Journal of Immunology Research The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. Uptake of CCR7 by KIR2DS4+ NK Cells Is Induced upon Recognition of Certain HLA-C Alleles Thu, 16 Apr 2015 10:39:51 +0000 The KIR2DS4 receptor is the oldest KIR2DS expressed by human NK lymphocytes. The specificity of recognition of this receptor for various HLA class I alleles has been demonstrated; however it remains poorly understood whether these interactions may result in the activation of some specific functions in NK cells. Here, we examined the functional outcome of the KIR2DS4/HLA class I interaction by the use of an alternative functional system based on the ability of KIR2DS4 to regulate the mechanism of trogocytosis by NK cells. We demonstrate that KIR2DS4 can induce the uptake of CCR7 by KIR2DS4+ NKG2A+ NK cell clones after interacting with CCR7+ target cells expressing HLA-Cw4 and HLA-Cw6 alleles. However this interaction is not always sufficient to override the inhibition generated by NKG2A expressed on the same NK cells. The recognition of HLA-Cw4 was confirmed by experiments of cytotoxicity against HLA-C-transfected cells. We also show that, different from resting NK cells, the acquisition of CCR7 in response to IL-18 cannot occur in IL2-activated NK cells because of a marked downregulation in their IL-18Rα expression. As a consequence trogocytosis represents the major mechanism by which KIR2DS4+ activated NK cells acquire the expression of this chemokine receptor. Silvia Pesce, Simona Carlomagno, Alessandro Moretta, Simona Sivori, and Emanuela Marcenaro Copyright © 2015 Silvia Pesce et al. All rights reserved. IL-21: A Pleiotropic Cytokine with Potential Applications in Oncology Wed, 15 Apr 2015 11:03:59 +0000 Interleukin- (IL-) 21 is a pleiotropic cytokine that regulates the activity of both innate and specific immunity. Indeed, it costimulates T and natural killer (NK) cell proliferation and function and regulates B cell survival and differentiation and the function of dendritic cells. In addition, IL-21 exerts divergent effects on different lymphoid cell leukemia and lymphomas, as it may support cell proliferation or on the contrary induce growth arrest or apoptosis of the neoplastic lymphoid cells. Several preclinical studies showed that IL-21 has antitumor activity in different tumor models, through mechanism involving the activation of NK and T or B cell responses. Moreover, IL-21’s antitumor activity can be potentiated by its combination with other immune-enhancing molecules, monoclonal antibodies recognizing tumor antigens, chemotherapy, or molecular targeted agents. Clinical phase I-II studies of IL-21 in cancer patients showed immune stimulatory properties, acceptable toxicity profile, and antitumor effects in a fraction of patients. In view of its tolerability, IL-21 is also suitable for combinational therapeutic regimens with other agents. This review will summarize the biological functions of IL-21, and address its role in lymphoid malignancies and preclinical and clinical studies of cancer immunotherapy. Michela Croce, Valentina Rigo, and Silvano Ferrini Copyright © 2015 Michela Croce et al. All rights reserved. Glucocorticoid-Induced Tumour Necrosis Factor Receptor-Related Protein: A Key Marker of Functional Regulatory T Cells Wed, 15 Apr 2015 08:11:11 +0000 Glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR, TNFRSF18, and CD357) is expressed at high levels in activated T cells and regulatory T cells (Tregs). In this review, we present data from mouse and human studies suggesting that GITR is a crucial player in the differentiation of thymic Tregs (tTregs), and expansion of both tTregs and peripheral Tregs (pTregs). The role of GITR in Treg expansion is confirmed by the association of GITR expression with markers of memory T cells. In this context, it is not surprising that GITR appears to be a marker of active Tregs, as suggested by the association of GITR expression with other markers of Treg activation or cytokines with suppressive activity (e.g., IL-10 and TGF-), the presence of GITR+ cells in tissues where Tregs are active (e.g., solid tumours), or functional studies on