore, a fine regulation of the effector immunity is required to avoid excessive tissue damage associated with fungal clearance, and this role could be attributed to regulatory T cells. Finally, in this work we reviewed the aspects involved in the complex interplay between the host immune response and the pathogen virulence factors, highlighting the immunological issues and the importance of its better understanding to the development of novel therapeutic approaches for invasive lung aspergillosis. Helioswilton Sales-Campos, Ludmilla Tonani, Cristina Ribeiro Barros Cardoso, and Márcia Regina Von Zeska Kress Copyright © 2013 Helioswilton Sales-Campos et al. All rights reserved. Celiac Disease and Autoimmune-Associated Conditions Wed, 24 Jul 2013 10:30:38 +0000 http://www.hindawi.com/journals/bmri/2013/127589/ Celiac disease (CD) is frequently accompanied by a variety of extradigestive manifestations, thus making it a systemic disease rather than a disease limited to the gastrointestinal tract. This is primarily explained by the fact that CD belongs to the group of autoimmune diseases. The only one with a known etiology is related to a permanent intolerance to gluten. Remarkable breakthroughs have been achieved in the last decades, due to a greater interest in the diagnosis of atypical and asymptomatic patients, which are more frequent in adults. The known presence of several associated diseases provides guidance in the search of oligosymptomatic cases as well as studies performed in relatives of patients with CD. The causes for the onset and manifestation of associated diseases are diverse; some share a similar genetic base, like type 1 diabetes mellitus (T1D); others share pathogenic mechanisms, and yet, others are of unknown nature. General practitioners and other specialists must remember that CD may debut with extraintestinal manifestations, and associated illnesses may appear both at the time of diagnosis and throughout the evolution of the disease. The implementation of a gluten-free diet (GFD) improves the overall clinical course and influences the evolution of the associated diseases. In some cases, such as iron deficiency anemia, the GFD contributes to its disappearance. In other disorders, like T1D, this allows a better control of the disease. In several other complications and/or associated diseases, an adequate adherence to a GFD may slow down their evolution, especially if implemented during an early stage. Eugenia Lauret and Luis Rodrigo Copyright © 2013 Eugenia Lauret and Luis Rodrigo. All rights reserved. Aspergillus-Associated Airway Disease, Inflammation, and the Innate Immune Response Sun, 21 Jul 2013 11:02:47 +0000 http://www.hindawi.com/journals/bmri/2013/723129/ Aspergillus moulds exist ubiquitously as spores that are inhaled in large numbers daily. Whilst most are removed by anatomical barriers, disease may occur in certain circumstances. Depending on the underlying state of the human immune system, clinical consequences can ensue ranging from an excessive immune response during allergic bronchopulmonary aspergillosis to the formation of an aspergilloma in the immunocompetent state. The severest infections occur in those who are immunocompromised where invasive pulmonary aspergillosis results in high mortality rates. The diagnosis of Aspergillus-associated pulmonary disease is based on clinical, radiological, and immunological testing. An understanding of the innate and inflammatory consequences of exposure to Aspergillus species is critical in accounting for disease manifestations and preventing sequelae. The major components of the innate immune system involved in recognition and removal of the fungus include phagocytosis, antimicrobial peptide production, and recognition by pattern recognition receptors. The cytokine response is also critical facilitating cell-to-cell communication and promoting the initiation, maintenance, and resolution of the host response. In the following review, we discuss the above areas with a focus on the innate and inflammatory response to airway Aspergillus exposure and how these responses may be modulated for therapeutic benefit. Sanjay H. Chotirmall, Mazen Al-Alawi, Bojana Mirkovic, Gillian Lavelle, P. Mark Logan, Catherine M. Greene, and Noel G. McElvaney Copyright © 2013 Sanjay H. Chotirmall et al. All rights reserved. CTLA-4 Expression and Polymorphisms in Lung Tissue of Patients with Diagnosed Non-Small-Cell Lung Cancer Tue, 09 Jul 2013 12:00:05 +0000 http://www.hindawi.com/journals/bmri/2013/576486/ Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a potent immunoregulatory molecule that downregulates T-cell activation and thus influences the antitumor immune response. CTLA-4 polymorphisms are associated with various cancers, and CTLA-4 mRNA/protein increased expression is found in several tumor types. However, most of the studies are based on peripheral blood mononuclear cells, and much less is known about the relationship between CTLA-4 expression, especially gene expression, and its polymorphic variants in cancer tissue. In our study we assessed the distribution of CTLA-4 two polymorphisms (+49A/G and −318C/T), using TaqMan probes (rs231775 and rs5742909, resp.), and CTLA-4 gene expression in real-time PCR assay in non-small-cell lung cancer (NSCLC) tissue samples. The increased CTLA-4 expression was observed in the majority of NSCLC patients, and it was significantly correlated with TT genotype (−318C/T) and with tumor size (T2 versus T3 + T4). The presence of G allele and GG genotype in cancer tissue (+49A/G) was significantly associated with the increased NSCLC risk. Additionally, we compared genotype distributions in the corresponding tumor and blood samples and found statistically significant differences. The shift from one genotype in the blood to another in the tumor may confirm the complexity of gene functionality in cancer tissue. Adam Antczak, Dorota Pastuszak-Lewandoska, Paweł Górski, Daria Domańska, Monika Migdalska-Sęk, Karolina Czarnecka, Ewa Nawrot, Jacek Kordiak, and Ewa Brzeziańska Copyright © 2013 Adam Antczak et al. All rights reserved. Interleukin-33 Drives Activation of Alveolar Macrophages and Airway Inflammation in a Mouse Model of Acute Exacerbation of Chronic Asthma Mon, 08 Jul 2013 13:48:15 +0000 http://www.hindawi.com/journals/bmri/2013/250938/ We investigated the role of interleukin-33 (IL-33) in airway inflammation in an experimental model of an acute exacerbation of chronic asthma, which reproduces many of the features of the human disease. Systemically sensitized female BALB/c mice were challenged with a low mass concentration of aerosolized ovalbumin for 4 weeks to induce chronic asthmatic inflammation and then received a single moderate-level challenge to trigger acute airway inflammation simulating an asthmatic exacerbation. The inflammatory response and expression of cytokines and activation markers by alveolar macrophages (AM) were assessed, as was the effect of pretreatment with a neutralizing antibody to IL-33. Compared to chronically challenged mice, AM from an acute exacerbation exhibited significantly enhanced expression of markers of alternative activation, together with enhanced expression of proinflammatory cytokines and of cell surface proteins associated with antigen presentation. In parallel, there was markedly increased expression of both mRNA and immunoreactivity for IL-33 in the airways. Neutralization of IL-33 significantly decreased both airway inflammation and the expression of proinflammatory cytokines by AM. Collectively, these data indicate that in this model of an acute exacerbation of chronic asthma, IL-33 drives activation of AM and has an important role in the pathogenesis of airway inflammation. Melissa M. Bunting, Alexander M. Shadie, Rylie P. Flesher, Valentina Nikiforova, Linda Garthwaite, Nicodemus Tedla, Cristan Herbert, and Rakesh K. Kumar Copyright © 2013 Melissa M. Bunting et al. All rights reserved. Supplementation with Natural Forms of Vitamin E Augments Antigen-Specific TH1-Type Immune Response to Tetanus Toxoid Sun, 07 Jul 2013 15:07:01 +0000 http://www.hindawi.com/journals/bmri/2013/782067/ This study compared the ability of three forms of vitamin E [tocotrienol-rich fraction (TRF), alpha-tocopherol (-T), and delta-tocotrienol (-T3)] to enhance immune response to tetanus toxoid (TT) immunisation in a mouse model. Twenty BALB/c mice were divided into four groups of five mice each. The mice were fed with the different forms of vitamin E (1 mg) or vehicle daily for two weeks before they were given the TT vaccine [4 Lf] intramuscularly (i.m.). Booster vaccinations were given on days 28 and 42. Serum was collected (days 0, 28, and 56) to quantify anti-TT levels. At autopsy, splenocytes harvested were cultured with TT or mitogens. The production of anti-TT antibodies was augmented () in mice that were fed with -T3 or TRF compared to controls. The production of IFN- and IL-4 by splenocytes from the vitamin E treated mice was significantly () higher than that from controls. The IFN- production was the highest in animals supplemented with -T3 followed by TRF and finally -T. Production of TNF- was suppressed in the vitamin E treated group compared to vehicle-supplemented controls. Supplementation with -T3 or TRF can enhance immune response to TT immunisation and production of cytokines that promote cell-mediated (TH1) immune response. Ammu Kutty Radhakrishnan, Dashayini Mahalingam, Kanga Rani Selvaduray, and Kalanithi Nesaretnam Copyright © 2013 Ammu Kutty Radhakrishnan et al. All rights reserved. Natural Killer Dendritic Cells Enhance Immune Responses Elicited by α-Galactosylceramide-Stimulated Natural Killer T Cells Wed, 26 Jun 2013 17:42:44 +0000 http://www.hindawi.com/journals/bmri/2013/460706/ Natural killer dendritic cells (NKDCs) possess potent anti-tumor activity, but the cellular effect of NKDC interactions with other innate immune cells is unclear. In this study, we demonstrate that the interaction of NKDCs and natural killer T (NKT) cells is required for the anti-tumor immune responses that are elicited by α-galactosylceramide (α-GC) in mice. The rapid and strong expression of interferon-γ by NKDCs after α-GC stimulation was dependent on NKT cells. Various NK and DC molecular markers and cytotoxic molecules were up-regulated following α-GC administration. This up-regulation could improve NKDC presentation of tumor antigens and increase cytotoxicity against tumor cells. NKDCs were required for the stimulation of DCs, NK cells, and NKT cells. The strong anti-tumor immune responses elicited by α-GC may be due to the down-regulation of regulatory T cells. Furthermore, the depletion of NKDCs dampened the tumor clearance mediated by α-GC-stimulated NKT cells in vivo. Taken together, these results indicate that complex interactions of innate immune cells might be required to achieve optimal anti-tumor immune responses during the early stages of tumorigenesis. Sung Won Lee, Hyun Jung Park, Nayoung Kim, and Seokmann Hong Copyright © 2013 Sung Won Lee et al. All rights reserved. Update on Anticytokine Treatment for Asthma Tue, 18 Jun 2013 13:54:27 +0000 http://www.hindawi.com/journals/bmri/2013/104315/ Current advances in the knowledge of asthma pathobiology suggest that anticytokine therapies can be potentially useful for the treatment of this complex and heterogeneous airway disease. Recent evidence is accumulating in support of the efficacy of anti-IL-4, anti-IL-5, and anti-IL-13 drugs. Therefore, these new developments are now changing the global scenario of antiasthma therapies, especially with regard to more severe disease. Current findings referring to variability of individual therapeutic responses highlight that the different asthma subtypes need to be well characterized, in order to implement phenotype-targeted treatments which in the near future will hopefully be mainly based on cytokine-directed biologics. Luca Gallelli, Maria Teresa Busceti, Alessandro Vatrella, Rosario Maselli, and Girolamo Pelaia Copyright © 2013 Luca Gallelli et al. All rights reserved. Effect of Ex Vivo Culture Conditions on Immunosuppression by Human Mesenchymal Stem Cells Tue, 04 Jun 2013 09:01:01 +0000 http://www.hindawi.com/journals/bmri/2013/154919/ A microarray analysis was performed to investigate whether ex vivo culture conditions affect the characteristics of MSCs. Gene expression profiles were mainly influenced by the level of cell confluence rather than initial seeding density. The analysis showed that 276 genes were upregulated and 230 genes downregulated in MSCs harvested at ). The genes that were highly expressed in MSCs largely corresponded to chemotaxis, inflammation, and immune responses, indicating direct or indirect involvement in immunomodulatory functions. Specifically, PTGES and ULBP1 were up-regulated in MSCs harvested at high density. Treatment of MSCs with PTGES or ULBP1 siRNA reversed their inhibition of T-cell proliferation in vitro. The culture conditions such as cell confluence at harvest seem to be important for gene expression profile of MSCs; therefore, the results of this study may provide useful guidelines for the harvest of MSCs that can appropriately suppress the immune response. Myoung Woo Lee, Dae Seong Kim, Somi Ryu, In Keun Jang, Hye Jin Kim, Jin Mo Yang, Doo-Hoon Lee, Soo Hyun Lee, Meong Hi Son, Hee Won Cheuh, Hye Lim Jung, Keon Hee Yoo, Ki Woong Sung, and Hong Hoe Koo Copyright © 2013 Myoung Woo Lee et al. All rights reserved. Heat Shock Proteins: Stimulators of Innate and Acquired Immunity Sat, 25 May 2013 13:35:01 +0000 http://www.hindawi.com/journals/bmri/2013/461230/ Adjuvants were reintroduced into modern immunology as the dirty little secret of immunologists by Janeway and thus began the molecular definition of innate immunity. It is now clear that the binding of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) on antigen presenting cells (APCs) activates the innate immune response and provides the host with a rapid mechanism for detecting infection by pathogens and initiates adaptive immunity. Ironically, in addition to advancing the basic science of immunology, Janeway’s revelation on induction of the adaptive system has also spurred an era of rational vaccine design that exploits PRRs. Thus, defined PAMPs that bind to known PRRs are being specifically coupled to antigens to improve their immunogenicity. However, while PAMPs efficiently activate the innate immune response, they do not mediate the capture of antigen that is required to elicit the specific responses of the acquired immune system. Heat shock proteins (HSPs) are molecular chaperones that are found complexed to client polypeptides and have been studied as potential cancer vaccines. In addition to binding PRRs and activating the innate immune response, HSPs have been shown to both induce the maturation of APCs and provide chaperoned polypeptides for specific triggering of the acquired immune response. Camilo A. Colaco, Christopher R. Bailey, K. Barry Walker, and James Keeble Copyright © 2013 Camilo A. Colaco et al. All rights reserved. Malaria Vaccine Adjuvants: Latest Update and Challenges in Preclinical and Clinical Research Tue, 23 Apr 2013 10:17:39 +0000 http://www.hindawi.com/journals/bmri/2013/282913/ There is no malaria vaccine currently available, and the most advanced candidate has recently reported a modest 30% efficacy against clinical malaria. Although many efforts have been dedicated to achieve this goal, the research was mainly directed to identify antigenic targets. Nevertheless, the latest progresses on understanding how immune system works and the data recovered from vaccination studies have conferred to the vaccine formulation its deserved relevance. Additionally to the antigen nature, the manner in which it is presented (delivery adjuvants) as well as the immunostimulatory effect of the formulation components (immunostimulants) modulates the immune response elicited. Protective immunity against malaria requires the induction of humoral, antibody-dependent cellular inhibition (ADCI) and effector and memory cell responses. This review summarizes the status of adjuvants that have been or are being employed in the malaria vaccine development, focusing on the pharmaceutical and immunological aspects, as well as on their immunization outcomings at clinical and preclinical stages. Elena Mata, Aiala Salvador, Manoli Igartua, Rosa María Hernández, and José Luis Pedraz Copyright © 2013 Elena Mata et al. All rights reserved. 1,25-Dihydroxyvitamin D3 Inhibits the RANKL Pathway and Impacts on the Production of Pathway-Associated Cytokines in Early Rheumatoid Arthritis Mon, 22 Apr 2013 11:20:57 +0000 http://www.hindawi.com/journals/bmri/2013/101805/ Objectives. To study effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on RANKL signaling pathway and pathway-associated cytokines in patients with rheumatoid arthritis (RA). Methods. Receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), IFN-γ, IL-6, TNF-α, IL-17, and IL-4 were examined in 54 patients with incipient RA using a cytometric bead array (CBA) or an enzyme-linked immunosorbent assay (ELISA). Results. After 72 hours of incubation of peripheral blood mononuclear cells (PBMCs) with 1,25(OH)2D3 in RA patients, the levels of RANKL, TNF-α, IL-17 and IL-6 significantly decreased compared to those of the control. 