Tregs. Furthermore, some Treg subsets including Tr1 cells express either low or no classical Treg markers (e.g., FoxP3 and CD25) and do express GITR. Therefore, when evaluating changes in the number of Tregs in human diseases, GITR expression must be evaluated. Moreover, GITR should be considered as a marker for isolating Tregs. Simona Ronchetti, Erika Ricci, Maria Grazia Petrillo, Luigi Cari, Graziella Migliorati, Giuseppe Nocentini, and Carlo Riccardi Copyright © 2015 Simona Ronchetti et al. All rights reserved. Progress and Challenges toward the Development of Vaccines against Avian Infectious Bronchitis Tue, 14 Apr 2015 11:30:14 +0000 Avian infectious bronchitis (IB) is a widely distributed poultry disease that has huge economic impact on poultry industry. The continuous emergence of new IBV genotypes and lack of cross protection among different IBV genotypes have been an important challenge. Although live attenuated IB vaccines remarkably induce potent immune response, the potential risk of reversion to virulence, neutralization by the maternal antibodies, and recombination and mutation events are important concern on their usage. On the other hand, inactivated vaccines induce a weaker immune response and may require multiple dosing and/or the use of adjuvants that probably have potential safety risks and increased economic burdens. Consequently, alternative IB vaccines are widely sought. Recent advances in recombinant DNA technology have resulted in experimental IB vaccines that show promise in antibody and T-cells responses, comparable to live attenuated vaccines. Recombinant DNA vaccines have also been enhanced to target multiple serotypes and their efficacy has been improved using delivery vectors, nanoadjuvants, and in ovo vaccination approaches. Although most recombinant IB DNA vaccines are yet to be licensed, it is expected that these types of vaccines may hold sway as future vaccines for inducing a cross protection against multiple IBV serotypes. Faruku Bande, Siti Suri Arshad, Mohd Hair Bejo, Hassan Moeini, and Abdul Rahman Omar Copyright © 2015 Faruku Bande et al. All rights reserved. Increased NY-ESO-1 Expression and Reduced Infiltrating CD3+ T Cells in Cutaneous Melanoma Tue, 14 Apr 2015 06:14:40 +0000 NY-ESO-1 is a cancer-testis antigen aberrantly expressed in melanomas, which may serve as a robust and specific target in immunotherapy. NY-ESO-1 antigen expression, tumor features, and the immune profile of tumor infiltrating lymphocytes were assessed in primary cutaneous melanoma. NY-ESO-1 protein was detected in 20% of invasive melanomas (16/79), rarely in in situ melanoma (1/10) and not in benign nevi (0/20). Marked intratumoral heterogeneity of NY-ESO-1 protein expression was observed. NY-ESO-1 expression was associated with increased primary tumor thickness () and inversely correlated with superficial spreading melanoma (). NY-ESO-1 expression was also associated with reduced numbers and density of CD3+ tumor infiltrating lymphocytes (). When NY-ESO-1 protein was expressed, CD3+ T cells were less diffusely infiltrating the tumor and were more often arranged in small clusters () or as isolated cells () than in large clusters of more than five lymphocytes. No correlation of NY-ESO-1 expression with gender, age, tumor site, ulceration, lymph node sentinel status, or survival was observed. NY-ESO-1 expression in melanoma was associated with tumor progression, including increased tumor thickness, and with reduced tumor infiltrating lymphocytes. Mara Giavina-Bianchi, Pedro Giavina-Bianchi, Mirian Nacagami Sotto, Alona Muzikansky, Jorge Kalil, Cyro Festa-Neto, and Lyn M. Duncan Copyright © 2015 Mara Giavina-Bianchi et al. All rights reserved. TACI Expression and Signaling in Chronic Lymphocytic Leukemia Thu, 09 Apr 2015 12:00:15 +0000 TACI is a membrane receptor of BAFF and APRIL, contributing to the differentiation and survival of normal B cells. Although malignant B cells are also subjected on TACI signaling, there is a remarkable intradisease and interindividual variability of TACI expression in B-cell malignancies. The aim of our study was to explore the possible role of TACI signaling in the biology of chronic lymphocytic leukemia (CLL), including its phenotypic and clinical characteristics and prognosis. Ninety-four patients and 19 healthy controls were studied. CLL patients exhibited variable TACI expression, with the majority of cases displaying low to undetectable TACI, along with low to undetectable BAFF and increased APRIL serum levels compared to healthy controls. CLL cells with high TACI expression displayed a better survival capacity in vitro, when cultured with BAFF and/or APRIL. Moreover, TACI expression was positively correlated with the presence of monoclonal gammopathy and inversely with CD11c expression. Therefore, our study provides further evidence for the contribution of BAFF/APRIL signaling to CLL biology, suggesting also that TACI detection might be useful in the selection of patients for novel targeting therapeutic approaches. Antigoni Mamara, Anastasios E. Germenis, Maria Kompoti, Maria Palassopoulou, Eudokia Mandala, Anastasia Banti, Nikolaos Giannakoulas, and Matthaios Speletas Copyright © 2015 Antigoni Mamara et al. All rights reserved. Low Baseline Interleukin-17A Levels Are Associated with Better Treatment Response at 12 Weeks to Tocilizumab Therapy in Rheumatoid Arthritis Patients Thu, 02 Apr 2015 11:19:24 +0000 T helper 17-related cytokines have been implicated in rheumatoid arthritis (RA) pathogenesis. The study aimed to identify cytokines associated with the treatment response of RA patients to tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin- (IL-) 6 receptor. As an independent substudy of the 24-week, randomized, double-blinded CWP-TCZ301 trial of TCZ in RA patients with an inadequate response to disease-modifying antirheumatic drugs, serum levels of cytokines including tumor necrosis factor-alpha, IL-17A, IL-21, IL-23, IL-6, and soluble IL-6 receptor were measured. Baseline IL-17A levels were significantly lower in RA patients who achieved disease activity score 28 (DAS28) remission at 12 weeks of TCZ treatment, compared to patients not in remission. Patients were stratified into IL-17A low group and IL-17A high group. Significantly more patients in the IL-17A low group achieved remission as compared to the IL-17A high group (47.6 versus 17.4%, ). DAS28 improvement was significantly better in the IL-17A low group than in the IL-17A high group at 12 weeks and 24 weeks after adjustment. Other baseline cytokines were not associated with treatment response to TCZ. The data demonstrate that low baseline IL-17A levels are associated with better clinical response to TCZ treatment in RA patients. Sang Jin Lee, Won Park, Sung Hwan Park, Seung-Cheol Shim, Han Joo Baek, Dae-Hyun Yoo, Hyun Ah Kim, Soo Kon Lee, Yun Jong Leee, Young Eun Park, Hoon-Suk Cha, Jin Kyun Park, Eun Young Lee, Eun Bong Lee, and Yeong Wook Song Copyright © 2015 Sang Jin Lee et al. All rights reserved. Acceleration of Wound Healing by -gal Nanoparticles Interacting with the Natural Anti-Gal Antibody Wed, 01 Apr 2015 06:55:10 +0000 Application of α-gal nanoparticles to wounds and burns induces accelerated healing by harnessing the natural anti-Gal antibody which constitutes ~1% of human immunoglobulins. α-gal nanoparticles present multiple α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R), the carbohydrate ligand of anti-Gal. Studied α-gal nanoparticles were comprised of glycolipids with α-gal epitopes, phospholipids, and cholesterol. Binding of anti-Gal to α-gal nanoparticles in wounds activates the complement cascade, resulting in formation of chemotactic complement cleavage peptides that induce rapid recruitment of many macrophages. The Fc/Fcγ receptors interaction between anti-Gal coating α-gal nanoparticles and the recruited macrophages activates macrophages to produce cytokines/growth factors that promote wound healing and recruit stem cells. Studies of wound healing by α-gal nanoparticles were feasible in α1,3galactosyltransferase knockout mice and pigs. In contrast to other nonprimate mammals, these mice and pigs lack the α-gal epitope, and thus they are not immunotolerant to it and produce anti-Gal. Treatment of skin wounds and burns with α-gal nanoparticles