1,25(OH)2D3 had no significantly impact on the levels of OPG, RANKL/OPG, and IL-4. Conclusions. The present study demonstrated that 1,25(OH)2D3 reduced the production of RANKL and the secretion of TNF-α, IL-17, and IL-6 in PBMCs of RA patients, which indicated that 1,25(OH)2D3 might be able to decrease damage of cartilage and bone in RA patients by regulating the expression of RANKL signaling pathway and pathway-associated cytokines. Jing Luo, Hongyan Wen, Hui Guo, Qi Cai, Shuangtian Li, and Xiaofeng Li Copyright © 2013 Jing Luo et al. All rights reserved. Role of M2 Muscarinic Receptor in the Airway Response to Methacholine of Mice Selected for Minimal or Maximal Acute Inflammatory Response Thu, 18 Apr 2013 14:05:56 +0000 http://www.hindawi.com/journals/bmri/2013/805627/ Airway smooth muscle constriction induced by cholinergic agonists such as methacholine (MCh), which is typically increased in asthmatic patients, is regulated mainly by muscle muscarinic M3 receptors and negatively by vagal muscarinic M2 receptors. Here we evaluated basal (intrinsic) and allergen-induced (extrinsic) airway responses to MCh. We used two mouse lines selected to respond maximally (AIRmax) or minimally (AIRmin) to innate inflammatory stimuli. We found that in basal condition AIRmin mice responded more vigorously to MCh than AIRmax. Treatment with a specific M2 antagonist increased airway response of AIRmax but not of AIRmin mice. The expression of M2 receptors in the lung was significantly lower in AIRmin compared to AIRmax animals. AIRmax mice developed a more intense allergic inflammation than AIRmin, and both allergic mouse lines increased airway responses to MCh. However, gallamine treatment of allergic groups did not affect the responses to MCh. Our results confirm that low or dysfunctional M2 receptor activity is associated with increased airway responsiveness to MCh and that this trait was inherited during the selective breeding of AIRmin mice and was acquired by AIRmax mice during allergic lung inflammation. Juciane Maria de Andrade Castro, Rodrigo R. Resende, Luciana Mirotti, Esther Florsheim, Layra Lucy Albuquerque, Adriana Lino-dos-Santos-Franco, Eliane Gomes, Wothan Tavares de Lima, Marcelo de Franco, Orlando Garcia Ribeiro, and Momtchilo Russo Copyright © 2013 Juciane Maria de Andrade Castro et al. All rights reserved. The Role of E3 Ubiquitin Ligase Cbl Proteins in Interleukin-2-Induced Jurkat T-Cell Activation Wed, 27 Mar 2013 08:29:31 +0000 http://www.hindawi.com/journals/bmri/2013/430861/ Interleukin- (IL-) 2 is the major growth factor for T-cell activation and proliferation. IL-2 has multiple functions in the regulation of immunological processes. Although most studies focus on T-cell immunomodulation, T-cell activation by IL-2 is the foundation of priming the feedback loop. Here, we investigated the effect of MAPK/ERK and PI3K/Akt signaling pathways on IL-2-induced cell activation and the regulatory mechanisms of upstream ubiquitin ligase Cbl-b and c-Cbl. Morphological analysis of Jurkat T cells was performed by cytospin preparations with Wright-Giemsa stain. CD25 expression on Jurkat T cells was determined by flow cytometry. Changes in cell activation proteins such as p-ERK, ERK, p-Akt, Akt, and ubiquitin ligase Casitas B-cell Lymphoma (Cbl) proteins were analyzed by western blot. Following IL-2-induced activation of Jurkat T cells, p-ERK expression was upregulated, while there was no change in p-Akt, ERK, or Akt expression. Thus, the MAPK/ERK signaling pathway, but not PI3K/Akt, was involved in IL-2-induced T-cell activation. Either using PD98059 (a specific inhibitor for p-ERK) or depletion of ERK with small interfering RNA (siRNA) reduced the expression of CD25. This study also showed that ubiquitin ligase proteins Cbl-b and c-Cbl might be involved in IL-2-induced Jurkat T-cell activation by negatively regulating the MAPK/ERK signaling pathway. Ming-Fang Zhao, Xiu-Juan Qu, Jing-Lei Qu, You-Hong Jiang, Ye Zhang, Ke-Zuo Hou, Hao Deng, and Yun-Peng Liu Copyright © 2013 Ming-Fang Zhao et al. All rights reserved. CpG ODN and ISCOMATRIX Adjuvant: A Synergistic Adjuvant Combination Inducing Strong T-Cell IFN- Responses Sat, 23 Mar 2013 13:07:55 +0000 http://www.hindawi.com/journals/bmri/2013/636847/ For the induction of robust humoral and cellular immune responses, a strong rationale exists to use vaccine-adjuvant combinations possessing both immune modulatory and enhanced delivery capabilities. Herein, we evaluated the combination of 2 different adjuvants, a TLR9 agonist, composed of synthetic oligodeoxynucleotides (ODN) containing immunostimulatory CpG motifs (CpG), and ISCOMATRIX adjuvant (ISCOMATRIX), composed of saponin, phospholipid, and cholesterol, which possesses both immunostimulatory and delivery properties. While both individual adjuvants have been shown effective in numerous preclinical and clinical studies, it is likely that for optimal adjuvant activity a combined adjuvant approach will be necessary. Herein, using three different antigens, namely, hepatitis B surface antigen (HBsAg), ovalbumin (OVA), and influenza A haemagglutinin antigen (HA), we show in mice that some adjuvant effects of CpG and ISCOMATRIX are further enhanced if they are used in combination. In particular, with all three antigens, IFN- levels were greatly increased with the CpG/ISCOMATRIX combination. The ability of the CpG/ISCOMATRIX combination to induce antitumor responses when administered with OVA following administration to mice of a highly metastatic OVA-secreting tumor cell line (B16-OVA melanoma) was also demonstrated. Thus the CpG/ISCOMATRIX combination may prove to be a valuable tool in the development of novel or improved vaccines. Michael J. McCluskie, Risini D. Weeratna, Dana M. Evans, Shawn Makinen, Debbie Drane, and Heather L. Davis Copyright © 2013 Michael J. McCluskie et al. All rights reserved. Inflammation and Immunity in Radiation Damage to the Gut Mucosa Tue, 19 Mar 2013 08:17:24 +0000 http://www.hindawi.com/journals/bmri/2013/123241/ Erythema was observed on the skin of the first patients treated with radiation therapy. It is in particular to reduce this erythema, one feature of tissue inflammation, that prescribed dose to the tumor site started to be fractionated. It is now well known that radiation exposure of normal tissues generates a sustained and apparently uncontrolled inflammatory process. Radiation-induced inflammation is always observed, often described, sometimes partly explained, but still today far from being completely understood. The thing with the gut and especially the gut mucosa is that it is at the frontier between the external milieu and the organism, is in contact with a plethora of commensal and foreign antigens, possesses a dense-associated lymphoid tissue, and is particularly radiation sensitive because of a high mucosal turnover rate. All these characteristics make the gut mucosa a strong responsive organ in terms of radiation-induced immunoinflammation. This paper will focus on what has been observed in the normal gut and what remains to be done concerning the immunoinflammatory response following localized radiation exposure. Agnès François, Fabien Milliat, Olivier Guipaud, and Marc Benderitter Copyright © 2013 Agnès François et al. All rights reserved. CXCR1/CXCR2 Antagonism Is Effective in Pulmonary Defense against Klebsiella pneumoniae Infection Mon, 18 Mar 2013 09:07:07 +0000 http://www.hindawi.com/journals/bmri/2013/720975/ Klebsiella pneumoniae-associated pathology is largely mediated by neutrophilic inflammation. In this study, we administered Klebsiella pneumoniae to experimental guinea pig groups and the ELR-CXC chemokine antagonist , ceftazidime, and dexamethasone to different groups, respectively. After 24 h, we assessed the animal’s pulmonary inflammatory levels, including gross histopathology, airway neutrophilia, lung myeloperoxidase levels, expressions of CXCL8 and TNF, and airway bacterial loads. Compared with ceftazidime and dexamethasone treatments, the administration of the ELR-CXC chemokine antagonist alone was more effective than other methods, although it did not markedly attenuate the bacterial load. These results suggest new methods for the treatment of Klebsiella pneumoniae pathology. Jing Wei, Jing Peng, Bing Wang, Hong Qu, Shiyi Wang, Aziz Faisal, Jia-Wei Cheng, John R. Gordon, and Fang Li Copyright © 2013 Jing Wei et al. All rights reserved. Increasing Hematopoietic Stem Cell Yield to Develop Mice with Human Immune Systems Thu, 14 Feb 2013 09:02:41 +0000 http://www.hindawi.com/journals/bmri/2013/740892/ Hematopoietic stem cells (HSCs) are unique in their capacity to give rise to all mature cells of the immune system. For years, HSC transplantation has been used for treatment of genetic and neoplastic diseases of the hematopoietic and immune systems. The sourcing of HSCs from human umbilical cord blood has salient advantages over isolation from mobilized peripheral blood. However, poor sample yield has prompted development of methodologies to expand HSCs ex vivo. Cytokines, trophic factors, and small molecules have been variously used to promote survival and proliferation of HSCs in culture, whilst strategies to lower the concentration of inhibitors in the culture media have recently been applied to promote HSC expansion. In this paper, we outline strategies to expand HSCs in vitro, and to improve engraftment and reconstitution of human immune systems in immunocompromised mice. To the extent that these “humanized” mice are representative of the endogenous human immune system, they will be invaluable tools for both basic science and translational medicine. Juan-Carlos Biancotti and Terrence Town Copyright © 2013 Juan-Carlos Biancotti and Terrence Town. All rights reserved. Chronic Stress Induces Structural Alterations in Splenic Lymphoid Tissue That Are Associated with Changes in Corticosterone Levels in Wistar-Kyoto Rats Sun, 10 Feb 2013 08:35:50 +0000 http://www.hindawi.com/journals/bmri/2013/868742/ Major depressive disorder patients present chronic stress and decreased immunity. The Wistar-Kyoto rat (WKY) is a strain in which the hypothalamic-pituitary-adrenal axis is overactivated. To determine whether chronic stress induces changes in corticosterone levels and splenic lymphoid tissue, 9-week-old male rats were subject to restraint stress (3 h daily), chemical stress (hydrocortisone treatment, 50 mg/Kg weight), mixed stress (restraint plus hydrocortisone), or control treatment (without stress) for 1, 4, and 7 weeks. The serum corticosterone levels by RIA and spleens morphology were analyzed. Corticosterone levels as did the structure, size of the follicles and morphology of the parenchyma (increase in red pulp) in the spleen, varied depending on time and type of stressor. These changes indicate that chronic stress alters the immune response in the spleen in WKY rats by inducing morphological changes, explaining in part the impaired immunity that develops in organisms that are exposed to chronic stress. María Eugenia Hernandez, Lucia Martinez-Mota, Citlaltepetl Salinas, Ricardo Marquez-Velasco, Nancy G. Hernandez-Chan, Jorge Morales-Montor, Mayra Pérez-Tapia, María L. Streber, Ivonne Granados-Camacho, Enrique Becerril, Baquera-Heredia Javier, and Lenin Pavón Copyright © 2013 María Eugenia Hernandez et al. All rights reserved. Cytotoxic T Lymphocytes and Vaccine Development 2013 Mon, 04 Feb 2013 15:11:17 +0000 http://www.hindawi.com/journals/bmri/2013/865314/ Zhengguo Xiao, Kim Klonowski, Hanchun Yang, and Julie Curtsinger Copyright © 2013 Zhengguo Xiao et al. All rights reserved. Clinical Use and Mechanisms of Infliximab Treatment on Inflammatory Bowel Disease: A Recent Update Mon, 21 Jan 2013 14:42:08 +0000 http://www.hindawi.com/journals/bmri/2013/581631/ The pathogenesis and treatment of inflammatory bowel disease (IBD) have been recently advanced, while it is still challenged with high morbidity and poor prognosis. Infliximab, a monoclonal antibody of tumor necrosis factor (TNF), has emerged as an efficient treatment with many clinical benefits such as quick disease activity reduction and IBD patient life quality improvement. However, the biological effects of infliximab on IBD need to be elucidated. This paper reviewed the clinical use and recently advanced biological action of infliximab on IBD. By forming the stable complex with the soluble or the membrane form of TNF in fluid environment or on cell surface of immune cell, fibroblast, endothelium, and epithelium, infliximab quenches TNF activity and performs the important biological actions which lead to amelioration and remission of immune responses. The mechanisms of infliximab treatment for IBD were intensively discussed. The recent advances on two topics including predictors and side effects of infliximab treatment were also reviewed. Yuan Guo, Nonghua Lu, and Aiping Bai Copyright © 2013 Yuan Guo et al. All rights reserved. Anti-Inflammatory and Antiapoptotic Responses to Infection: A Common Denominator of Human and Bovine Macrophages Infected with Mycobacterium avium Subsp. paratuberculosis Sun, 20 Jan 2013 07:40:49 +0000 http://www.hindawi.com/journals/bmri/2013/908348/ Mycobacterium avium subsp. paratuberculosis (Map) is the causative agent of a chronic intestinal inflammation in ruminants named Johne's disease or paratuberculosis and a possible etiopathological agent of human Crohn's disease (CD). Analysis of macrophage transcriptomes in response to Map infection is expected to provide key missing information in the understanding of the role of this pathogen in establishing an inappropriate and persistent infection in a susceptible host and of the molecular mechanisms that might underlie the early phases of CD. In this paper we summarize transcriptomic studies of human and bovine peripheral blood mononuclear cells (PBMC), monocyte-derived macrophages (MDMs), and macrophages-like cell lines in vitro infected with Map. Most studies included in this paper consistently reported common gene expression signatures of bovine and human macrophages in response to Map such as enhanced expression of the anti-inflammatory cytokines IL-10 and IL-6, which promote bacterial survival. Overexpression of IL-10 could be responsible for the Map-associated reduction in the expression of the proapoptotic TNF-α gene observed in bovine and human macrophages. Naiara Abendaño, Ramon A. Juste, and Marta Alonso-Hearn Copyright © 2013 Naiara Abendaño et al. All rights reserved. Characterization of CD8+ T-Cell Responses in the Peripheral Blood and Skin Injection Sites of Melanoma Patients Treated with mRNA Electroporated Autologous Dendritic Cells (TriMixDC-MEL) Thu, 03 Jan 2013 10:37:43 +0000 http://www.hindawi.com/journals/bmri/2013/976383/ Treatment of melanoma patients with mRNA electroporated dendritic cells (TriMixDC-MEL) stimulates T-cell responses against the presented tumor-associated antigens (TAAs). In the current clinical trials, melanoma patients with systemic metastases are treated, requiring priming and/or expansion of preexisting TAA-specific T cells that are able to migrate to both the skin and internal organs. We monitored the presence of TAA-specific CD8+ T cells infiltrating the skin at sites of intradermal TriMixDC-MEL injection (SKILs) and within the circulation of melanoma patients treated in two clinical trials. In 10 out of fourteen (71%) patients screened, CD8+ T cells recognizing any of the four TAA presented by TriMixDC-MEL cellular vaccine were found in both compartments. In total, 30 TAA-specific T-cell responses were detected among the SKILs and 29 among peripheral blood T cells, of which 24 in common. A detailed characterization of the antigen specificity of CD8+ T-cell populations in four patients indicates that the majority of the epitopes detected were only recognized by CD8+ T cells derived from either skin biopsies or peripheral blood, indicating that some compartmentalization occurs after TriMix-DC therapy. To conclude, functional TAA-specific CD8+ T cells distribute both to the skin and peripheral blood of patients after TriMixDC-MEL therapy. Daphné Benteyn, An M. T. Van Nuffel, Sofie Wilgenhof, Jurgen Corthals, Carlo Heirman, Bart Neyns, Kris Thielemans, and Aude Bonehill Copyright © 2013 Daphné Benteyn et al. All rights reserved. IL-6 Production by Dendritic Cells Is Dispensable for CD8+ Memory T-Cell Generation Sun, 30 Dec 2012 18:03:22 +0000 http://www.hindawi.com/journals/bmri/2013/126189/ Following activation, naïve CD8+ T cells will differentiate into effectors that differ in their ability to survive: some will persist as memory cells while the majority will die by apoptosis. Signals given by antigen-presenting cells (APCs) at the time of priming modulate this differential outcome. We have recently shown that, in opposition to dendritic cell (DC), CD40-activated B-(CD40-B) cell vaccination fails to efficiently produce CD8+ memory T cells. Understanding why CD40-B-cell vaccination does not lead to the generation of functional long-lived memory cells is essential to define the signals that should be provided to naïve T cells by APCs. Here we show that CD40-B cells produce very low amount of IL-6 when compared to DCs. However, supplementation with IL-6 during CD40-B-cell vaccination did not improve memory generation. Furthermore, IL-6-deficient DCs maintained the capacity to promote the formation of functional CD8+ effectors and memory cells. Our results suggest that in APC vaccination models, IL-6 provided by the APCs is dispensable for proper CD8+ T-cell memory generation. Jean-François Daudelin, Mélissa Mathieu, Salix Boulet, and Nathalie Labrecque Copyright © 2013 Jean-François Daudelin et al. All rights reserved. Regulation of Tight Junctions in Upper Airway Epithelium Sat, 29 Dec 2012 11:40:13 +0000 http://www.hindawi.com/journals/bmri/2013/947072/ The mucosal barrier of the upper respiratory tract including the nasal cavity, which is the first site of exposure to inhaled antigens, plays an important role in host defense in terms of innate immunity and is regulated in large part by tight junctions of epithelial cells. Tight junction molecules are expressed in both M cells and dendritic cells as well as epithelial cells of upper airway. Various antigens are sampled, transported, and released to lymphocytes through the cells in nasal mucosa while they maintain the integrity of the barrier. Expression of tight junction molecules and the barrier function in normal human nasal epithelial cells (HNECs) are affected by various stimuli including growth factor, TLR ligand, and cytokine. In addition, epithelial-derived thymic stromal lymphopoietin (TSLP), which is a master switch for allergic inflammatory diseases including allergic rhinitis, enhances the barrier function together with an increase of tight junction molecules in HNECs. Furthermore, respiratory syncytial virus infection in HNECs in vitro induces expression of tight junction molecules and the barrier function together with proinflammatory cytokine release. This paper summarizes the recent progress in our understanding of the regulation of tight junctions in the upper airway epithelium under normal, allergic, and RSV-infected conditions. Takashi Kojima, Mitsuru Go, Ken-ichi Takano, Makoto Kurose, Tsuyoshi Ohkuni, Jun-ichi Koizumi, Ryuta Kamekura, Noriko Ogasawara, Tomoyuki Masaki, Jun Fuchimoto, Kazufumi Obata, Satoshi Hirakawa, Kazuaki Nomura, Takashi Keira, Ryou Miyata, Nobuhiro Fujii, Hiroyuki Tsutsumi, Tetsuo Himi, and Norimasa Sawada Copyright © 2013 Takashi Kojima et al. All rights reserved. Increased Toll-Like Receptor Signaling Pathways Characterize CD8+ Cells in Rapidly Progressive SIV Infection Thu, 27 Dec 2012 13:39:31 +0000 http://www.hindawi.com/journals/bmri/2013/796014/ Similar to HIV infection in humans, SIV infection in macaques induces progressive loss of immune cell components and function, resulting in immune deficiency in nearly all untreated infected subjects. In SIV-infected macaques, 25% of animals develop terminal AIDS within 6 months of infection. The factors responsible for the development of such rapid progression are unknown. We have previously found that defects in CD8+ T cells detectable from early infection correlate to rapid progression to simian AIDS. The transcriptional screening of molecular fingerprints on different steps along the activation/effector process of splenic CD8+ cells at termination revealed a distinction in rapid compared to regular progressors, which was characterized by a decrease in classic T cell receptor (TCR) components, and an increase in Toll-like receptor (TLR) and apoptotic pathways. A TLR pathway screening in lymphoid and myeloid cells from both the spleen and from the central nervous system of infected macaques revealed that the upregulation of TLR is not in the innate immune compartment, but rather in lymphoid cells that contain adaptive immune cells. Our findings suggest that opposing effects of TCR specific signaling and TLR engagement may drive the CD8 phenotypic failure that determines a rapid disease course in HIV infection. Maria Cecilia Garibaldi Marcondes, Celsa Spina, Eduardo Bustamante, and Howard Fox Copyright © 2013 Maria Cecilia Garibaldi Marcondes et al. All rights reserved. Preparation, Characterization, and Determination of Immunological Activities of Transfer Factor Specific to Human Sperm Antigen Thu, 27 Dec 2012 13:33:03 +0000 http://www.hindawi.com/journals/bmri/2013/126923/ Objective. The objective of this study was to prepare, characterize, and determine immunological activities of specific transfer factor (STF) specific to human sperm antigen (HSA) for the preparation of antisperm contraceptive vaccine that can be used as an immunocontraceptive. Methods. HSA-STF was prepared using the spleens of rabbits vaccinated with HSA. The specific immunological activities were examined by lymphocyte proliferation test (LPT), leukocyte adhesion inhibition test (LAIT), and by determining the concentrations of IL-4, γ-IFN, and IL-21. HSA-STF was a helveolous substance, having a pH value of and UV absorption maxima at  nm. It contained seventeen amino acids; glycine and glutamic acids were the highest in terms of concentrations (38.8 μg/mL and 36.3 μg/mL, resp.). Results. The concentration of polypeptide was  mg/mL, and ribose was  mg/mL. The stimulation index for lymphocyte proliferation test was 1.84, and the leukocyte adhesion inhibition rate was 37.7%. There was a statistically significant difference between the cultural lymphocytes with HSA-STF and non-HSA-STF for γ-IFN and IL-21 (), but there was no statistical significance for IL-4 (). Conclusion. HSA-STF was prepared and characterized successfully. It had immunological activity which could transfer the immune response specific to HSA and prove to be a potential candidate for the development of male immunocontraceptive agents. Jianwei Zhou, Cui Kong, Zhaohong Yuan, Junmin Luo, Rui Ma, Jiang Yu, and Jinghe Cao Copyright © 2013 Jianwei Zhou et al. All rights reserved. What Is Recent in Pancreatic Cancer Immunotherapy? Wed, 26 Dec 2012 14:18:50 +0000 http://www.hindawi.com/journals/bmri/2013/492372/ Pancreatic cancer (PC) represents an unresolved therapeutic challenge, due to the poor prognosis and the reduced response to currently available treatments. Pancreatic cancer is the most lethal type of digestive cancers, with a median survival of 4–6 months. Only a small proportion of PC patients is curative by surgical resection, whilst standard chemotherapy for patients in advanced disease generates only modest effects with considerable toxic damages. Thus, new therapeutic approaches, specially specific treatments such as immunotherapy, are needed. In this paper we analyze recent preclinical and clinical efforts towards immunotherapy of pancreatic cancer, including passive and active immunotherapy approaches, designed to target pancreatic-cancer-associated antigens and to elicit an antitumor response in vivo. Elena Niccolai, Domenico Prisco, Mario Milco D'Elios, and Amedeo Amedei Copyright © 2013 Elena Niccolai et al. All rights reserved. MUC1-Specific Cytotoxic T Lymphocytes in Cancer Therapy: Induction and Challenge Wed, 26 Dec 2012 14:00:50 +0000 http://www.hindawi.com/journals/bmri/2013/871936/ MUC1 glycoprotein is often found overexpressed and hypoglycosylated in tumor cells from numerous cancer types. Since its discovery MUC1 has been an attractive target for antitumor immunotherapy. Indeed, in vitro and in vivo experiments have shown T-cell-specific responses against MUC1 in an HLA-restricted and HLA-unrestricted manner, although some animal models have highlighted the possible development of tolerogenic responses against this antigen. These observations permit the development of new T-cell vaccine strategies capable of inducing an MUC1-specific cytotoxic T cell response in cancer patients. Some of these strategies are now being tested in clinical trials against different types of cancer. To date, encouraging clinical responses have been observed with some MUC1 vaccines in phase II/III clinical trials. This paper compiles knowledge regarding MUC1 as a promising tumor antigen for antitumor therapeutic vaccines applicable to numerous cancers. We also summarize the results of MUC1-vaccine-based clinical trials. David Roulois, Marc Grégoire, and Jean-François Fonteneau Copyright © 2013 David Roulois et al. All rights reserved. Conformation-Dependent High-Affinity Potent Ricin-Neutralizing Monoclonal Antibodies Wed, 26 Dec 2012 09:21:43 +0000 http://www.hindawi.com/journals/bmri/2013/471346/ Ricin is a potential biothreat agent with no approved antidote available for ricin poisoning. The aim of this study was to develop potent antibody-based antiricin antidotes. Four strong ricin resistant hybridoma clones secreting antiricin monoclonal antibodies (mAbs) were developed. All four mAbs are bound to conformational epitopes of ricin toxin B (RTB) with high affinity ( values from 2.55 to 36.27 nM). RTB not only triggers cellular uptake of ricin, but also facilitates transport of the ricin toxin A (RTA) from the endoplasmic reticulum to the cytosol, where RTA exerts its toxic activity. The four mAbs were found to have potent ricin-neutralizing capacities and synergistic effects among them as determined by an in vitro neutralization assay. In vivo protection assay demonstrated that all four mAbs had strong efficacy against ricin challenges. D9 was found to be exceptionally effective. Intraperitoneal (i.p.) administration of D9, at a dose of 5 μg, 6 weeks before or 6 hours after an i.p. challenge with 5 × LD50 of ricin was able to protect or rescue 100% of the mice, indicating that mAb D9 is an excellent candidate to be developed as a potent antidote against ricin poisoning for both prophylactic and therapeutic purposes. Wei-Gang Hu, Junfei Yin, Damon Chau, Charles Chen Hu, Dustin Lillico, Justin Yu, Laurel M. Negrych, and John W. Cherwonogrodzky Copyright © 2013 Wei-Gang Hu et al. All rights reserved. Effects of Sodium Octanoate on Innate Immune Response of Mammary Epithelial Cells during Staphylococcus aureus Internalization Mon, 24 Dec 2012 08:09:04 +0000 http://www.hindawi.com/journals/bmri/2013/927643/ Bovine mammary epithelial cells (bMECs) are capable of initiating an innate immune response to invading bacteria. Short chain fatty acids can reduce Staphylococcus aureus internalization into bMEC, but it has not been evaluated if octanoic acid (sodium octanoate, NaO), a medium chain fatty acid (MCFA), has similar effects. In this study we determined the effect of NaO on S. aureus internalization into bMEC and on the modulation of innate immune elements. NaO (0.25–2 mM) did not affect S. aureus growth and bMEC viability, but it differentially modulated bacterial internalization into bMEC, which was induced at 0.25–0.5 mM (~60%) but inhibited at 1-2 mM (~40%). Also, bMEC showed a basal expression of all the innate immune genes evaluated, which were induced by S. aureus. NaO induced BNBD4, LAP, and BNBD10 mRNA expression, but BNBD5 and TNF-α were inhibited. Additionally, the pretreatment of bMEC with NaO inhibited the mRNA expression induction generated by bacteria which coincides with the increase in internalization; only TAP and BNDB10 showed an increase in their expression; it coincides with the greatest effect on the reduction of bacterial internalization. In conclusion, NaO exerts a dual effect on S. aureus internalization in bMEC and modulates elements of innate immune response. Nayeli Alva-Murillo, Alejandra Ochoa-Zarzosa, and Joel E. López-Meza Copyright © 2013 Nayeli Alva-Murillo et al. All rights reserved. CpG and Interleukin-15 Synergize to Enhance IFN-γ Production by Activated CD8+ T Cells Sun, 23 Dec 2012 16:10:52 +0000 http://www.hindawi.com/journals/bmri/2013/924023/ Interleukin-15 (IL-15) regulates the development and maintenance of memory CD8+ T cells. Paradoxically, we previously reported that IL-15 could enhance CD8+ T-cell responses to IL-12, a proinflammatory cytokine required for optimal priming of effector CD8+ T cells. To expand the physiological relevance of these findings, we tested IL-15 for its ability to enhance T-cell responses to bacterial CpG. Expectedly, CpG enhanced the production of IFN- by CD8+ T cells polyclonally activated with anti-CD3. However, addition of IL-15 to CpG-stimulated cultures led to a striking increase in IFN- production. The effect of CpG and IL-15 was also evident with CD8+ T cells recovered from mice infected with the parasite Trypanosoma cruzi (T. cruzi) and restimulated with antigen. The observed synergy between CpG and IL-15 occurred in an IL-12-dependent manner, and this effect could even be demonstrated in cocultures of activated CD8+ T cells and CD4+CD25+ regulatory T cells. Although IFN- was not essential for CpG-induced IL-12, the ability of CpG and IL-15 to act on CD8+ T cells required expression of the IFN--inducible transcription factor T-bet. These data have important implications for development of vaccines and design of therapies to boost CD8+ T-cell responses to infectious agents and tumors. Dustin Cobb, Siqi Guo, and Ronald B. Smeltz Copyright © 2013 Dustin Cobb et al. All rights reserved. Innate Immunity Modulation by the IL-33/ST2 System in Intestinal Mucosa Tue, 04 Dec 2012 16:26:00 +0000 http://www.hindawi.com/journals/bmri/2013/142492/ Innate immunity prevents pathogens from entering and spreading within the body. This function is especially important in the gastrointestinal tract and skin, as these organs have a large surface contact area with the outside environment. In the intestine, luminal commensal bacteria are necessary for adequate food digestion and play a crucial role in tolerance to benign antigens. Immune system damage can create an intestinal inflammatory response, leading to chronic disease including inflammatory bowel diseases (IBD). Ulcerative colitis (UC) is an IBD of unknown etiology with increasing worldwide prevalence. In the intestinal mucosa of UC patients, there is an imbalance in the IL-33/ST2 axis, an important modulator of the innate immune response. This paper reviews the role of the IL-33/ST2 system in innate immunity of the intestinal mucosa and its importance in inflammatory bowel diseases, especially ulcerative colitis. Marina García-Miguel, M. Julieta González, Rodrigo Quera, and Marcela A. Hermoso Copyright © 2013 Marina García-Miguel et al. All rights reserved. Improved Binding Activity of Antibodies against Major Histocompatibility Complex Class I Chain-Related Gene A by Phage Display Technology for Cancer-Targeted Therapy Wed, 21 Nov 2012 08:25:22 +0000 http://www.hindawi.com/journals/bmri/2012/597647/ Major histocompatibility complex class I chain-related gene A (MICA) is an NKG2D ligand that is over-expressed under cellular stress including cancer transformation and viral infection. High expression of MICA in cancer tissues or patients' sera is useful for prognostic or follow-up markers in cancer patients. In this study, phage display technology was employed to improve antigen-binding activities of anti-MICA monoclonal antibodies (WW2G8, WW6B7, and WW9B8). The 12 amino acid residues in the complementarity determining regions (CDRs) on the V domain of the heavy chain CDR3 (HCDR3) of these anti-MICA antibodies were modified by PCR-random mutagenesis, and phages displaying mutated anti-MICA Fab were constructed. After seven rounds of panning, five clones of phages displaying mutant anti-MICA Fab which exhibited 3–7-folds higher antigen-binding activities were isolated. Two clones of the mutants (phage-displayed mutant Fab WW9B8.1 and phage-displayed mutant Fab WW9B8.21) were confirmed to have antigen-binding specificity for cell surface MICA proteins by flow cytometry. These phage clones are able to recognize MICA in a native form according to positive results obtained by indirect ELISA and flow cytometry. Thus, these phage particles could be potentially used for further development of nanomedicine specifically targeting cancer cells expressing MICA proteins. Achara Phumyen, Amonrat Jumnainsong, and Chanvit Leelayuwat Copyright © 2012 Achara Phumyen et al. All rights reserved. NK Cells in Healthy Aging and Age-Associated Diseases Tue, 20 Nov 2012 07:32:01 +0000 http://www.hindawi.com/journals/bmri/2012/195956/ NK cells exhibit the highest cytotoxic capacity within the immune system. Alteration of their number or functionality may have a deep impact on overall immunity. This is of particular relevance in aging where the elderly population becomes more susceptible to infection, cancer, autoimmune diseases, and neurodegenerative diseases amongst others. As the fraction of elderly increases worldwide, it becomes urgent to better understand the aging of the immune system to prevent and cure the elderly population. For this, a better understanding of the function and phenotype of the different immune cells and their subsets is necessary. We review here NK cell functions and phenotype in healthy aging as well as in various age-associated diseases. Xavier Camous, Alejandra Pera, Rafael Solana, and Anis Larbi Copyright © 2012 Xavier Camous et al. All rights reserved. Natural Killer Cell Regulation by MicroRNAs in Health and Disease Mon, 19 Nov 2012 17:03:45 +0000 http://www.hindawi.com/journals/bmri/2012/632329/ Natural killer (NK) cells are innate immune lymphocytes that are critical for normal host defense against infections and mediate antitumor immune responses. MicroRNAs (miRNAs) are a family of small, noncoding RNAs that posttranscriptionally regulate the majority of cellular processes and pathways. Our understanding of how miRNAs regulate NK cells biology is limited, but recent studies have provided novel insight into their expression by NK cells, and how they contribute to the regulation of NK cell development, maturation, survival, and effector function. Here, we review the expression of miRNAs by NK cells, their contribution to cell intrinsic and extrinsic control of NK cell development and effector response, and their dysregulation in NK cell malignancies. Jeffrey W. Leong, Ryan P. Sullivan, and Todd A. Fehniger Copyright © 2012 Jeffrey W. Leong et al. All rights reserved. Comprehensive Evaluation of Different T-Helper Cell Subsets Differentiation and Function in Rheumatoid Arthritis Wed, 03 Oct 2012 09:57:27 +0000 http://www.hindawi.com/journals/bmri/2012/535361/ Rheumatoid arthritis (RA) is the most common autoimmune disorder. Loss of Th1/Th2 and Th17/Treg balance has been reported in several inflammatory autoimmune diseases. This study was to investigate Th1, Th2, Th17, and Treg differentiation and related cytokines in RA patients. The frequencies of Th1, Th2, Th17, and Treg cells in peripheral blood of RA patients (𝑛=76) and healthy controls (𝑛=18) were determined by flow cytometry. Eight serum cytokines were analyzed using cytometric bead array. The results demonstrated that RA patients exhibited increased peripheral Th1/Th17 cells and Th1/Th17-related cytokines. However, Th1 cells only reached significant difference at advanced stage, but Th17 at all stages, suggesting more important roles in Th17 cells. For Th2 and Treg cells, there was a different function pattern in RA progression. Although with the increase of DAS28 score, Th2 cell experienced some degree of decrease in RA patients, no significant difference was observed. IL-4 and IL-10 showed a significant increase in RA patients. These indicated that Th2 cells might exert immunosuppression effects mainly by secreting cytokines. Treg cells were found significantly decreased in RA patients, but no difference was observed in TGF-β expression, indicating a cell-cell interaction pattern in Treg cell. Junwei Chen, Junxia Li, Huiying Gao, Caihong Wang, Jing Luo, Zhiqin Lv, and Xiaofeng Li Copyright © 2012 Junwei Chen et al. All rights reserved. Frequency of TLR 2, 4, and 9 Gene Polymorphisms in Chinese Population and Their Susceptibility to Type 2 Diabetes and Coronary Artery Disease Wed, 03 Oct 2012 08:10:31 +0000 http://www.hindawi.com/journals/bmri/2012/373945/ Toll-like receptors (TLRs) are pivotal components of the innate immune response. Activation of the innate immune system and subsequent chronic low-grade inflammation are thought to be involved in the pathogenesis of atherosclerosis and type 2 diabetes. In the study, we genotyped TLRs gene polymorphisms, including TLR2 Arg677Trp and Arg753Gln, TLR4 Asp299Gly and Thr399Ile, TLR9-1486T/C and -1237T/C. The frequencies of TT, TC and CC genotype of TLR9-1486T/C mutation were 39.6%, 45.8% and 14.6%, respectively; the frequencies of T allele and C allele were 62.5% and 37.5%. However, neither of these parameters was statistically significant among study groups. In addition, we were surprised to find that the commonly reported TLR SNPs in the Western countries, like TLR2 Arg677Trp or Arg753Gln, TLR4 Asp299Gly or Thr399Ile and TLR9-1237T/C, were not polymorphic at all in all study subjects. In conclusion, our data suggests that TLR2 Arg677Trp or Arg753Gln, TLR4 Asp299Gly or Thr399Ile and TLR9-1237T/C polymorphisms have low frequency and TLR9-1486T/C polymorphism may not be a suitable marker in predicting the susceptibility to type 2 diabetes or coronary artery disease in the Chinese Han population. Fengjing Liu, Weixin Lu, Qiaohui Qian, Weigang Qi, Jifan Hu, and Bo Feng Copyright © 2012 Fengjing Liu et al. All rights reserved. Strategies for Enhancing Vaccine-Induced CTL Antitumor Immune Responses Tue, 02 Oct 2012 14:26:11 +0000 http://www.hindawi.com/journals/bmri/2012/605045/ Vaccine-induced cytotoxic T lymphocytes (CTLs) play a critical role in adaptive immunity against cancers. An important goal of current vaccine research is to induce durable and long-lasting functional CTLs that can mediate cytotoxic effects on tumor cells. To attain this goal, there are four distinct steps that must be achieved. To initiate a vaccine-induced CTL antitumor immune response, dendritic cells (DCs) must capture antigens derived from exogenous tumor vaccines in vivo or autologous DCs directly loaded in vitro with tumor antigens must be injected. Next, tumor-antigen-loaded DCs must activate CTLs in lymphoid organs. Subsequently, activated CTLs must enter the tumor microenvironment to perform their functions, at which point a variety of negative regulatory signals suppress the immune response. Finally, CTL-mediated cytotoxic effects must overcome the tolerance induced by tumor cells. Each step is a complex process that may be impeded in many ways. However, if these steps happen under appropriate regulation, the vaccine-induced CTL antitumor immune response will be more successful. For this reason, we should gain a better understanding of the basic mechanisms that govern the immune response. This paper, based on the steps necessary to induce an immune response, discusses current strategies for enhancing vaccine-induced CTL antitumor immune responses. Xin Yong, Yü-Feng Xiao, Gang Luo, Bin He, Mu-Han Lü, Chang-Jiang Hu, Hong Guo, and Shi-Ming Yang Copyright © 2012 Xin Yong et al. All rights reserved. Identification of HLA-A24-Restricted Novel T Cell Epitope Peptides Derived from P-Cadherin and Kinesin Family Member 20A Tue, 19 Jun 2012 17:18:14 +0000 http://www.hindawi.com/journals/bmri/2012/848042/ We here identified human leukocyte antigen-(HLA-)A∗2402-restricted epitope peptides from Cadherin 3, type 1, P-cadherin (CDH3) and kinesin family member 20A (KIF20A) that were found to be specifically expressed in cancer cells through genome-wide expression profile analysis. CDH3-10-807 peptide and KIF20A-10-66 peptide successfully induced specific CTL clones, and these selectively responded to COS7 cells expressing both HLA-A∗2402 and respective protein while did not respond to parental cells or COS7 cells expressing either HLA-A∗2402 or respective protein. Furthermore, CTL clones responded to cancer cells that endogenously express HLA-A∗2402 and respective protein, suggesting that CDH3-10-807 peptide and KIF20A-10-66 peptide are naturally presented