resulted in 40–60% decrease in healing time in comparison with control wounds treated with saline. This accelerated healing is associated with increased recruitment of macrophages and extensive angiogenesis in wounds, faster regrowth of epidermis, and regeneration of the dermis. The accelerated healing further decreases and may completely eliminate fibrosis and scar formation in wounds. Since healing of internal injuries is mediated by mechanisms similar to those in external wound healing, it is suggested that α-gal nanoparticles treatment may also improve regeneration and restoration of biological function following internal injuries such as surgical incisions, myocardial ischemia following infarction, and nerve injuries. Uri Galili Copyright © 2015 Uri Galili. All rights reserved. Enhanced Cysteinyl-Leukotriene Type 1 Receptor Expression in T Cells from House Dust Mite-Allergic Individuals following Stimulation with Der p Tue, 31 Mar 2015 10:08:40 +0000 In order to determine the potential for allergen to modulate T cell expression of the CysLT1 receptor and responsiveness to leukotrienes, peripheral blood mononuclear cells from house dust mite-allergic or nonallergic individuals were incubated with D. pteronyssinus allergen (Der p). Baseline CysLT1 expression was similar in both groups of donors, but Der p significantly enhanced CysLT1 expression in CD4+ and CD8+ T cells of only allergic individuals and induced enhanced responsiveness of CD4+ T cells to LTD4 in terms of calcium mobilisation. This effect was prevented by the CysLT1 antagonist MK571. Der p also induced IL-4 and IL-10 production, and neutralizing antibody to IL-4 prevented both the enhanced CysLT1 expression and the enhanced responsiveness of T cells to LTD4 induced by Der p. In allergic individuals, Der p also induced T cell proliferation and a Th2-biased phenotype. Our data suggest that, in allergen-sensitized individuals, exposure to allergen can enhance T cell expression of CysLT1 receptors through a mechanism involving IL-4 production. This, in turn, would induce CD4+ T cell responsiveness to cysteinyl-leukotrienes and Th2 cell activation. Maryse Thivierge, Sylvie Turcotte, Marek Rola-Pleszczynski, and Jana Stankova Copyright © 2015 Maryse Thivierge et al. All rights reserved. Mesenchymal Stem Cells from Patients with Rheumatoid Arthritis Display Impaired Function in Inhibiting Th17 Cells Tue, 31 Mar 2015 07:04:08 +0000 Mesenchymal stem cells (MSCs) possess multipotent and immunomodulatory properties and are suggested to be involved in the pathogenesis of immune-related diseases. This study explored the function of bone marrow MSCs from rheumatoid arthritis (RA) patients, focusing on immunomodulatory effects. RA MSCs showed decreased proliferative activity and aberrant migration capacity. No significant differences were observed in cytokine profiles between RA and control MSCs. The effects of RA MSCs on proliferation of peripheral blood mononuclear cells (PBMCs) and distribution of specific CD4+ T cell subtypes (Th17, Treg, and Tfh cells) were investigated. RA MSCs appeared to be indistinguishable from controls in suppressing PBMC proliferation, decreasing the proportion of Tfh cells, and inducing the polarization of Treg cells. However, the capacity to inhibit Th17 cell polarization was impaired in RA MSCs, which was related to the low expression of CCL2 in RA MSCs after coculture with CD4+ T cells. These findings indicated that RA MSCs display defects in several important biological activities, especially the capacity to inhibit Th17 cell polarization. These functionally impaired MSCs may contribute to the development of RA disease. Yue Sun, Wei Deng, Linyu Geng, Lu Zhang, Rui Liu, Weiwei Chen, Genhong Yao, Huayong Zhang, Xuebing Feng, Xiang Gao, and Lingyun Sun Copyright © 2015 Yue Sun et al. All rights reserved. Gamma-Irradiated Bacille Calmette-Guérin Vaccination Does Not Modulate the Innate Immune Response during Experimental Human Endotoxemia in Adult Males Thu, 26 Mar 2015 12:24:53 +0000 Bacille Calmette-Guérin (BCG) vaccine exerts nonspecific immunostimulatory effects and may therefore represent a novel therapeutic option