on HLA-A∗2402 molecule of human cancer cells. Our results demonstrated that CDH3-10-807 peptide and KIF20A-10-66 peptide are novel HLA-A24-restricted tumor-associated antigens and would be applicable for CTL-inducing cancer therapies. Ryuji Osawa, Takuya Tsunoda, Sachiko Yoshimura, Tomohisa Watanabe, Motoki Miyazawa, Masaji Tani, Kazuyoshi Takeda, Hidewaki Nakagawa, Yusuke Nakamura, and Hiroki Yamaue Copyright © 2012 Ryuji Osawa et al. All rights reserved. Ustekinumab in Psoriasis Immunopathology with Emphasis on the Th17-IL23 Axis: A Primer Tue, 12 Jun 2012 08:19:27 +0000 http://www.hindawi.com/journals/bmri/2012/147413/ Psoriasis is a chronic relapsing immunoinflammatory dermatosis that is commonly associated with systemic comorbidities. The pathogenic importance of interleukin (IL)-12 and IL-23 is beyond doubt, as well as the involvement of T helper cells (Th)1 and Th17 cells. There is upregulation of the p40 subunit shared by IL-12 and IL-23 and of the IL-23 p19 subunit, but not an increased expression of the IL-12 p35 subunit. This indicates that IL-23 appears more involved than IL-12 in the pathogenesis of psoriatic plaques. Ustekinumab is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 class targeting the p40 subunit common to both IL-12 and IL-23, thus inhibiting both IL-12 and IL-23 receptor-mediated signalling. Ustekinumab is part of the recent biologic therapies active in psoriasis, autoimmune arthritides, and inflammatory bowel diseases. Pascale Quatresooz, Trinh Hermanns-Lê, Gérald E. Piérard, Philippe Humbert, Philippe Delvenne, and Claudine Piérard-Franchimont Copyright © 2012 Pascale Quatresooz et al. All rights reserved. Assessment of the Immune Responses Induced in Cattle after Inoculation of a Mycobacterium bovis Strain Deleted in Two mce2 Genes Tue, 05 Jun 2012 11:12:05 +0000 http://www.hindawi.com/journals/bmri/2012/258353/ The generation of efficient candidate vaccines against bovine tuberculosis will contribute to the control of this zoonotic disease. Rationally attenuated Mycobacterium bovis strains generated by knockout of virulence genes are promising candidate vaccines. However, to be effective, these candidate vaccines should at least maintain the immunological properties of their virulent parental M. bovis strains. Therefore, the aim of this study was to obtain an M. bovis strain deleted in the mce2 genes and evaluate the effect of the mutation on the immunological profile elicited by the bacteria in cattle. We showed that the activation of CD4+ T cells in cattle inoculated with the mutant strain was equivalent to that in animals inoculated with the parental strain. Moreover, after in vitro stimulation, peripheral blood mononuclear cells from animals inoculated with the mutant produced higher levels of mRNA Th-1 cytokines than the parental strain. Therefore, these results indicate that the mce2 mutant is a promising candidate vaccine against bovine tuberculosis. Federico Carlos Blanco, Marcelo Soria, María José Gravisaco, María Verónica Bianco, Virginia Meikle, Sergio Garbaccio, Lucas Vagnoni, Angel Adrián Cataldi, and Fabiana Bigi Copyright © 2012 Federico Carlos Blanco et al. All rights reserved. Attenuated Salmonella typhimurium SV4089 as a Potential Carrier of Oral DNA Vaccine in Chickens Mon, 04 Jun 2012 14:34:49 +0000 http://www.hindawi.com/journals/bmri/2012/264986/ Attenuated Salmonella has been used as a carrier for DNA vaccine. However, in vitro and in vivo studies on the bacteria following transfection of plasmid DNA were poorly studied. In this paper, eukaryotic expression plasmids encoding avian influenza virus (AIV) subtype H5N1 genes, pcDNA3.1/HA, NA, and NP, were transfected into an attenuated Salmonella enteric typhimurium SV4089. In vitro stability of the transfected plasmids into Salmonella were over 90% after 100 generations. The attenuated Salmonella were able to invade MCF-7 (1.2%) and MCF-10A (0.5%) human breast cancer cells. Newly hatched specific-pathogen-free (SPF) chicks were inoculated once by oral gavage with 109 colony-forming unit (CFU) of the attenuated Salmonella. No abnormal clinical signs or deaths were recorded after inoculation. Viable bacteria were detected 3 days after inoculation by plating from spleen, liver, and cecum. Fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR) were carried out for confirmation. Salmonella was not detected in blood cultures although serum antibody immune responses to Salmonella O antiserum group D1 factor 1, 9, and 12 antigens were observed in all the inoculated chickens after 7 days up to 35 days. Our results showed that live attenuated S. typhimurium SV4089 harboring pcDNA3.1/HA, NA, and NP may provide a unique alternative as a carrier for DNA oral vaccine in chickens. Seyed Davoud Jazayeri, Aini Ideris, Zunita Zakaria, and Abdul Rahman Omar Copyright © 2012 Seyed Davoud Jazayeri et al. All rights reserved. Expression of GA733-Fc Fusion Protein as a Vaccine Candidate for Colorectal Cancer in Transgenic Plants Wed, 23 May 2012 10:45:51 +0000 http://www.hindawi.com/journals/bmri/2012/364240/ The tumor-associated antigen GA733 is a cell-surface glycoprotein highly expressed in colorectal carcinomas. In this study, 3 recombinant genes were constructed as follows: GA733 tagged to the ER retention sequence KDEL (GA733K), GA733 fused to the immunoglobulin Fc fragment (GA733-Fc), and GA733-Fc fused to the ER retention sequence (GA733-FcK). Agrobacterium-mediated transformation was used to generate transgenic plants expressing recombinant genes. The presence of transgenes was confirmed by genomic PCR. Western blot, confocal immunofluorescence, and sandwich ELISA showed the expression of recombinant proteins. The stability, flexibility, and bioactivity of recombinant proteins were analyzed and demonstrated through N-glycosylation analysis, animal trials, and sera ELISA. Our results suggest that the KDEL retained proteins in ER with oligomannose glycan structure and enhanced protein accumulation level. The sera of mice immunized with GA733-FcK purified from plants contained immunoglobulins which were at least as efficient as the mammalian-derived GA733-Fc at recognizing human colorectal cancer cell lines. Thus, a plant system can be used to express the KDEL fusion protein with oligomannose glycosylation, and this protein induces an immune response which is comparable to non-KDEL-tagged, mammalian-derived proteins. Zhe Lu, Kyung-Jin Lee, Yingxue Shao, Jeong-Hwan Lee, Yangkang So, Young-Kug Choo, Doo-Byoung Oh, Kyung-A Hwang, Seung Han Oh, Yeon Soo Han, and Kisung Ko Copyright © 2012 Zhe Lu et al. All rights reserved. Multiple Signaling Pathways Are Involved in the Interleukine-4 Regulated Expression of DC-SIGN in THP-1 Cell Line Thu, 17 May 2012 08:37:52 +0000 http://www.hindawi.com/journals/bmri/2012/357060/ Dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) is an important pattern recognition receptor on dendritic cells (DCs), and its expression shows significant cytological and histological specificity, being interleukine-4 (IL-4) dependent. The signaling pathways through which IL-4 regulates expression of DC-SIGN are still unclear. We used phorbol 12-myristate 13-acetate- (PMA-) differentiated THP-1 cells as the in vitro model of monocyte/macrophage cells to study the signaling pathways involved in IL-4-regulated expression of DC-SIGN. We found that a high expression of DC-SIGN could be induced by IL-4 at the levels of mRNA and cell surface protein. Upregulated expression of DC-SIGN was almost completely blocked by the specific inhibitor of ERK pathway, and partly reduced by the specific inhibitors of JAK-STAT and NF-κB pathways. The activation of the three signaling pathways was directly confirmed by testing the phosphorylation of protein kinase within the cytoplasm and nucleus over time. The analysis of cis-acting elements of DC-SIGN promoter showed that the activity of DC-SIGN promoter without Ets-1 transcription factors binding site almost completely disappeared. Our results demonstrated that multiple signaling pathways are involved in IL-4 induced high expression of DC-SIGN on THP-1 cells, in which ERK pathway is the main signaling pathway and mediated by the Ets-1 transcription factors binding site. Changzhong Jin, Lijuan Wu, Jie Li, Meixin Fang, Linfang Cheng, and Nanping Wu Copyright © 2012 Changzhong Jin et al. All rights reserved. Role of Cytokines in Systemic Lupus Erythematosus: Recent Progress from GWAS and Sequencing Thu, 10 May 2012 15:15:48 +0000 http://www.hindawi.com/journals/bmri/2012/798924/ Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, known to have a strong genetic component. Concordance between monozygotic twins is approximately 30–40%, which is 8–20 times higher than that of dizygotic twins. In the last decade, genome-wide approaches to understanding SLE have yielded many candidate genes, which are important to understanding the pathophysiology of the disease and potential targets for pharmaceutical intervention. In this paper, we focus on the role of cytokines and examine how genome-wide association studies, copy number variation studies, and next-generation sequencing are being employed to understand the etiology of SLE. Prominent genes identified by these approaches include BLK, FCγR3B, and TREX1. Our goal is to present a brief overview of genomic approaches to SLE and to introduce some of the key discussion points pertinent to the field. John J. Connolly and Hakon Hakonarson Copyright © 2012 John J. Connolly and Hakon Hakonarson. All rights reserved. Cytotoxic T Lymphocytes and Vaccine Development 2011 Sun, 06 May 2012 14:28:45 +0000 http://www.hindawi.com/journals/bmri/2011/756864/ Zhengguo Xiao, Kim Klonowski, Hanchun Yang, and Julie Curtsinger Copyright © 2011 Zhengguo Xiao et al. All rights reserved. Vaxjo: A Web-Based Vaccine Adjuvant Database and Its Application for Analysis of Vaccine Adjuvants and Their Uses in Vaccine Development Tue, 13 Mar 2012 14:20:04 +0000 http://www.hindawi.com/journals/bmri/2012/831486/ Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO) in the Web Ontology Language (OWL) format. Samantha Sayers, Guerlain Ulysse, Zuoshuang Xiang, and Yongqun He Copyright © 2012 Samantha Sayers et al. All rights reserved. Effects of Reactive Nitrogen Scavengers on NK-Cell-Mediated Killing of K562 Cells Mon, 12 Mar 2012 09:20:53 +0000 http://www.hindawi.com/journals/bmri/2012/101737/ This study explored the effects of reactive nitrogen metabolites (RNMS) on natural-killer- (NK-) cell-mediated killing of K562 cells and the influence of RNM scavengers, such as tiopronin (TIP), glutamylcysteinylglycine (GSH), and histamine dihydrochloride (DHT), on reversing the suppressing effect of RNM. We administered exogenous and endogenous RNM in the NK + K562 culture system and then added RNM scavengers. The concentrations of RNM, TNF-β and IFN-γ, and NK-cell cytotoxicity (NCC) and the percentage of living NK cells were then examined. We found that both exogenous and endogenous RNM caused the KIR to decrease (𝑃<0.01); however, RNM scavengers such as TIP and GSH rescued this phenomenon dose dependently. In conclusion, our data suggests that RNM scavengers such as TIP and GSH enhance the antineoplasmic activity of NK cells. Yili Zeng, Qinmiao Huang, Meizhu Zheng, Jianxin Guo, and Jingxin Pan Copyright © 2012 Yili Zeng et al. All rights reserved. Cytokines in Systemic Lupus Erythematosus 2011 Sun, 11 Mar 2012 16:08:08 +0000 http://www.hindawi.com/journals/bmri/2012/427824/ Brian D. Poole, Timothy B. Niewold, and George C. Tsokos Copyright © 2012 Brian D. Poole et al. All rights reserved. Effects of IRF5 Lupus Risk Haplotype on Pathways Predicted to Influence B Cell Functions Wed, 22 Feb 2012 09:52:06 +0000 http://www.hindawi.com/journals/bmri/2012/594056/ Both genetic and environmental interactions affect systemic lupus erythematosus (SLE) development and pathogenesis. One known genetic factor associated with lupus is a haplotype of the interferon regulatory factor 5 (IRF5) gene. Analysis of global gene expression microarray data using gene set enrichment analysis identified multiple interferon- and inflammation-related gene sets significantly overrepresented in cells with the risk haplotype. Pathway analysis using expressed genes from the significant gene sets impacted by the IRF5 risk haplotype confirmed significant correlation with the interferon pathway, Toll-like receptor pathway, and the B-cell receptor pathway. SLE patients with the IRF5 risk haplotype have a heightened interferon signature, even in an unstimulated state (𝑃=0.011), while patients with the IRF5 protective haplotype have a B cell interferon signature similar to that of controls. These results identify multiple genes in functionally significant pathways which are affected by IRF5 genotype. They also establish the IRF5 risk haplotype as a key determinant of not only the interferon response, but also other B-cell pathways involved in SLE. Joel M. Guthridge, Daniel N. Clark, Amanda Templeton, Nicolas Dominguez, Rufei Lu, Gabriel S. Vidal, Jennifer A. Kelly, Kenneth M. Kauffman, John B. Harley, Patrick M. Gaffney, Judith A. James, and Brian D. Poole Copyright © 2012 Joel M. Guthridge et al. All rights reserved. The Immunogenicity of the Tumor-Associated Antigen α-Fetoprotein Is Enhanced by a Fusion with a Transmembrane Domain Tue, 21 Feb 2012 10:49:13 +0000 http://www.hindawi.com/journals/bmri/2012/878657/ Aim. To investigate the ability of recombinant modified vaccinia virus Ankara (rMVA) vector to induce an immune response against a well-tolerated self-antigen. Methods. rMVA vectors expressing different form of α-fetoprotein (AFP) were produced and characterized. Naïve mice were vaccinated with MVA vectors expressing the AFP antigen in either a secreted, or a membrane-bound, or an intracellular form. The immune response was monitored by an IFNΓ ELISpot assay and antibody detection. Results. Vaccination with the membrane-associated form of AFP induced a stronger CD8+ T-cell response compared to the ones obtained with the MVA encoding the secreted or the intracellular forms of AFP. Moreover, the vaccination with the membrane-bound AFP elicited the production of AFP-specific antibodies. Conclusions. The AFP transmembrane form is more immunogenic. Expressing a membrane-bound form in the context of an MVA vaccination could enhance the immunogenicity of a self-antigen. Lucile Tran, Jean-Paul Judor, Vanessa Gauttier, Michel Geist, Chantal Hoffman, Ronald Rooke, Georges Vassaux, and Sophie Conchon Copyright © 2012 Lucile Tran et al. All rights reserved. Urinary Neutrophil Gelatinase-Associated Lipocalin Is a Potential Biomarker for Renal Damage in Patients with Systemic Lupus Erythematosus Wed, 15 Feb 2012 10:51:49 +0000 http://www.hindawi.com/journals/bmri/2012/759313/ Neutrophil gelatinase-associated lipocalin (NGAL) has been demonstrated to be a novel biomarker in acute and chronic kidney disease. We hypothesized that 24-hour urinary NGAL excretion may be a predictor for renal damage in patients with systemic lupus erythematosus (SLE). Thirty-four SLE patients with renal involvement (SLE-renal group), 8 SLE patients without renal involvement (SLE-nonrenal group), 14 patients with non-SLE autoimmune diseases (disease control or DC group), and 12 healthy volunteers (normal control or NC group) were compared for 24-hour urinary excretion of NGAL and different cytokines. We found that the 24-hour urinary NGAL excretion in the SLE-renal group was higher than that in the SLE-non-renal, DC, and NC groups. However, the excretion of interleukin-10, transforming growth factor-𝛽1, and tumor necrosis factor-𝛼 was not different between the SLE-renal and SLE-non-renal groups. Furthermore, NGAL excretion in the SLE-renal group was correlated with serum creatinine levels and creatinine clearance, but not with the SLE Disease Activity Index score. Multivariate logistic regression analysis and receiver operating characteristic curve analysis revealed that 24-hour urinary NGAL excretion is a potential biomarker for renal damage in SLE patients, with higher sensitivity and specificity than anti-dsDNA antibody titers. Chun-Chen Yang, Song-Chou Hsieh, Ko-Jen Li, Cheng-Han Wu, Ming-Chi Lu, Chang-Youh Tsai, and Chia-Li Yu Copyright © 2012 Chun-Chen Yang et al. All rights reserved. Roles of Pro- and Anti-Inflammatory Cytokines in the Pathogenesis of SLE Wed, 15 Feb 2012 10:46:03 +0000 http://www.hindawi.com/journals/bmri/2012/347141/ SLE is an autoimmune inflammatory disease in which various pro- and anti-inflammatory cytokines, including TGF-β, IL-10, BAFF, IL-6, IFN-α, IFN-γ, IL-17, and IL-23, play crucial pathogenic roles. Virtually, all these cytokines can be generated by both innate and adaptive immune cells and exert different effects depending on specific local microenvironment. They can also interact with each other, forming a complex network to maintain delicate immune homeostasis. In this paper, we elaborate on the abnormal secretion and functions of these cytokines in SLE, analyze their potential pathogenic roles, and probe into the possibility of them being utilized as targets for therapy. Ding-Lei Su, Zhi-Min Lu, Min-Ning Shen, Xia Li, and Ling-Yun Sun Copyright © 2012 Ding-Lei Su et al. All rights reserved. Targeting Costimulatory Molecules to Improve Antitumor Immunity Sun, 12 Feb 2012 11:40:32 +0000 http://www.hindawi.com/journals/bmri/2012/926321/ The full activation of T cells necessitates the concomitant activation of two signals, the engagement of T-cell receptor by peptide/major histocompatibility complex II and an additional signal delivered by costimulatory molecules. The best characterized costimulatory molecules belong to B7/CD28 and TNF/TNFR families and play crucial roles in the modulation of immune response and improvement of antitumor immunity. Unfortunately, tumors often generate an immunosuppressive microenvironment, where T-cell response is attenuated by the lack of costimulatory molecules on the surface of cancer cells. Thus, targeting costimulatory pathways represent an attractive therapeutic strategy to enhance the antitumor immunity in several human cancers. Here, latest therapeutic approaches targeting costimulatory molecules will be described. Daria Capece, Daniela Verzella, Mariafausta Fischietti, Francesca Zazzeroni, and Edoardo Alesse Copyright © 2012 Daria Capece et al. All rights reserved. Neisseria gonorrhoeae Pilus Attenuates Cytokine Response of Human Fallopian Tube Explants Tue, 24 Jan 2012 14:33:55 +0000 http://www.hindawi.com/journals/bmri/2012/491298/ Background. A role for pilus during attachment of Neisseria gonorrhoeae to epithelia of the female reproductive tract is currently assumed. However, Pil− gonococci have been observed during infection of the reproductive tract, which prompted us to examine the effect of pili on the dynamics of infection and the inflammatory responses of mucosal explants of the human Fallopian tube. Methods. Mucosal explants were infected in vitro with Opa negative Pil− and Pil+N. gonorrhoeae strains. Results. Piliation enhanced gonococcal adherence to the epithelium within 3 h of infection (𝑃<0.05) but thereafter did not offer advantage to gonococci to colonize the epithelial cell surface (𝑃>0.05). No differences were found between the strains in numbers of gonococci inside epithelial cells. Pil− bacteria induced higher levels (𝑃<0.05) of IL-1β, TNF-α, GM-CSF, MCP-1, and MIP-1β than Pil+ bacteria. There were no differences between both strains in LOS pattern, and Pil expression did not change after coincubation with mucosal strips. Conclusions. Results show that gonococcal invasion of the human Fallopian tube can occur independently of pilus or Opa expression, and suggest that pilus, by inhibition of several key elements of the initial inflammatory response, facilitates sustained infection of this organ. Luis Velasquez, Katherine García, Francisco Morales, John E. Heckels, Pedro Orihuela, Paula I. Rodas, Myron Christodoulides, and Hugo Cardenas Copyright © 2012 Luis Velasquez et al. All rights reserved. Protective Role of Cytotoxic T Lymphocytes in Filovirus Hemorrhagic Fever Wed, 28 Dec 2011 10:59:57 +0000 http://www.hindawi.com/journals/bmri/2011/984241/ Infection with many emerging viruses, such as the hemorrhagic fever disease caused by the filoviruses, Marburg (MARV), and Ebola virus (EBOV), leaves the host with a short timeframe in which to mouse a protective immune response. In lethal cases, uncontrolled viral replication and virus-induced immune dysregulation are too severe to overcome, and mortality is generally associated with a lack of notable immune responses. Vaccination studies in animals have demonstrated an association of IgG and neutralizing antibody responses against the protective glycoprotein antigen with survival from lethal challenge. More recently, studies in animal models of filovirus hemorrhagic fever have established that induction of a strong filovirus-specific cytotoxic T lymphocyte (CTL) response can facilitate complete viral clearance. In this review, we describe assays used to discover CTL responses after vaccination or live filovirus infection in both animal models and human clinical trials. Unfortunately, little data regarding CTL responses have been collected from infected human survivors, primarily due to the low frequency of disease and the inability to perform these studies in the field. Advancements in assays and technologies may allow these studies to occur during future outbreaks. Kelly Lyn Warfield and Gene Garrard Olinger Copyright © 2011 Kelly Lyn Warfield and Gene Garrard Olinger. All rights reserved. Novel Immunotherapeutic Strategies of Gastric Cancer Treatment Tue, 27 Dec 2011 14:03:32 +0000 http://www.hindawi.com/journals/bmri/2011/437348/ Gastric cancer (GC) is the fourth most common cancer and the second most frequent cause of cancer-related deaths, accounting for 10.4% of cancer deaths worldwide. Despite the improvements, estimated cure rates for patients with advanced stages remain poor, and in the metastatic setting, chemotherapy is the mainstay of palliative therapy and results in objective response rates (ORRs) of only 20–40% and median overall survivals (OS) of 8–10 months. Therefore, many investigators believe that the potential for making significant progress lies in understanding and exploiting the molecular biology of these tumors to investigate new therapeutic strategies to combat GC, such as specific immunotherapy. In this paper, we analyze the different approaches used for immune-based (especially dendritic and T cells) therapies to gastric cancer treatment and discuss the results obtained in preclinical models as in clinical trials. Amedeo Amedei, Marisa Benagiano, Chiara della Bella, Elena Niccolai, and Mario M. D'Elios Copyright © 2012 Amedeo Amedei et al. All rights reserved. Regulatory T-Cell-Associated Cytokines in Systemic Lupus Erythematosus Sun, 18 Dec 2011 14:04:52 +0000 http://www.hindawi.com/journals/bmri/2011/463412/ Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production, complement activation, and immune complex deposition, resulting in tissue and organ damage. An understanding of the mechanisms responsible for homeostatic control of inflammation, which involve both innate and adoptive immune responses, will enable the development of novel therapies for SLE. Regulatory T cells (Treg) play critical roles in the induction of peripheral tolerance to self- and foreign antigens. Naturally occurring CD4+CD25+ Treg, which characteristically express the transcription factor forkhead box protein P3 (Foxp3), have been intensively studied because their deficiency abrogates self-tolerance and causes autoimmune disease. Moreover, regulatory cytokines such as interleukin-10 (IL-10) also play a central role in controlling inflammatory processes. This paper focuses on Tregs and Treg-associated cytokines which might regulate the pathogenesis of SLE and, hence, have clinical applications. Akiko Okamoto, Keishi Fujio, Tomohisa Okamura, and Kazuhiko Yamamoto Copyright © 2011 Akiko Okamoto et al. All rights reserved. A Rapid Culture Technique Produces Functional Dendritic-Like Cells from Human Acute Myeloid Leukemia Cell Lines Mon, 05 Dec 2011 11:08:07 +0000 http://www.hindawi.com/journals/bmri/2011/172965/ Most anti-cancer immunotherapeutic strategies involving dendritic cells (DC) as vaccines rely upon the adoptive transfer of DC loaded with exogenous tumour-peptides. This study utilized human acute myeloid leukemia (AML) cells as progenitors from which functional dendritic-like antigen presenting cells (DLC) were generated, that constitutively express tumour antigens for recognition by CD8+ T cells. DLC were generated from AML cell lines KG-1 and MUTZ-3 using rapid culture techniques and appropriate cytokines. DLC were evaluated for their cell-surface phenotype, antigen uptake and ability to stimulate allogeneic responder cell proliferation, and production of IFN-γ; compared with DC derived from normal human PBMC donors. KG-1 and MUTZ-3 DLC increased expression of CD80, CD83, CD86, and HLA-DR, and MUTZ-3 DLC downregulated CD14 and expressed CD1a. Importantly, both KG-1 and MUTZ-3-derived DLC promoted proliferation of allogeneic responder cells more efficiently than unmodified cells; neither cells incorporated FITC-labeled dextran, but both stimulated IFN-γ production from responding allogeneic CD8+ T cells. Control DC produced from PBMC using the FastDC culture also expressed high levels of critical cell surface ligands and demonstrated good APC function. This paper indicates that functional DLC can be cultured from the AML cell lines KG-1 and MUTZ-3, and FastDC culture generates functional KG-1 DLC. Jian Ning, David Morgan, and Derwood Pamphilon Copyright © 2011 Jian Ning et al. All rights reserved. Cytotoxic CD4 T Cells in Antiviral Immunity Tue, 22 Nov 2011 09:41:47 +0000 http://www.hindawi.com/journals/bmri/2011/954602/ CD4 T cells that acquire cytotoxic phenotype and function have been repeatedly identified in humans, mice, and other species in response to many diverse pathogens. Since CD4 cytotoxic T cells are able to recognize antigenic determinants unique from those recognized by the parallel CD8 cytotoxic T cells, they can potentially contribute additional immune surveillance and direct effector function by lysing infected or malignant cells. Here, we briefly review much of what is known about the generation of cytotoxic CD4 T cells and describe our current understanding of their role in antiviral immunity. Furthering our understanding of the many roles of CD4 T cells during an anti-viral response is important for developing effective vaccine strategies that promote long-lasting protective immunity. Nikki B. Marshall and Susan L. Swain Copyright © 2011 Nikki B. Marshall and Susan L. Swain. All rights reserved. Activation of Type I Interferon Pathway in Systemic Lupus Erythematosus: Association with Distinct Clinical Phenotypes Wed, 16 Nov 2011 13:33:21 +0000 http://www.hindawi.com/journals/bmri/2011/273907/ Growing evidence over the last few years suggests a central role of type I IFN pathway in the pathogenesis of systemic autoimmune disorders. Data from clinical and genetic studies in patients with systemic lupus erythematosus (SLE) and lupus-prone mouse models, indicates that the type I interferon system may play a pivotal role in the pathogenesis of several lupus and associated clinical features, such as nephritis, neuropsychiatric and cutaneous lupus, premature atherosclerosis as well as lupus-specific autoantibodies particularly against ribonucleoproteins. In the current paper, our aim is to summarize the latest findings supporting the association of type I IFN pathway with specific clinical manifestations in the setting of SLE providing insights on the potential use of type I IFN as a therapeutic target. Theophanis P. Karageorgas, Dimitrios D. Tseronis, and Clio P. Mavragani Copyright © 2011 Theophanis P. Karageorgas et al. All rights reserved. Tumor Evasion from T Cell Surveillance Tue, 15 Nov 2011 15:55:10 +0000 http://www.hindawi.com/journals/bmri/2011/918471/ An intact immune system is essential to prevent the development and progression of neoplastic cells in a process termed immune surveillance. During this process the innate and the adaptive immune systems closely cooperate and especially T cells play an important role to detect and eliminate tumor cells. Due to the mechanism of central tolerance the frequency of T cells displaying appropriate arranged tumor-peptide-specific-T-cell receptors is very low and their activation by professional antigen-presenting cells, such as dendritic cells, is frequently hampered by insufficient costimulation resulting in peripheral tolerance. In addition, inhibitory immune circuits can impair an efficient antitumoral response of reactive T cells. It also has been demonstrated that large tumor burden can promote a state of immunosuppression that in turn can facilitate neoplastic progression. Moreover, tumor cells, which mostly are genetically instable, can gain rescue mechanisms which further impair immune surveillance by T cells. Herein, we summarize the data on how tumor cells evade T-cell immune surveillance with the focus on solid tumors and describe approaches to improve anticancer capacity of T cells. Katrin Töpfer, Stefanie Kempe, Nadja Müller, Marc Schmitz, Michael Bachmann, Marc Cartellieri, Gabriele Schackert, and Achim Temme Copyright © 2011 Katrin Töpfer et al. All rights reserved. Role of Positive Selection in Functional Divergence of Mammalian Neuronal Apoptosis Inhibitor Proteins during Evolution Thu, 10 Nov 2011 11:30:59 +0000 http://www.hindawi.com/journals/bmri/2011/809765/ Neuronal apoptosis inhibitor proteins (NAIPs) are members of Nod-like receptor (NLR) protein family. Recent research demostrated that some NAIP genes were strongly associated with both innate immunity and many inflammatory diseases in humans. However, no similar phenomena have been reported in other mammals. Furthermore, some NAIP genes have undergone pseudogenization or have been lost during the evolution of some higher mammals. We therefore aimed to determine if functional divergence had occurred, and if natural selection had played an important role in the evolution of these genes. The results showed that NAIP genes have undergone pseudogenization and functional divergence, driven by positive selection. Positive selection has also influenced NAIP protein structure, resulting in further functional divergence. Fanzhi Kong, Zhaoliang Su, Chenglin Zhou, Caixia Sun, Yanfang Liu, Dong Zheng, Hongyan Yuan, Jingping Yin, Jie Fang, Shengjun Wang, and Huaxi Xu Copyright © 2011 Fanzhi Kong et al. All rights reserved. T Cells as Vehicles for Cancer Vaccination Thu, 27 Oct 2011 15:33:54 +0000 http://www.hindawi.com/journals/bmri/2011/417403/ The success of cancer vaccines is dependent on the delivery of tumor-associated antigens (TAAs) within lymphoid tissue in the context of costimulatory molecules and immune stimulatory cytokines. Dendritic cells (DCs) are commonly utilized to elicit antitumor immune responses due to their attractive costimulatory molecule and cytokine expression profile. However, the efficacy of DC-based vaccines is limited by the poor viability and lymph-node migration of exogenously generated DCs in vivo. Alternatively, adoptively transferred T cells persist for long periods of time in vivo and readily migrate between the lymphoid and vascular compartments. In addition, T cells may be genetically modified to express both TAA and DC-activating molecules, suggesting that T cells may be ideal candidates to serve as cellular vehicles for antigen delivery to lymph node-resident DCs in vivo. This paper discusses the concept of using T cells to induce tumor-specific immunity for vaccination against cancer. Adham S. Bear, Conrad R. Cruz, and Aaron E. Foster Copyright © 2011 Adham S. Bear et al. All rights reserved. Osteopontin Alleles Are Associated with Clinical Characteristics in Systemic Lupus Erythematosus Wed, 26 Oct 2011 18:51:39 +0000 http://www.hindawi.com/journals/bmri/2011/802581/ Variants of the osteopontin (OPN) gene have been associated with systemic lupus erythematosus (SLE) susceptibility and cytokine profiles in SLE patients. It is not known whether these alleles are associated with specific clinical phenotypes in SLE. We studied 252 well-characterized SLE patients from a multiethnic cohort, genotyping the rs11730582, rs28357094, rs6532040, and rs9138 SNPs in the OPN gene. Ancestry informative markers were used to control for genetic ancestry. The SLE-risk allele rs9138C in the 3′ UTR region was associated with photosensitivity in lupus patients across all ancestral backgrounds (meta-analysis OR=3.2, 95% CI = 1.6–6.5, 𝑃=1.0×10−3). Additionally, the promoter variant rs11730582C demonstrated suggestive evidence for association with two hematologic traits: thrombocytopenia (OR=2.1, 𝑃=0.023) and hemolytic anemia (OR=2.6, 𝑃=0.036). These clinical associations with SNPs in the promoter and 3′ UTR regions align with previously reported SLE-susceptibility SNPs in OPN and suggest potential roles for these variants in antibody-mediated cytopenias and skin inflammation in SLE. Tarak Trivedi, Beverly S. Franek, Stephanie L. Green, Silvia N. Kariuki, Marissa Kumabe, Rachel A. Mikolaitis, Meenakshi Jolly, Tammy O. Utset, and Timothy B. Niewold Copyright © 2011 Tarak Trivedi et al. All rights reserved. The Role of Cytokine in the Lupus Nephritis Tue, 18 Oct 2011 13:24:54 +0000 http://www.hindawi.com/journals/bmri/2011/594809/ Lupus nephritis (LN) is a major clinical manifestation of systemic lupus erythematosus (SLE). Although numerous abnormalities of immune system have been proposed, cytokine overexpression plays an essential role in the pathogenesis of LN. In the initial phase of the disease, the immune deposits and/or autoantibodies induce cytokine production in renal resident cells, leading to further inflammatory cytokine/chemokine expression and leukocyte infiltration and activation. Then, infiltrate leukocytes, such as macrophages (Mφ) and dendritic cells (DCs), secrete a variety of cytokines and activate naïve T cells, leading the cytokine profile towards T helper (Th)1, Th2, and/or Th17. Recent studies revealed these inflammatory processes in experimental animal models as well as human LN. The cytokine targeted intervention may have the therapeutic potentials for LN. This paper focuses on the expression of cytokine and its functional role in the pathogenesis of LN. Yasunori Iwata, Kengo Furuichi, Shuichi Kaneko, and Takashi Wada Copyright © 2011 Yasunori Iwata et al. All rights reserved. Inflammatory Cytokines in Systemic Lupus Erythematosus Sun, 16 Oct 2011 13:22:09 +0000 http://www.hindawi.com/journals/bmri/2011/432595/ Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin affecting virtually all organ systems. Beyond genetic and environmental factors, cytokine imbalances contribute to immune dysfunction, trigger inflammation, and induce organ damage. The key cytokine that is involved in SLE pathogenesis is interferon alpha. Interferon secretion is induced by immune complexes and leads to upregulation of several inflammatory proteins, which account for the so-called IFN signature that can be found in the majority of SLE PBMCs. Additionally IL-6 and IFN-y as well as T-cell-derived cytokines like IL-17, IL-21, and IL-2 are dysregulated in SLE. The latter induce a T-cell phenotype that is characterized by enhanced B-cell help and enhanced secretion of proinflammatory cytokines but reduced induction of suppressive T cells and activation-induced cell death. This paper will focus on these cytokines and highlights pathophysiological approaches and therapeutic potential. Kim Ohl and Klaus Tenbrock Copyright © 2011 Kim Ohl and Klaus Tenbrock. All rights reserved. Computational Vaccinology: An Important Strategy to Discover New Potential S. mansoni Vaccine Candidates Sat, 15 Oct 2011 09:24:34 +0000 http://www.hindawi.com/journals/bmri/2011/503068/ The flatworm Schistosoma mansoni is a blood fluke parasite that causes schistosomiasis, a debilitating disease that occurs throughout the developing world. Current schistosomiasis control strategies are mainly based on chemotherapy, but many researchers believe that the best long-term strategy to control schistosomiasis is through immunization with an antischistosomiasis vaccine combined with drug treatment. Several papers on Schistosoma mansoni vaccine and drug development have been published in the past few years, representing an important field of study. The advent of technologies that allow large-scale studies of genes and proteins had a remarkable impact on the screening of new and potential vaccine candidates in schistosomiasis. In this postgenomic scenario, bioinformatic technologies have emerged as important tools to mine transcriptomic, genomic, and proteomic databases. These new perspectives are leading to a new round of rational vaccine development. Herein, we discuss different strategies to identify potential S. mansoni vaccine candidates using computational vaccinology. Carina S. Pinheiro, Vicente P. Martins, Natan R. G. Assis, Bárbara C. P. Figueiredo, Suellen B. Morais, Vasco Azevedo, and Sergio C. Oliveira Copyright © 2011 Carina S. Pinheiro et al. All rights reserved. Streptococcus thermophilus ST28 Ameliorates Colitis in Mice Partially by Suppression of Inflammatory Th17 Cells Wed, 12 Oct 2011 16:42:24 +0000 http://www.hindawi.com/journals/bmri/2011/378417/ The effects of Streptococcus thermophilus ST28 on cytokine production by murine splenocytes stimulated with transforming growth factor-β plus interleukin- (IL-) 6 were evaluated. The addition of ST28 significantly repressed IL-17 production compared to ATCC 19258 (type strain). ST28 also decreased the number of Th17 cells in the stimulated splenocytes. The anti-inflammatory effects of ST28 administration were evaluated in mice with colitis induced by dextran sodium sulphate (DSS). Oral treatment of mice with ST28 ameliorated the intestinal lesions by DSS. Upon DSS treatment, IL-17 production in lamina propria lymphocytes (LPLs) was induced, but ST28 significantly decreased its production. ST28 also decreased the percentage of Th17 cells in LPL from DSS-induced colitis. The present results imply that ST28 suppresses the Th17 response in inflamed intestines and would be useful in the treatment of Th17-mediated diseases, such as inflammatory bowel disease. Tasuku Ogita, Megumi Nakashima, Hidetoshi Morita, Yasuo Saito, Takuya Suzuki, and Soichi Tanabe Copyright © 2011 Tasuku Ogita et al. All rights reserved. Serum Antibodies Protect against Intraperitoneal Challenge with Enterotoxigenic Escherichia coli Sun, 09 Oct 2011 11:19:10 +0000 http://www.hindawi.com/journals/bmri/2011/632396/ To assess whether anticolonization factor antigen I (CFA/I) fimbriae antibodies (Abs) from enterotoxigenic