to treat sepsis-induced immunoparalysis. We investigated whether BCG vaccination modulates the systemic innate immune response in humans in vivo during experimental endotoxemia. We used inactivated gamma-irradiated BCG vaccine because of the potential risk of disseminated disease with the live vaccine in immunoparalyzed patients. In a randomized double-blind placebo-controlled study, healthy male volunteers were vaccinated with gamma-irradiated BCG () or placebo () and received 1 ng/kg lipopolysaccharide (LPS) intravenously on day 5 after vaccination to assess the in vivo immune response. Peripheral blood mononuclear cells were stimulated with various related and unrelated pathogens 5, 8 to 10, and 25 to 35 days after vaccination to assess ex vivo immune responses. BCG vaccination resulted in a scar in 90% of vaccinated subjects. LPS administration elicited a profound systemic immune response, characterized by increased levels of pro- and anti-inflammatory cytokines, hemodynamic changes, and flu-like symptoms. However, BCG modulated neither this in vivo immune response, nor ex vivo leukocyte responses at any time point. In conclusion, gamma-irradiated BCG is unlikely to represent an effective treatment option to restore immunocompetence in patients with sepsis-induced immunoparalysis. This trial is registered with NCT02085590. Linda A. C. Hamers, Matthijs Kox, Rob J. W. Arts, Bastiaan Blok, Jenneke Leentjens, Mihai G. Netea, and Peter Pickkers Copyright © 2015 Linda A. C. Hamers et al. All rights reserved. Immunodiagnostic Significance of Anti-RA33 Autoantibodies in Saudi Patients with Rheumatoid Arthritis Wed, 25 Mar 2015 09:08:51 +0000 The primary objective of this study was to evaluate and compare the immunodiagnostic significance and utility of anti-RA33 with anti-CCP, RF, and CRP in Saudi patients with rheumatoid arthritis. Methods. This was a prospective controlled clinical study conducted at King Abdul Aziz University Tertiary Medical Centre. The sera of 41 RA patients, 31 non-RA patients, and 29 healthy controls were collected. Anti-RA33 and anti-CCP were measured using commercially available ELISA principle kits. RF and CRP were measured using nephelometry. Results. Anti-RA33 antibodies had the lowest positive and negative predictive values and showed a sensitivity of 7.32% with 95.12% specificity. Of the other three markers (including anti-CCP antibodies, CRP, and RF), only anti-CCP showed specificity of 90.46% with sensitivity of 63.41% compared to non-RA patients + healthy control. There was a significant correlation with rheumatoid factor positivity with anti-CCP. With respect to CRP, a notable correlation was seen only with anti-RA33. Conclusion. Compared to rheumatoid factor, anti-CCP antibodies, and C-reactive proteins, the anti-RA33 autoantibodies seem to be not representing as an important additional immunodiagnostic marker in Saudi patients with established RA. RA33 may have more interest in early RA or less severe RA and other systemic connective tissue disorders. Jamil A. Al-Mughales Copyright © 2015 Jamil A. Al-Mughales. All rights reserved. A Novel PET Imaging Using 64Cu-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells Wed, 25 Mar 2015 08:21:30 +0000 Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secreting monoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb to in vivo imaging to detect MSLN-expressing tumors. In in vitro and ex vivo immunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with 64Cu via a chelating agent DOTA and was used in both in vitro cell binding assay and in vivo positron emission tomography (PET) imaging in the tumor-bearing mice. We confirmed that 64Cu-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN-negative ones. The 64Cu-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than 18F-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions. Kazuko Kobayashi, Takanori Sasaki, Fumiaki Takenaka, Hiromasa Yakushiji, Yoshihiro Fujii, Yoshiro Kishi, Shoichi Kita, Lianhua Shen, Hiromi Kumon, and Eiji Matsuura Copyright © 2015 Kazuko Kobayashi et al. All rights reserved. MBL2 Genotypes and Their Associations with MBL Levels and