Escherichia coli (ETEC) can protect against various routes of challenge, BALB/c mice were immunized with a live attenuated Salmonella vaccine vector expressing CFA/I fimbriae. Vaccinated mice elicited elevated systemic IgG and mucosal IgA Abs, unlike mice immunized with the empty Salmonella vector. Mice were challenged with wild-type ETEC by the oral, intranasal (i.n.), and intraperitoneal (i.p.) routes. Naïve mice did not succumb to oral challenge, but did to i.n. challenge, as did immunized mice; however, vaccinated mice were protected against i.p. ETEC challenge. Two intramuscular (i.m.) immunizations with CFA/I fimbriae without adjuvant conferred 100% protection against i.p. ETEC challenge, while a single 30 μg dose conferred 88% protection. Bactericidal assays showed that ETEC is highly sensitive to anti-CFA/I sera. These results suggest that parenteral immunization with purified CFA/I fimbriae can induce protective Abs and may represent an alternative method to elicit protective Abs for passive immunity to ETEC. Xinghong Yang, Theresa Thornburg, Kathryn Holderness, Zhiyong Suo, Ling Cao, Timothy Lim, Recep Avci, and David W. Pascual Copyright © 2011 Xinghong Yang et al. All rights reserved. Induction of Virus-Specific Cytotoxic T Lymphocytes as a Basis for the Development of Broadly Protective Influenza Vaccines Wed, 05 Oct 2011 18:21:17 +0000 http://www.hindawi.com/journals/bmri/2011/939860/ There is considerable interest in the development of broadly protective influenza vaccines because of the continuous emergence of antigenic drift variants of seasonal influenza viruses and the threat posed by the emergence of antigenically distinct pandemic influenza viruses. It has been recognized more than three decades ago that influenza A virus-specific cytotoxic T lymphocytes recognize epitopes located in the relatively conserved proteins like the nucleoprotein and that they cross-react with various subtypes of influenza A viruses. This implies that these CD8+ T lymphocytes may contribute to protective heterosubtypic immunity induced by antecedent influenza A virus infections. In the present paper, we review the evidence for the role of virus-specific CD8+ T lymphocytes in protective immunity against influenza virus infections and discuss vaccination strategies that aim at the induction of cross-reactive virus-specific T-cell responses. Marine L. B. Hillaire, Albert D. M. E. Osterhaus, and Guus F. Rimmelzwaan Copyright © 2011 Marine L. B. Hillaire et al. All rights reserved. Immunogenicity of a Recombinant Influenza Virus Bearing Both the CD4+ and CD8+ T Cell Epitopes of Ovalbumin Wed, 05 Oct 2011 14:31:22 +0000 http://www.hindawi.com/journals/bmri/2011/497364/ Recombinant influenza viruses that bear the single immunodominant CD8+ T cell epitope OVA257−264 or the CD4+ T cell epitope OVA323−339 of the model antigen ovalbumin (OVA) have been useful tools in immunology. Here, we generated a recombinant influenza virus, WSN-OVAI/II, that bears both OVA-specific CD8+ and CD4+ epitopes on its hemagglutinin molecule. Live and heat-inactivated WSN-OVAI/II viruses were efficiently presented by dendritic cells in vitro to OT-I TCR transgenic CD8+ T cells and OT-II TCR transgenic CD4+ T cells. In vivo, WSN-OVAI/II virus was attenuated in virulence, highly immunogenic, and protected mice from B16-OVA tumor challenge in a prophylactic model of vaccination. Thus, WSN-OVAI/II virus represents an additional tool, along with OVA TCR transgenic mice, for further studies on T cell responses and may be of value in vaccine design. Bruno Garulli, Giuseppina Di Mario, Ester Sciaraffia, Yoshihiro Kawaoka, and Maria R. Castrucci Copyright © 2011 Bruno Garulli et al. All rights reserved. Characterization of an Effective CTL Response against HIV and SIV Infections Thu, 29 Sep 2011 13:26:39 +0000 http://www.hindawi.com/journals/bmri/2011/103924/ A vaccine inducing protective immunity in mucosal tissues and secretions may stop or limit HIV infection. Although cytotoxic T lymphocytes (CTLs) are clearly associated with control of viral replication in HIV and simian immunodeficiency virus (SIV) infections, there are examples of uncontrolled viral replication in the face of strong CD8+ T-cell responses. The number of functions, breadth, avidity, and magnitude of CTL response are likely to be important factors in the effectiveness of anti-HIV T-cell response, but the location and persistence of effector CD8+ T cells are also critical factors. Although the only HIV vaccine clinical trial targeting cellular immunity to prevent HIV infection failed, vaccine strategies using persistent agents against pathogenic mucosal challenge in macaque models are showing unique success. Thus, the key to control the initial focus of viral replication at the portal of entry may rely on the continuous generation of effector CTL responses at mucosal level. Meritxell Genescà Copyright © 2011 Meritxell Genescà. All rights reserved. Microarray Analysis for a Comprehensive Immunological-Status Evaluation during Cancer Vaccine Immune Monitoring Thu, 29 Sep 2011 10:17:22 +0000 http://www.hindawi.com/journals/bmri/2011/307297/ Anticancer immune responses can be enhanced by immune intervention that promotes complex biological mechanisms involving several cellular populations. The classical immune monitoring for biological-based cancer clinical trials is often based on single-cell analysis. However, the overall effect could be lost by such a reductionist approach explaining the lack of correlation among clinical and immunological endpoints often reported. Microarray technology could give the possibility of studying in a multiparametric setting the immune therapy effects. The application of microarray is leading to an improved understanding of the immune responses to tumor immunotherapy. In fact, analysis of cancer vaccine-induced host responses using microarrays is proposed as valuable alternative to the standard cell-based methods. This paper shows successful examples of how high-throughput gene expression profiling contributed to the understanding of anticancer immune responses during biological therapy, introducing as well the integrative platforms that allow the network analysis in molecular biology studies. Vladia Monsurrò and Francesco M. Marincola Copyright © 2011 Vladia Monsurrò and Francesco M. Marincola. All rights reserved. The PD-1/PD-L1 (B7-H1) Pathway in Chronic Infection-Induced Cytotoxic T Lymphocyte Exhaustion Sun, 25 Sep 2011 14:21:42 +0000 http://www.hindawi.com/journals/bmri/2011/451694/ Cytotoxic CD8 T lymphocytes (CTLs) play a pivotal role in the control of infection. Activated CTLs, however, often lose effector function during chronic infection. PD-1 receptor and its ligand PD-L1 of the B7/CD28 family function as a T cell coinhibitory pathway and are emerging as major regulators converting effector CTLs into exhausted CTLs during chronic infection with human immunodeficiency virus, hepatitis B virus, hepatitis C virus, and other pathogens capable of establishing chronic infections. Importantly, blockade of the PD-1/PD-L1 pathway is able to restore functional capabilities to exhausted CTLs and early clinical trials have shown promise. Further research will reveal how chronic infection induces upregulation of PD-1 on CTLs and PD-L1 on antigen-presenting cells and other tissue cells and how the PD-1/PD-L1 interaction promotes CTLs exhaustion, which is crucial for developing effective prophylactic and therapeutic vaccination against chronic infections. Kimberly A. Hofmeyer, Hyungjun Jeon, and Xingxing Zang Copyright © 2011 Kimberly A. Hofmeyer et al. All rights reserved. Proteomic Analysis of Sera from Common Variable Immunodeficiency Patients Undergoing Replacement Intravenous Immunoglobulin Therapy Thu, 22 Sep 2011 15:56:40 +0000 http://www.hindawi.com/journals/bmri/2011/706746/ Common variable immunodeficiency is the most common form of symptomatic primary antibody failure in adults and children. Replacement immunoglobulin is the standard treatment of these patients. By using a differential proteomic approach based on 2D-DIGE, we examined serum samples from normal donors and from matched, naive, and immunoglobulin-treated patients. The results highlighted regulated expression of serum proteins in naive patients. Among the identified proteins, clusterin/ApoJ serum levels were lower in naive patients, compared to normal subjects. This finding was validated in a wider collection of samples from newly enrolled patients. The establishment of a cellular system, based on a human hepatocyte cell line HuH7, allowed to ascertain a potential role in the regulation of CLU gene expression by immunoglobulins. Giuseppe Spadaro, Concetta D'Orio, Arturo Genovese, Antonella Galeotafiore, Chiara D'Ambrosio, Stefano Di Giovanni, Monica Vitale, Mario Capasso, Vincenzo Lamberti, Andrea Scaloni, Gianni Marone, and Nicola Zambrano Copyright © 2011 Giuseppe Spadaro et al. All rights reserved. Natural Killer Cells in Healthy and Diseased Subjects Mon, 29 Aug 2011 11:16:38 +0000 http://www.hindawi.com/journals/bmri/2011/795251/ Roberto Biassoni, John E. Coligan, and Lorenzo Moretta Copyright © 2011 Roberto Biassoni et al. All rights reserved. Th Subset Balance in Lupus Nephritis Sun, 28 Aug 2011 10:26:22 +0000 http://www.hindawi.com/journals/bmri/2011/980286/ Lupus nephritis, which has various histological patterns and variable clinical outcomes, is one of the most important complications of systemic lupus nephritis (SLE). This pathogenetic mechanism in each histologically different type of lupus nephritis (LN) remains unclear. Although SLE is suggested to be a Th2-driven disease, elevation of both Th1 and Th2 cytokines occurs in both humans and mice, suggesting that SLE is a complex disease driven by different lymphocyte subsets with high heterogeneity of clinical manifestations and organ involvement. Recent findings in LN elucidate an essential role for the Th1, IL-17 producing T cells and Th17 cells in the development of diffuse proliferative lupus nephritis (DPLN), and Th2 cytokine in that of membranous lupus nephritis (MLN). These data support the hypothesis that individual Th1/Th2 balance is one of the critical determinants for histopathology of LN. Katsuhisa Miyake, Mitsuteru Akahoshi, and Hitoshi Nakashima Copyright © 2011 Katsuhisa Miyake et al. All rights reserved. The Construction of Chimeric T-Cell Receptor with Spacer Base of Modeling Study of VHH and MUC1 Interaction Mon, 22 Aug 2011 10:49:07 +0000 http://www.hindawi.com/journals/bmri/2011/578128/ Adaptive cell immunotherapy with the use of chimeric receptors leads to the best and most specific response against tumors. Chimeric receptors consist of a signaling fragment, extracellular spacer, costimulating domain, and an antibody. Antibodies cause immunogenicity; therefore, VHH is a good replacement for ScFv in chimeric receptors. Since peptide sequences have an influence on chimeric receptors, the effect of peptide domains on each other's conformation were investigated. CD3Zeta, CD28, VHH and CD8α, and FcgIIα are used as signaling moieties, costimulating domain, antibody, and spacers, respectively. To investigate the influence of the ligation of spacers on the conformational structure of VHH, models of VHH were constructed. Molecular dynamics simulation was run to study the influence of the presence of spacers on the conformational changes in the binding sites of VHH. Root mean square deviation and root mean square fluctuation of critical segments in the binding site showed no noticeable differences with those in the native VHH. Results from molecular docking revealed that the presence of spacer FcgIIα causes an increasing effect on VHH with MUC1 interaction. Each of the constructs was transformed into the Jurkat E6.1. Expression analysis and evaluation of their functions were examined. The results showed good expression and function. Nazanin Pirooznia, Sadegh Hasannia, Majid Taghdir, Fatemeh Rahbarizadeh, and Morteza Eskandani Copyright © 2011 Nazanin Pirooznia et al. All rights reserved. Involvement of Activating NK Cell Receptors and Their Modulation in Pathogen Immunity Thu, 11 Aug 2011 14:04:26 +0000 http://www.hindawi.com/journals/bmri/2011/152430/ Natural Killer (NK) cells are endowed with cell-structure-sensing receptors providing inhibitory protection from self-destruction (inhibitory NK receptors, iNKRs, including killer inhibitory receptors and other molecules) and rapid triggering potential leading to functional cell activation by Toll-like receptors (TLRs), cytokine receptors, and activating NK cell receptors including natural cytotoxicity receptors (NCRs, i.e., NKp46, NKp46, and NKp44). NCR and NKG2D recognize ligands on infected cells which may be endogenous or may directly bind to some structures derived from invading pathogens. In this paper, we address the known direct or indirect interactions between activating receptors and pathogens and their expression during chronic HIV and HCV infections. Francesco Marras, Federica Bozzano, and Andrea De Maria Copyright © 2011 Francesco Marras et al. All rights reserved. Development of a 2-Plex Luminex-Based Competitive Immunoassay to Quantify Neutralizing Antibodies Induced by Virus-Like Particles for Human Papillomavirus 16 and 18 Mon, 25 Jul 2011 10:22:15 +0000 http://www.hindawi.com/journals/bmri/2011/272806/ Human papillomavirus (HPV) L1 virus-like particles (VLPs) were proven an effective vaccine candidate to prevent against HPV-16 and -18 infections. In order to evaluate the potency of our produced HPV-16 and -18 L1 VLPs-based vaccine candidates, also to quantify neutralizing antibodies induced by them, a 2-plex Luminex-based competitive immunoassay was developed. Unlike the published paper, the no-biotin conjugated neutralizing mAbs spiked normal human serum (NHS) was used for standard curve preparation, while phycoerythrin (PE) was not labeled directly to neutralizing mAbs for signaling. After the coupling optimization of VLPs to microspheres and the neutralizing mAbs biotinylation, the 2-plex standard curve was prepared with good fit and high dynamic range. In addition, no cross-reactivity was also confirmed. The 2-plex Luminex-based immunoassay represents good potential not only for vaccine candidate's evaluation but also for its further clinical use. Pin Lv, Hongmei Zhu, Hongfang Wang, and George Wang Copyright © 2011 Pin Lv et al. All rights reserved. How the Virus Outsmarts the Host: Function and Structure of Cytomegalovirus MHC-I-Like Molecules in the Evasion of Natural Killer Cell Surveillance Thu, 30 Jun 2011 12:57:41 +0000 http://www.hindawi.com/journals/bmri/2011/724607/ Natural killer (NK) cells provide an initial host immune response to infection by many viral pathogens. Consequently, the viruses have evolved mechanisms to attenuate the host response, leading to improved viral fitness. One mechanism employed by members of the β-herpesvirus family, which includes the cytomegaloviruses, is to modulate the expression of cell surface ligands recognized by NK cell activation molecules. A novel set of cytomegalovirus (CMV) genes, exemplified by the mouse m145 family, encode molecules that have structural and functional features similar to those of host major histocompatibility-encoded (MHC) class I molecules, some of which are known to contribute to immune evasion. In this review, we explore the function, structure, and evolution of MHC-I-like molecules of the CMVs and speculate on the dynamic development of novel immunoevasive functions based on the MHC-I protein fold. Maria Jamela Revilleza, Rui Wang, Janet Mans, Manqing Hong, Kannan Natarajan, and David H. Margulies Copyright © 2011 Maria Jamela Revilleza et al. All rights reserved. Mucosal Immunization Induces a Higher Level of Lasting Neutralizing Antibody Response in Mice by a Replication-Competent Smallpox Vaccine: Vaccinia Tiantan Strain Mon, 20 Jun 2011 14:30:05 +0000 http://www.hindawi.com/journals/bmri/2011/970424/ The possible bioterrorism threat using the variola virus, the causative agent of smallpox, has promoted us to further investigate the immunogenicity profiles of existing vaccines. Here, we study for the first time the immunogenicity profile of a replication-competent smallpox vaccine (vaccinia Tiantan, VTT strain) for inducing neutralizing antibodies (Nabs) through mucosal vaccination, which is noninvasive and has a critical implication for massive vaccination programs. Four different routes of vaccination were tested in parallel including intramuscular (i.m.), intranasal (i.n.), oral (i.o.), and subcutaneous (s.c.) inoculations in mice. We found that one time vaccination with an optimal dose of VTT was able to induce anti-VTT Nabs via each of the four routes. Higher levels of antiviral Nabs, however, were induced via the i.n. and i.o. inoculations when compared with the i.m. and s.c. routes. Moreover, the i.n. and i.o. vaccinations also induced higher sustained levels of Nabs overtime, which conferred better protections against homologous or alternating mucosal routes of viral challenges six months post vaccination. The VTT-induced immunity via all four routes, however, was partially effective against the intramuscular viral challenge. Our data have implications for understanding the potential application of mucosal smallpox vaccination and for developing VTT-based vaccines to overcome preexisting antivaccinia immunity. Bin Lu, Wenbo Yu, Xiaoxing Huang, Haibo Wang, Li Liu, and Zhiwei Chen Copyright © 2011 Bin Lu et al. All rights reserved. Role of Common-Gamma Chain Cytokines in NK Cell Development and Function: Perspectives for Immunotherapy Mon, 13 Jun 2011 08:47:40 +0000 http://www.hindawi.com/journals/bmri/2011/861920/ NK cells are components of the innate immunity system and play an important role as a first-line defense mechanism against viral infections and in tumor immune surveillance. Their development and their functional activities are controlled by several factors among which cytokines sharing the usage of the common cytokine-receptor gamma chain play a pivotal role. In particular, IL-2, IL-7, IL-15, and IL-21 are the members of this family predominantly involved in NK cell biology. In this paper, we will address their role in NK cell ontogeny, regulation of functional activities, development of specialized cell subsets, and acquisition of memory-like functions. Finally, the potential application of these cytokines as recombinant molecules to NK cell-based immunotherapy approaches will be discussed. Raffaella Meazza, Bruno Azzarone, Anna Maria Orengo, and Silvano Ferrini Copyright © 2011 Raffaella Meazza et al. All rights reserved. Immunologic Monitoring of Cellular Immune Responses in Cancer Vaccine Therapy Tue, 07 Jun 2011 15:40:29 +0000 http://www.hindawi.com/journals/bmri/2011/370374/ Theresa L. Whiteside, James L. Gulley, Timothy M. Clay, and Kwong Yok Tsang Copyright © 2011 Theresa L. Whiteside et al. All rights reserved. Pathogen Recognition by the Long Pentraxin PTX3 Thu, 02 Jun 2011 09:40:33 +0000 http://www.hindawi.com/journals/bmri/2011/830421/ Innate immunity represents the first line of defence against pathogens and plays key roles in activation and orientation of the adaptive immune response. The innate immune system comprises both a cellular and a humoral arm. Components of the humoral arm include soluble pattern recognition molecules (PRMs) that recognise pathogen-associated molecular patterns (PAMPs) and initiate