NICU Morbidity in a Cohort of Greek Neonates Tue, 24 Mar 2015 06:42:13 +0000 The objective of this study was to assess the frequency of MBL2 genotypes and their associations with MBL levels and various morbidities of a neonatal intensive care unit (NICU). One hundred and thirty-four (134) NICU (83 term and 51 preterm) and 150 healthy neonates were enrolled in the study. MBL2 genotype and MBL serum levels at birth were determined prospectively by PCR-RFLP-sequencing and enzyme-linked immunosorbent assay, respectively. NICU neonates displayed significantly lower MBL serum levels compared to healthy ones. MBL deficiency, defined as the low MBL2 expression group (XA/O and O/O), was significantly associated with an increased risk of respiratory morbidity, especially transient tachypnea of the newborn and respiratory distress syndrome (RDS). Moreover, an increase of 100 ng/mL of serum MBL levels decreases by 5% the risk of total respiratory morbidity and by 7% the risk of RDS, after correction for prematurity and sex and regardless of the presence of infections. Our study further supports the notion that neonates with MBL deficiency and low MBL serum levels at birth may be at higher risk of developing severe respiratory complications. Matthaios Speletas, Antonios Gounaris, Eirini Sevdali, Maria Kompoti, Katerina Konstantinidi, Rozeta Sokou, Elena Tsitsami, and Anastasios E. Germenis Copyright © 2015 Matthaios Speletas et al. All rights reserved. “New” Antigenic Targets and Methodological Approaches for Refining Laboratory Diagnosis of Antiphospholipid Syndrome Thu, 19 Mar 2015 07:33:39 +0000 Antiphospholipid antibodies (aPLs) are a heterogeneous group of antibodies directed against phospholipids or protein/phospholipid complexes. Currently, aPLs are assessed using either “solid-phase” assays that identify anticardiolipin antibodies and anti-β2-glycoprotein I antibodies or “liquid-phase” assay that identifies lupus anticoagulant. However, in the last few years, “new” antigenic targets and methodological approaches have been employed for refining laboratory diagnosis of antiphospholipid syndrome (APS). In this review the potential diagnostic value of antibodies to domains of β2-GPI, prothrombin/phosphatidylserine, vimentin/cardiolipin, protein S, protein C, annexin A2, annexin A5, and phospholipid antigens is discussed. Moreover, new technical approaches, including chemiluminescence, multiline dot assay, and thin layer chromatography (TLC) immunostaining, which utilize different supports for detection of aPL, have been developed. A special focus has been dedicated on “seronegative” APS, that is, those patients with a clinical profile suggestive of APS (thromboses, recurrent miscarriages, or foetal loss), who are persistently negative for the routinely used aPL. Recent findings suggest that, in sera from patients with SN-APS, antibodies may be detected using “new” antigenic targets (mainly vimentin/cardiolipin) or methodological approaches different from traditional techniques (TLC immunostaining). Thus, APS represents a mosaic, in which antibodies against different antigenic targets may be detected thanks to the continuously evolving new technologies. Roberta Misasi, Antonella Capozzi, Agostina Longo, Serena Recalchi, Emanuela Lococo, Cristiano Alessandri, Fabrizio Conti, Guido Valesini, and Maurizio Sorice Copyright © 2015 Roberta Misasi et al. All rights reserved. Effect of TACI Signaling on Humoral Immunity and Autoimmune Diseases Tue, 17 Mar 2015 14:20:26 +0000 Transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) is one of the receptors of B cell activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL). TACI is a regulator in the immune responses. TACI inhibits B cell expansion and promotes the differentiation and survival of plasma cells. The mechanisms underlying these effects probably involve changed expressions of some crucial molecules, such as B lymphocyte induced maturation protein-1 (Blimp-1) and inducible T-cell costimulator ligand (ICOSL) in B cells and/or plasma cells. However, abnormal TACI signaling may relate to autoimmune disorders. Common variable immune deficiency (CVID) patients with heterozygous mutations in TACI alleles increase susceptibility to autoimmune diseases. Taci−/− mice and BAFF transgenic mice both develop signs of human SLE. These findings that indicate inappropriate levels of TACI signaling may disrupt immune system balance, thereby promoting the development of autoimmune diseases. In this review, we summarize the basic characteristics of the TACI ligands BAFF and APRIL, and detail the research findings on the role of TACI in humoral immunity. We also discuss the possible mechanisms underlying the susceptibility of CVID patients with TACI mutations to autoimmune diseases and the role of TACI in the pathogenesis of SLE. Yi Zhang, Jun Li, Ya-Min Zhang, Xiao-Ming Zhang, and Juan Tao Copyright © 2015 Yi Zhang et al. All rights reserved. Growth Modeling of the Maternal Cytokine Milieu throughout Normal Pregnancy: Macrophage-Derived Chemokine Decreases as Inflammation/Counterregulation Increases Tue, 17 Mar 2015 07:29:12 +0000 Several recent studies have shown differences in the maternal immune milieu at different phases of pregnancy, but most studies have been cross-sectional or of relatively few time points. Levels of 42 cytokines were determined using a multiplex bead-based assay on archived serum from a cohort of pregnant women at median of 18 time points tested, from the first trimester through to parturition, per woman. Unconditional growth modeling was then used to determine time-dependent changes in levels of these cytokines. Macrophage-derived chemokine (MDC, aka CCL22) decreases as pregnancy progresses. IL-1β, IL-6, IL-8, IL-12p70, IL-13, IL-15, IP-10, and FLT3-ligand increase as a function of gestational weeks, and IFNα2, IL-1ra, IL-3, IL-9, IL-12p40, and soluble CD40 ligand increase as a function of trimester. As pregnancy normally progresses, a maternal shift away from a type 2-biased immune response and toward an inflammatory/counterregulatory response is observed. Shernan G. Holtan, Yiyi Chen, Rajani Kaimal, Douglas J. Creedon, Elizabeth Ann L. Enninga, Wendy K. Nevala, and Svetomir N. Markovic Copyright © 2015 Shernan G. Holtan et al. All rights reserved. HIV Vaccine Research: The Challenge and the Way Forward Sun, 15 Mar 2015 09:00:23 +0000 Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) is a worldwide epidemic, with over 35 million people infected currently. Therefore, the development of a safe and effective HIV-1 vaccine is on top of the global health priority. In the past few years, there have been many promising advances in the prevention of HIV/AIDS, among which the RV144 Thai trial has been encouraging and suggests optimization of the current vaccine strategies or search for novel strategies. Here we reviewed the brief history of HIV-1 vaccine, analyzed key challenges existing now, and illustrated future research priority/directions for a therapeutic or prophylactic HIV-1 vaccine, with the hope of accelerating the speed of vaccine development. We believe that an effective HIV-1 vaccine, together with other prevention approaches, will bring an end to this epidemic in the near future. Hai-Bo Wang, Qiu-Hua Mo, and Ze Yang Copyright © 2015 Hai-Bo Wang et al. All rights reserved. Vaccines and Therapies for Biodefence Agents Sun, 08 Mar 2015 13:02:10 +0000 Julia A. Tree, E. Diane Williamson, Caroline A. Rowland, and Louise M. Pitt Copyright © 2015 Julia A. Tree et al. All rights reserved. The Story of CD4+CD28− T Cells Revisited: Solved or Still Ongoing? Thu, 05 Mar 2015 13:52:33 +0000 CD4+CD28− T cells are a unique type of proinflammatory T cells characterised by blockade of costimulatory CD28 receptor expression at the transcriptional level, which is still reversible by IL-12. In healthy individuals older than 65 years, these cells may accumulate to up to 50% of total CD4+ T lymphocytes as in many immune-mediated diseases, immunodeficiency, and specific infectious diseases. Here we focus on CD4+CD28− T cells in chronic immune-mediated diseases, summarizing various phenotypic and functional characteristics, which vary depending on the underlying disease, disease activity, and concurrent treatment. CD4+CD28− T cells present as effector/memory