the immune response in coordination with the cellular arm, therefore acting as functional ancestors of antibodies. The long pentraxin PTX3 is a prototypic soluble PRM that is produced at sites of infection and inflammation by both somatic and immune cells. Gene targeting of this evolutionarily conserved protein has revealed a nonredundant role in resistance to selected pathogens. Moreover, PTX3 exerts important functions at the cross-road between innate immunity, inflammation, and female fertility. Here, we review the studies on PTX3, with emphasis on pathogen recognition and cross-talk with other components of the innate immune system. Federica Moalli, Sebastien Jaillon, Antonio Inforzato, Marina Sironi, Barbara Bottazzi, Alberto Mantovani, and Cecilia Garlanda Copyright © 2011 Federica Moalli et al. All rights reserved. Potential Role of NK Cells in the Pathogenesis of Inflammatory Bowel Disease Wed, 01 Jun 2011 15:26:22 +0000 http://www.hindawi.com/journals/bmri/2011/348530/ NK cells are a major component of the innate immune system and play an important role in the tissue inflammation associated with autoimmune diseases such as inflammatory bowel disease (IBD). NK cells are unique in bearing both stimulatory and inhibitory receptors specific for MHC class I molecules, and their function is regulated by a series of inhibiting or activating signals. The delicate balance between activation and inhibition that decides NK cell final action provides an opportunity for their possible modulatory effect on specific therapeutic settings. Intestinal NK cells are phenotypically distinct from their counterparts in the blood and resemble “helper” NK cells, which have potentially important functions both in promoting antipathogen responses and in the maintenance of intestinal epithelial homeostasis. NK cell activities have been found to be significantly below normal levels in both remissive and active stages of IBD patients. However, some proinflammatory cytokines (e.g., IL-15, IL-21, and IL-23) could potently induce NK cell activation to secret high levels of proinflammatory cytokines (e.g., IFN-γ and TNF) and promote the cytolytic activities against the target cells. This paper provides the characteristics of intestinal NK cells and their potential role in the pathogenesis of IBD. Praveen K. Yadav, Chi Chen, and Zhanju Liu Copyright © 2011 Praveen K. Yadav et al. All rights reserved. Chronic Heat Stress Weakened the Innate Immunity and Increased the Virulence of Highly Pathogenic Avian Influenza Virus H5N1 in Mice Sun, 29 May 2011 13:26:16 +0000 http://www.hindawi.com/journals/bmri/2011/367846/ Chronic heat stress (CHS) can negatively affect immune response in animals. In this study we assessed the effects of CHS on host innate immunity and avian influenza virus H5N1 infection in mice. Mice were divided into two groups: CHS and thermally neutral (TN). The CHS treatment group exhibited reduced local immunity in the respiratory tract, including the number of pulmonary alveolar macrophages and lesions in the nasal mucosa, trachea, and lungs. Meanwhile, CHS retarded dendritic cells (DCs) maturation and reduced the mRNA levels of IL-6 and IFN-𝛽 significantly (𝑃<.05). After the CHS treatment, mice were infected with H5N1 virus. The mortality rate and viral load in the lungs of CHS group were higher than those of TN group. The results suggest that the CHS treatment could suppress local immunity in the respiratory tract and innate host immunity in mice significantly and moderately increased the virulence in H5N1-infected mice. Yi Jin, Yanxin Hu, Deping Han, and Ming Wang Copyright © 2011 Yi Jin et al. All rights reserved. NK Cells and Psoriasis Thu, 26 May 2011 15:55:08 +0000 http://www.hindawi.com/journals/bmri/2011/248317/ Psoriasis is a chronic condition of the skin characterised by distinctive scaly plaques. The immune system is now thought to play a major role in the development and pathogenesis of psoriasis with immune cells and cytokines influencing keratinocyte function. Keratinocytes in turn, can activate and recruit immune cells leading to a positive feedback loop in disease. Natural Killer (NK) cells are lymphocytes that are best known for killing virally infected and cancer cells. However, evidence is emerging to support a role for NK cells in psoriasis. NK cells are found in the inflammatory infiltrate in psoriatic skin lesions. They can produce a range of inflammatory cytokines, many of which are important in the pathogenesis of psoriasis. Recent genetic studies have identified a range of potential molecules relating to NK cell biology that are known to be important in psoriasis. This paper will discuss the evidence, both cellular and genetic, for NK cell involvement in psoriasis. Sinéad Dunphy and Clair M. Gardiner Copyright © 2011 Sinéad Dunphy and Clair M. Gardiner. All rights reserved. Clinical Cancer Therapy by NK Cells via Antibody-Dependent Cell-Mediated Cytotoxicity Tue, 24 May 2011 11:00:46 +0000 http://www.hindawi.com/journals/bmri/2011/379123/ Natural killer (NK) cells are powerful effector cells that can be directed to eliminate tumor cells through tumor-targeted monoclonal antibodies (mAbs). Some tumor-targeted mAbs have been successfully applied in the clinic and are included in the standard of care for certain malignancies. Strategies to augment the antitumor response by NK cells have led to an increased understanding of how to improve their effector responses. Next-generation reagents, such as molecularly modified mAbs and mAb-cytokine fusion proteins (immunocytokines, ICs) designed to augment NK-mediated killing, are showing promise in preclinical and some clinical settings. Continued research into the antitumor effects induced by NK cells and tumor-targeted mAbs suggests that additional intrinsic and extrinsic factors may influence the antitumor response. Therefore more research is needed that focuses on evaluating which NK cell and tumor criteria are best predictive of a clinical response and which combination immunotherapy regimens to pursue for distinct clinical settings. Kory L. Alderson and Paul M. Sondel Copyright © 2011 Kory L. Alderson and Paul M. Sondel. All rights reserved. The Impact of Ly49-NK Cell-Dependent Recognition of MCMV Infection on Innate and Adaptive Immune Responses Sun, 22 May 2011 15:49:58 +0000 http://www.hindawi.com/journals/bmri/2011/641702/ Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in the response against herpesviruses, especially cytomegaloviruses (CMV). Indeed, in mice, NK cells, due to the expression of germline encoded Ly49 receptors, possess multiple mechanisms to recognize CMV infection. Classically, this results in NK cell activation and the destruction of the infected cells. More recently, however, this unique host-pathogen interaction has permitted the discovery of novel aspects of NK cell biology, implicating them in the regulation of adaptive immune responses as well as in the development of immunological memory. Here, we will concisely review the newly acquired evidence pertaining to NK cell Ly49-dependent recognition of MCMV-infected cell and the ensuing NK cell regulatory responses. Michal Pyzik, Eve-Marie Gendron-Pontbriand, and Silvia M. Vidal Copyright © 2011 Michal Pyzik et al. All rights reserved. KIR/HLA Interactions and Pathogen Immunity Thu, 19 May 2011 11:42:59 +0000 http://www.hindawi.com/journals/bmri/2011/298348/ The innate immune system is the first line of defence in response to pathogen infection. Natural killer (NK) cells perform a vital role in this response with the ability to directly kill infected cells, produce cytokines, and cross-talk with the adaptive immune system. These effector functions are dependent on activation of NK cells which is determined by surface receptor interactions with ligands on target cells. Of these receptors, the polymorphic killer immunoglobulin-like receptors (KIRs), which interact with MHC class 1 (also highly polymorphic), are largely inhibitory, and exhibit substantial genetic diversity. The result is a significant variation of NK cell repertoire between individuals and also between populations, with a multitude of possible KIR:HLA combinations. As each KIR:ligand interaction may have differential effects on NK cell activation and inhibition, this diversity has important potential influences on the host response to infections. Genetic studies have demonstrated associations between specific KIR:ligand combinations and the outcome of viral (and other) infections, in particular hepatitis C and HIV infection. Detailed functional studies are not required to define the mechanisms underpinning these disease associations. Khaleel M. Jamil and Salim I. Khakoo Copyright © 2011 Khaleel M. Jamil and Salim I. Khakoo. All rights reserved. The Structural Basis of Ligand Recognition by Natural Killer Cell Receptors Wed, 18 May 2011 08:26:52 +0000 http://www.hindawi.com/journals/bmri/2011/203628/ Natural killer cells are a group of lymphocytes which function as tightly controlled surveillance operatives which identify transformed cells through a discrete balance of activating and inhibitory receptors ultimately leading to the destruction of incongruent cells. The understanding of this finely tuned balancing act has been aided by the high-resolution structure determination of activating and inhibitory receptors both alone and in complex with their ligands. This paper collates these structural studies detailing the aspects which directly relate to the natural killer cell function and serves to inform both the specialized structural biologist reader and a more general immunology audience. M. Gordon Joyce and Peter D. Sun Copyright © 2011 M. Gordon Joyce and Peter D. Sun. All rights reserved. The Role of Natural Killer Cells in Sepsis Sat, 14 May 2011 08:37:31 +0000 http://www.hindawi.com/journals/bmri/2011/986491/ Severe sepsis and septic shock are still deadly conditions urging to develop novel therapies. A better understanding of the complex modifications of the immune system of septic patients is needed for the development of innovative immunointerventions. Natural killer (NK) cells are characterized as CD3−NKp46+CD56+ cells that can be cytotoxic and/or produce high amounts of cytokines such as IFN-γ. NK cells are also engaged in crosstalks with other immune cells, such as dendritic cells, macrophages, and neutrophils. During the early stage of septic shock, NK cells may play a key role in the promotion of the systemic inflammation, as suggested in mice models. Alternatively, at a later stage, NK cells-acquired dysfunction could favor nosocomial infections and mortality. Standardized biological tools defining patients' NK cell status during the different stages of sepsis are mandatory to guide potential immuno-interventions. Herein, we review the potential role of NK cells during severe sepsis and septic shock. Laurent Chiche, Jean-Marie Forel, Guillemette Thomas, Catherine Farnarier, Fréderic Vely, Mathieu Bléry, Laurent Papazian, and Eric Vivier Copyright © 2011 Laurent Chiche et al. All rights reserved. Role of Natural Killer and Dendritic Cell Crosstalk in Immunomodulation by Commensal Bacteria Probiotics Tue, 03 May 2011 11:34:31 +0000 http://www.hindawi.com/journals/bmri/2011/473097/ A cooperative dialogue between natural killer (NK) cells and dendritic cells (DCs) has been elucidated in the last years. They help each other to acquire their complete functions, both in the periphery and in the secondary lymphoid organs. Thus, NK cells' activation by dendritic cells allows the killing of transformed or infected cells in the periphery but may also be important for the generation of adaptive immunity. Indeed, it has been shown that NK cells may play a key role in polarizing a Th1 response upon interaction with DCs exposed to microbial products. This regulatory role of DC/NK cross-talk is of particular importance at mucosal surfaces such as the intestine, where the immune system exists in intimate association with commensal bacteria such as lactic acid bacteria (LAB). We here review NK/DC interactions in the presence of gut-derived commensal bacteria and their role in bacterial strain-dependent immunomodulatory effects. We particularly aim to highlight the ability of distinct species of commensal bacterial probiotics to differently affect the outcome of DC/NK cross-talk and consequently to differently influence the polarization of the adaptive immune response. Valeria Rizzello, Irene Bonaccorsi, Maria Luisa Dongarrà, Lisbeth Nielsen Fink, and Guido Ferlazzo Copyright © 2011 Valeria Rizzello et al. All rights reserved. WF10 Stimulates NK Cell Cytotoxicity by Increasing LFA-1-Mediated Adhesion to Tumor Cells Tue, 03 May 2011 11:31:19 +0000 http://www.hindawi.com/journals/bmri/2011/436587/ The redox-active chlorite-based drug WF10 (Immunokine) was shown to have modulatory effects on both the innate and adaptive immune system in vitro and in vivo. Animal studies suggest that WF10 enhances immunity against tumors. One possible explanation for such an effect is that WF10 stimulates natural killer cell cytotoxicity against malignant cells. Here, we show that WF10 regulates human NK cell cytotoxicity in a time-dependent manner, following an S-shaped kinetic with an initial stimulation of activity followed by a decrease in activity relative to the untreated controls. WF10 does not activate NK cells on its own but co-stimulates NK cell activation mediated by different activating receptors. This is mediated by enhancing NK cell adhesion to target cells through promoting the activation of the integrin LFA-1. These data demonstrate a direct effect of WF10 on the cytotoxicity of human NK cells. Louisa Kühne, Mathias Konstandin, Yvonne Samstag, Stefan Meuer, Thomas Giese, and Carsten Watzl Copyright © 2011 Louisa Kühne et al. All rights reserved. Rapid Decrease of CD16 (FcγRIII) Expression on Heat-Shocked Neutrophils and Their Recognition by Macrophages Wed, 27 Apr 2011 11:19:07 +0000 http://www.hindawi.com/journals/bmri/2011/284759/ Accumulation of neutrophils in the site of inflammation is a typical mechanism of innate immunity. The accumulated neutrophils are exposed to stressogenic factors usually associated with inflammation. Here, we studied response of human peripheral blood neutrophils subjected to short, febrile-range heat stress. We show that 90 min heat stress slowed down the spontaneous apoptosis of neutrophils. In the absence of typical markers of apoptosis the heat-shocked neutrophils induced antiinflammatory effect in human monocyte-derived macrophages (hMDMs), yet without being engulfed. Importantly, the expression of FcγRIII (CD16) was sharply reduced. Surprisingly, concentration of the soluble CD16 did not change in heat-shocked neutrophil supernates indicating that the reduction of the cell surface CD16 was achieved mainly by inhibition of fresh CD16 delivery. Inhibitors of 90 kDa heat shock protein (HSP90), a molecular chaperone found in membrane platforms together with CD16 and CD11b, significantly increased the observed effects caused by heat shock. The presented data suggest a novel systemic aspect of increased temperature which relies on immediate modification by heat of a neutrophil molecular pattern. This effect precedes cell death and may be beneficial in the initial phase of inflammation providing a nonphlogistic signal to macrophages before it comes from apoptotic cells. Małgorzata Bzowska, Magda Hamczyk, Anna Skalniak, and Krzysztof Guzik Copyright © 2011 Małgorzata Bzowska et al. All rights reserved. Natural Killer Cells in Human Cancer: From Biological Functions to Clinical Applications Tue, 26 Apr 2011 14:37:56 +0000 http://www.hindawi.com/journals/bmri/2011/676198/ Natural killer (NK) cells are central components of the innate immunity. In murine models, it has been shown that NK cells can control both local tumor growth and metastasis due to their ability to exert direct cellular cytotoxicity without prior sensitization and to secrete immunostimulatory cytokines like IFN-𝛾. The latter participates in cancer elimination by inhibiting cellular proliferation and angiogenesis, promoting apoptosis, and stimulating the adaptive immune system, and it is instrumental for enhancing Ag processing and presentation. Nevertheless, NK cells display impaired functionality and capability to infiltrate tumors in cancer patients. Also, NK cells are feasible targets of stimulation to participate in immunotherapeutic approaches like antibody-based strategies and adoptive cell transfer. Thus, multiple attempts currently aim to manipulate NK for utilization in the immunotherapy of cancer. Estrella Mariel Levy, María Paula Roberti, and José Mordoh Copyright © 2011 Estrella Mariel Levy et al. All rights reserved. Autologous Peripheral Blood Mononuclear Cell Recognition of Autologous Proliferating Tumor Cells in the Context of a Patient-Specific Vaccine Trial Tue, 26 Apr 2011 14:35:24 +0000 http://www.hindawi.com/journals/bmri/2011/635850/ Metastatic melanoma patients who were treated with patient-specific vaccines consisting of dendritic cells loaded with autologous tumor cells had a 5-year survival of over 50%. Enzyme-linked immunospot (ELISPOT) has been used to detect antigen reactive T cells as a means of determining immune response. We wished to determine whether IFN-gamma secretion in an ELISPOT assay was prognostic or predictive for survival following treatment. Peripheral blood mononuclear cells (PBMCs) collected at weeks 0 and 4 were evaluated by ELISPOT assay for response to autologous tumor cells. Overall, there was slight increase in the number of tumor reactive lymphocytes from week 0 to week 4. Using >5 spots/100 K PBMC as the cutoff, a log-rank analysis revealed only a slight statistical significance in overall survival for patients who lacked tumor reactive PBMCs at week 4. The sensitivity of ELISPOT in the context of patient-specific cellular vaccines is unclear. A. N. Cornforth, G. Lee, and R. O. Dillman Copyright © 2011 A. N. Cornforth et al. All rights reserved. Immunologic Monitoring of Cellular Responses by Dendritic/Tumor Cell Fusion Vaccines Tue, 26 Apr 2011 09:15:13 +0000 http://www.hindawi.com/journals/bmri/2011/910836/ Although dendritic cell (DC)- based cancer vaccines induce effective antitumor activities in murine models, only limited therapeutic results have been obtained in clinical trials. As cancer vaccines induce antitumor activities by eliciting or modifying immune responses in patients with cancer, the Response Evaluation Criteria in Solid Tumors (RECIST) and WHO criteria, designed to detect early effects of cytotoxic chemotherapy in solid tumors, may not provide a complete assessment of cancer vaccines. The problem may, in part, be resolved by carrying out immunologic cellular monitoring, which is one prerequisite for rational development of cancer vaccines. In this review, we will discuss immunologic monitoring of cellular responses for the evaluation of cancer vaccines including fusions of DC and whole tumor cell. Shigeo Koido, Sadamu Homma, Akitaka Takahara, Yoshihisa Namiki, Hideo Komita, Eijiro Nagasaki, Masaki Ito, Keisuke Nagatsuma, Kan Uchiyama, Kenichi Satoh, Toshifumi Ohkusa, Jianlin Gong, and Hisao Tajiri Copyright © 2011 Shigeo Koido et al. All rights reserved. Extranodal NK/T-Cell Lymphoma: Toward the Identification of Clinical Molecular Targets Wed, 20 Apr 2011 15:27:43 +0000 http://www.hindawi.com/journals/bmri/2011/790871/ Extranodal natural killer (NK)/T-cell lymphoma of nasal type (NKTCL) is a malignant disorder of cytotoxic lymphocytes of NK or more rarely T cells associated with clonal Epstein-Barr virus infection. Extranodal NKTCL is rare in Western countries, but in Asia and Central and South America it can account for up to 10% of non-Hodgkin's lymphomas. It is an aggressive neoplasm with very poor prognosis. Although the pathogenesis of extranodal NKTCL remains poorly understood, some insights have been gained in the recent years, especially from genome-wide studies. Based on our own experience and knowledge of the literature, we here review some of the genomic and functional pathway alterations observed in NKTCL that could provide a rationale for the development of innovative therapeutic strategies. Christian Schmitt, Nouhoum Sako, Martine Bagot, Yenlin Huang, Philippe Gaulard, and Armand Bensussan Copyright © 2011 Christian Schmitt et al. All rights reserved. Interactions of Human Myeloid Cells with Natural Killer Cell Subsets In Vitro and In Vivo Thu, 31 Mar 2011 14:45:49 +0000 http://www.hindawi.com/journals/bmri/2011/251679/ In both human and mouse it has been recently realized that natural killer (NK) cells do not emerge from the bone marrow with full functional competence but rather acquire functions in interaction with antigen-presenting cells (APCs), primarily dendritic cells (DCs). Here we review the mechanisms and the consequences of this NK-cell preactivation, as well as discuss new experimental models that now allow investigating these interactions for human NK cells and their response to human pathogens in vivo. These investigations will allow harnessing NK cells during vaccination for improved innate and adaptive immunity. Obinna Chijioke and Christian Münz Copyright © 2011 Obinna Chijioke and Christian Münz. All rights reserved. Cytokines in Systemic Lupus Erythematosus Sun, 27 Mar 2011 09:58:05 +0000 http://www.hindawi.com/journals/bmri/2010/735169/ Brian D. Poole, Timothy B. Niewold, George C. Tsokos, and Charles S. Via Copyright © 2010 Brian D. Poole et al. All rights reserved. Immunological and Clinical Effects of Vaccines Targeting p53-Overexpressing Malignancies Tue, 15 Mar 2011 14:50:24 +0000 http://www.hindawi.com/journals/bmri/2011/702146/ Approximately 50% of human malignancies carry p53 mutations, which makes it a potential antigenic target for cancer immunotherapy. Adoptive transfer with p53-specific cytotoxic T-lymphocytes (CTL) and CD4+ T-helper cells eradicates p53-overexpressing tumors in mice. Furthermore, p53 antibodies and p53-specific CTLs can be detected in cancer patients, indicating that p53 is immunogenic. Based on these results, clinical trials were initiated. In this paper, we review immunological and clinical responses observed in cancer patients vaccinated with p53 targeting vaccines. In most trials, p53-specific vaccine-induced immunological responses were observed. Unfortunately, no clinical responses with significant reduction of tumor-burden have occurred. We will elaborate on possible explanations for this lack of clinical effectiveness. In the second part of this paper, we summarize several immunopotentiating combination strategies suitable for clinical use. In our opinion, future p53-vaccine studies should focus on addition of these immunopotentiating regimens to achieve clinically effective therapeutic vaccination strategies for cancer patients. R. Vermeij, N. Leffers, S. H. van der Burg, C. J. Melief, T. Daemen, and H. W. Nijman Copyright © 2011 R. Vermeij et al. All rights reserved. Comparative Study of Human Hematopoietic Cell Engraftment into Balb/c and C57BL/6 Strain of Rag-2/Jak3 Double-Deficient Mice Wed, 26 Jan 2011 10:17:55 +0000 http://www.hindawi.com/journals/bmri/2011/539748/ Immunodeficient mice are becoming invaluable tools in human stem cell and tumor research. In this study, we generated Rag-2/Jak3 double-deficient (Rag-2−/−Jak3−/−) mice with a C57/BL6 and Balb/c genetic background and compared the human lymphohematopoietic cell engraftment rate. Human cord blood-derived CD34+ hematopoietic stem cells were successfully engrafted into Balb/c Rag-2−/−Jak3−/− mice; however, the engraftment rate was far lower in C57/BL6 Rag-2−/−Jak3−/− mice. Transplantation of human peripheral blood mononuclear cells resulted in the same tendency. Thus, a Balb/c background offers superior engraftment capacity than a C57/BL6 background and provides an attractive model for human hematopoietic cell engraftment. Ayumi Ono, Shinichiro Hattori, Ryusho Kariya, Sumako Iwanaga, Manabu Taura, Hideki Harada, Shinya Suzu, and Seiji Okada Copyright © 2011 Ayumi Ono et al. All rights reserved. Immunotherapy for Lung Cancers Mon, 24 Jan 2011 11:55:56 +0000 http://www.hindawi.com/journals/bmri/2011/250860/ Lung cancer is the leading cause of cancer-related deaths worldwide. Although treatment methods in surgery, irradiation, and chemotherapy have improved, prognosis remains unsatisfactory and developing new therapeutic strategies is still an urgent demand. Immunotherapy is a novel therapeutic approach wherein activated immune cells can specifically kill tumor cells by recognition of tumor-associated antigens without damage to normal cells. Several lung cancer vaccines have demonstrated prolonged survival time in phase II and phase III trials, and several clinical trials are under investigation. However, many clinical trials involving cancer vaccination with defined tumor antigens work in only a small number of patients. Cancer immunotherapy is not completely effective in eradicating tumor cells because tumor cells escape from host immune scrutiny. Understanding of the mechanism of immune evasion regulated by tumor cells is required for the development of more effective immunotherapeutic approaches against lung cancer. This paper discusses the identification of tumor antigens in lung cancer, tumor immune escape mechanisms, and clinical vaccine trials in lung cancer. Ming-Yi Ho, Shye-Jye Tang, Kuang-Hui Sun, and Winnie Yang Copyright © 2011 Ming-Yi Ho et al. All rights reserved. The Consequence of Immune Suppressive Cells in the Use of Therapeutic Cancer Vaccines and Their Importance in Immune Monitoring Thu, 20 Jan 2011 10:19:25 +0000 http://www.hindawi.com/journals/bmri/2011/182413/ Evaluating the number, phenotypic characteristics, and function of immunosuppressive cells in the tumor microenvironment and peripheral blood could elucidate the antitumor immune response and provide information to evaluate the efficacy of cancer vaccines. Further studies are needed to evaluate the correlation between changes in immunosuppressive cells and clinical outcomes of patients in cancer vaccine clinical trials. This paper focuses on the role of T-regulatory cells, myeloid-derived suppressor cells, and tumor-associated macrophages in cancer and cancer immunotherapy and their role in immune monitoring. Matteo Vergati, Jeffrey Schlom, and Kwong Y. Tsang Copyright © 2011 Matteo Vergati et al. All rights reserved. IgG Responses to Tissue-Associated Antigens as Biomarkers of Immunological Treatment Efficacy Sun, 19 Dec 2010 12:05:06 +0000 http://www.hindawi.com/journals/bmri/2011/454861/ We previously demonstrated that IgG responses to a panel of 126 prostate tissue-associated antigens are common in patients with prostate cancer. In the current report we questioned whether changes in IgG responses to this panel might be used as a measure of immune response, and potentially antigen spread, following prostate cancer-directed immune-active therapies. Sera were obtained from prostate cancer patients prior to and three months following treatment with androgen deprivation therapy (𝑛=34), a poxviral vaccine (𝑛=31), and a DNA vaccine (𝑛=21). Changes in IgG responses to individual antigens were identified by phage immunoblot. Patterns of IgG recognition following three months of treatment were evaluated using a machine-learned Bayesian Belief Network (ML-BBN). We found that different antigens were recognized following androgen deprivation compared with vaccine therapies. While the number of clinical responders was low in the vaccine-treated populations, we demonstrate that ML-BBN can be used to develop potentially predictive models. Heath A. Smith, Brett B. Maricque, John Eberhardt, Benjamin Petersen, James L. Gulley, Jeffrey Schlom, and Douglas G. McNeel Copyright © 2011 Heath A. Smith et al. All rights reserved. Development of a Serum Biomarker Assay That Differentiates Tumor-Associated MUC5AC (NPC-1C ANTIGEN) from Normal MUC5AC Thu, 16 Dec 2010 13:16:00 +0000 http://www.hindawi.com/journals/bmri/2011/934757/ A serum ELISA using a monoclonal antibody that detects a MUC5AC-related antigen (NPC-1C antigen) expressed by pancreatic and colorectal cancer was developed. The NPC-1C antibody reacts with specific epitopes expressed by tumor-associated MUC5AC that does not appear on MUC5AC from normal tissues. Based on observations of a highly specific antibody, we tested the ELISA to differentiate serum from healthy blood donors compared to serum from patients with colorectal or pancreatic cancer. Additionally, patient tumor tissue was stained to examine the expression pattern of MUC5AC-related antigen in pancreatic and colorectal cancers. The results indicate the NPC-1C antibody ELISA distinguished serum of cancer patients from normal donors with very good sensitivity and specificity. Most patient's tumor biopsy exhibited NPC-1C antibody reactivity, indicating that tumor-associated MUC5AC antigen from tumor is shed into blood, where it can be detected by the NPC-1C antibody ELISA. This serum test provides a new tool to aid in the diagnosis of these cancers and immune monitoring of cancer treatment regimens. Janos Luka, Philip M. Arlen, and Andrew Bristol Copyright © 2011 Janos Luka et al. All rights reserved. Profile of a Serial Killer: Cellular and Molecular Approaches to Study Individual Cytotoxic T-Cells following Therapeutic Vaccination Sun, 14 Nov 2010 15:57:18 +0000 http://www.hindawi.com/journals/bmri/2011/452606/ T-cell vaccination may prevent or treat cancer and infectious diseases, but further progress is required to increase clinical efficacy. Step-by-step improvements of T-cell vaccination in phase I/II clinical studies combined with very detailed analysis of T-cell responses at the single cell level are the strategy of choice for the identification of the most promising vaccine candidates for testing in subsequent large-scale phase III clinical trials. Major aims are to fully identify the most efficient T-cells in anticancer therapy, to characterize their TCRs, and to pinpoint the mechanisms of T-cell recruitment and function in well-defined clinical situations. Here we discuss novel strategies for the assessment of human T-cell responses, revealing in part unprecedented insight into T-cell biology and novel structural principles that govern TCR-pMHC recognition. Together, the described approaches advance our knowledge of T-cell mediated-protection from human diseases. Emanuela M. Iancu, Petra Baumgaertner, Sébastien Wieckowski, Daniel E. Speiser, and Nathalie Rufer Copyright © 2011 Emanuela M. Iancu et al. All rights reserved. Cytotoxic T Lymphocytes and Vaccine Development Wed, 20 Oct 2010 11:36:31 +0000 http://www.hindawi.com/journals/bmri/2010/936549/ Zhengguo Xiao, Kim Klonowski, and Hanchun Yang Copyright © 2010 Zhengguo Xiao et al. All rights reserved. Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Role of Proinflammatory Cytokines and Therapeutic Approaches Sun, 26 Sep 2010 16:31:45 +0000 http://www.hindawi.com/journals/bmri/2010/607084/ Systemic lupus erythematosus (SLE), a chronic multisystem autoimmune disease with a broad range of clinical manifestations, is associated with accelerated atherosclerosis (AT) and increased risk of cardiovascular complications. Relevant factors directly influencing the development of AT comprise immune complex generation, complement activation, and changes in the production and activity of a complex network of cytokines, including type I and II interferons, B lymphocyte stimulator (BLyS), TNF𝛼, IL-6, IL-17 and migration macrophage inhibitor (MIF). Autoantibodies, also responsible for cytokine expression and activation, play a supplementary key role in the development of AT. Genomic and proteomic studies have contributed to the discovery of genes and proteins involved in AT, including some that may be suitable to be used as biomarkers. All that data has allowed the development of new drugs, most of them evaluated in clinical trials: inhibitors of IFN and TNF𝛼, B cell directed therapies, synthetic oligodeoxynucleotides, intravenous immunoglobulin, or statins. The focus of the present paper is to summarize recent evidence showing the role of cytokines in the development of AT in SLE and the rationale, and safety concerns, in the use of combined therapy to prevent AT and cardiovascular disease. Chary López-Pedrera, Maria Ángeles Aguirre, Nuria Barbarroja, and Maria José Cuadrado Copyright © 2010 Chary López-Pedrera et al. All rights reserved. Reduced Expression of TCR Zeta Is Involved in the Abnormal Production of Cytokines by Peripheral T Cells of Patients with Systemic Lupus Erythematosus Mon, 06 Sep 2010 09:13:49 +0000 http://www.hindawi.com/journals/bmri/2010/509021/ Accumulating evidence suggests that dysfunction of T cells underlies the pathogenesis of systemic lupus erythematosus (SLE). We revealed that SLE T cells produced an abnormally excessive amount of IFN-in vitro upon stimulation through TCR, and the expression level of TCR zeta was significantly reduced. The production of IFN- by SLE T cells was negatively correlated with the expression level of TCR zeta. This correlation was abolished when the cells were stimulated with TPA and ionomycin, which bypass TCR and introduce signals directly into the cells, but the production of IFN- by SLE T cells remained abnormally elevated. Taken together, these data suggest that regulatory mechanisms not only for the expression of TCR zeta but also for the production of IFN- were impaired in SLE T cells. These impairments may be responsible for the aberrant responses of SLE T cells and partly involved in the development of SLE. Keiko Yoshimoto, Yumiko Setoyama, Kensei Tsuzaka, Tohru Abe, and Tsutomu Takeuchi Copyright © 2010 Keiko Yoshimoto et al. All rights reserved. Therapeutic Strategies for SLE Involving Cytokines: Mechanism-Oriented Therapies Especially IFN-𝛾 Targeting Gene Therapy Tue, 17 Aug 2010 14:21:03 +0000 http://www.hindawi.com/journals/bmri/2010/461641/ Systemic lupus erythematosus (SLE: lupus) is a chronic complicated autoimmune disease and pathogenesis is still unclear. However, key cytokines have been recognized. Interferon (IFN)-𝛾 and also IFN𝛼/𝛽 are of particular importance. Depending on the concept that lupus is a helper T(Th)1 disease and that dendritic cells (DCs) determine the direction of lupus, balance shift of Th1/Th2 and immunogenic/tolerogenic DCs is reviewed for therapy. (IFN)-𝛾- and IFN-𝛼/𝛽-targeted (gene) therapies are introduced. These consist of Th1/Th2 balance shift and elimination of IFN-𝛾 and IFN-𝛾-related cytokines such as (interleukin)IL-12 and IL-18. Other approaches include suppression of immunocompetent cells, normalization of abnormal T-cell function, costimulation blockade, B lymphocyte stimulator (Blys) blockade, and suppression of nephritic kidney inflammation. Moreover, balance shift of IFN-𝛼/𝛽 and tumor necrosis factor (TNF)-𝛼 together with regulatory T(Treg) cells are briefely introduced. Clinical application will be discussed. Toshiharu Hayashi Copyright © 2010 Toshiharu Hayashi. All rights reserved. Intranasal Immunization with Chitosan/pCAGGS-flaA Nanoparticles Inhibits Campylobacter jejuni in a White Leghorn Model Mon, 16 Aug 2010 11:51:50 +0000 http://www.hindawi.com/journals/bmri/2010/589476/ Campylobacter jejuni is the most common zoonotic bacterium associated with human diarrhea, and chickens are considered to be one of the most important sources for human infection, with no effective prophylactic treatment available. We describe here a prophylactic strategy using chitosan-DNA intranasal immunization to induce specific immune responses. The chitosan used for intranasal administration is a natural mucus absorption enhancer, which results in transgenic DNA expression in chicken nasopharynx. Chickens immunized with chitosan-DNA nanoparticles, which carried a gene for the major structural protein FlaA, produced significantly increased levels of serum anti-Campylobacter jejuni IgG and intestinal mucosal antibody (IgA), compared to those treated with chitosan-DNA (pCAGGS). Chitosan-pCAGGS-flaA intranasal immunization induced reductions of bacterial expellation by 2-3 log10 and 2 log10 in large intestine and cecum of chickens, respectively, when administered with the isolated C. jejuni strain. This study demonstrated that intranasal delivery of chitosan-DNA vaccine successfully induced effective immune response and might be a promising vaccine candidate against C. jejuni infection. Jin-lin Huang, Yan-Xin Yin, Zhi-ming Pan, Gong Zhang, Ai-ping Zhu, Xiu-fan Liu, and Xin-an Jiao Copyright © 2010 Jin-lin Huang et al. All rights reserved. Tumor Microenvironment and Immune Effects of Antineoplastic Therapy in Lymphoproliferative Syndromes Thu, 12 Aug 2010 17:48:09 +0000 http://www.hindawi.com/journals/bmri/2010/846872/ Lymphomas represent a wide group of heterogenic diseases with different biological and clinical behavior. The underlying microenvironment-specific composition seems to play an essential role in this scenario, harboring the ability to develop successful immune responses or, on the contrary, leading to immune evasion and even promotion of tumor growth. Depending on surrounding lymphoid infiltrates, lymphomas may have different prognosis. Moreover, recent evidences have emerged that confer a significant impact of main lymphoma's treatment over microenvironment, with clinical consequences. In this review, we summarize these concepts from a pathological and clinical perspective. Also, the state of the art of lymphoma's anti-idiotype vaccine development is revised, highlighting the situations where this strategy has proven to be successful and eventual clues to obtain better results in the future. Tomás Álvaro, Luis de la Cruz-Merino, Fernando Henao-Carrasco, José Luis Villar Rodríguez, David Vicente Baz, Manuel Codes Manuel de Villena, and Mariano Provencio Copyright © 2010 Tomás Álvaro et al. All rights reserved. The Role of Genetic Variation Near Interferon-Kappa in Systemic Lupus Erythematosus Thu, 15 Jul 2010 11:24:37 +0000 http://www.hindawi.com/journals/bmri/2010/706825/ Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio=1.93, P=2.5×10−4), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin. Isaac T. W. Harley, Timothy B. Niewold, Rebecca M. Stormont, Kenneth M. Kaufman, Stuart B. Glenn, Beverly S. Franek, Jennifer A. Kelly, Jeffrey R. Kilpatrick, David Hutchings, Jasmin Divers, Gail R. Bruner, Jeffrey C. Edberg, Gerald McGwin Jr., Michelle A. Petri, Rosalind Ramsey-Goldman, John D. Reveille, Luis M. Vilá-Pérez, Joan T. Merrill, Gary S. Gilkeson, Timothy J. Vyse, Marta E. Alarcón-Riquelme, Soo-Kyung Cho, Chaim O. Jacob, Graciela S. Alarcón, Kathy L. Moser, Patrick M. Gaffney, Robert P. Kimberly, Sang-Cheol Bae, Carl D. Langefeld, John B. Harley, Joel M. Guthridge, and Judith A. James Copyright © 2010 Isaac T. W. Harley et al. All rights reserved.