cells with increased replicative history and oligoclonality but reduced apoptosis. As an alternative costimulatory signal instead of CD28, not only natural killer cell receptors and Toll-like receptors, but also CD47, CTLA-4, OX40, and 4-1BB have to be considered. The proinflammatory and cytotoxic capacities of these cells indicate an involvement in progression and maintenance of chronic immune-mediated disease. So far it has been shown that treatment with TNF-α blockers, abatacept, statins, and polyclonal antilymphocyte globulins (ATG) mediates reduction of the CD4+CD28− T cell level. The clinical relevance of targeting CD4+CD28− T cells as a therapeutic option has not been examined so far. Kathrin Maly and Michael Schirmer Copyright © 2015 Kathrin Maly and Michael Schirmer. All rights reserved. Significance of Circulating and Crevicular Matrix Metalloproteinase-9 in Rheumatoid Arthritis-Chronic Periodontitis Association Tue, 03 Mar 2015 11:07:13 +0000 In the recent years, statistically significant associations between rheumatoid arthritis (RA) and periodontal disease have been identified. Emerging as a chronic inflammatory joint disease, RA displays various features and pathogenetic events similar to chronic periodontitis (CP). The purpose of this study was to evaluate the utility of determining systemic and crevicular levels of metalloproteinase-9 (MMP-9) as potential biomarkers for association between RA and CP. A total of fifty-six patients were included in the study. The subjects were categorized into four groups as follows: healthy-control (), active RA (), CP (), and RA-CP association (). Assessment of serum and crevicular concentrations of total MMP-9 (active and pro-MMP-9) was based on ELISA technique. The results of this study showed statistically significant differences of serum MMP-9 between patients groups and control. Serum levels of MMP-9 were similar in RA and RA-CP associated patients. Gingival crevicular fluid (GCF) recorded increased MMP-9 levels in RA-CP association subjects as compared to CP. Considering that RA-CP association is characterized by a disregulation of the inflammatory response, MMP-9 may play a role in the pathogenesis of RA-CP association. MMP-9 is therefore a sensitive tool in the diagnosis and management of patients affected by this binomial association. Isabela Silosi, Manole Cojocaru, Lili Foia, Mihail Virgil Boldeanu, Florin Petrescu, Petra Surlin, and Viorel Biciusca Copyright © 2015 Isabela Silosi et al. All rights reserved. Intestinal Microbiota as Modulators of the Immune System Mon, 02 Mar 2015 09:35:03 +0000 Borja Sánchez, Miguel Gueimonde, Amado Salvador Peña, and David Bernardo Copyright © 2015 Borja Sánchez et al. All rights reserved. Effective Binding of a Phosphatidylserine-Targeting Antibody to Ebola Virus Infected Cells and Purified Virions Sun, 01 Mar 2015 11:12:35 +0000 Ebola virus is responsible for causing severe hemorrhagic fevers, with case fatality rates of up to 90%. Currently, no antiviral or vaccine is licensed against Ebola virus. A phosphatidylserine-targeting antibody (PGN401, bavituximab) has previously been shown to have broad-spectrum antiviral activity. Here, we demonstrate that PGN401 specifically binds to Ebola virus and recognizes infected cells. Our study provides the first evidence of phosphatidylserine-targeting antibody reactivity against Ebola virus. S. D. Dowall, V. A. Graham, K. Corbin-Lickfett, C. Empig, K. Schlunegger, C. B. Bruce, L. Easterbrook, and R. Hewson Copyright © 2015 S. D. Dowall et al. All rights reserved. Neutrophil Migration in the Activation of the Innate Immune Response to Different Flavobacterium psychrophilum Vaccines in Zebrafish (Danio rerio) Sat, 28 Feb 2015 12:41:48 +0000 Flavobacterium psychrophilum is a Gram-negative bacterium, responsible for the bacterial cold-water disease and the rainbow trout fry syndrome in freshwater salmonid fish. At present, there is only one commercial vaccine in Chile, made with two Chilean F. psychrophilum isolates and another licensed in Europe. The present study analyzed neutrophil migration, as a marker of innate immune activation, in zebrafish (Danio rerio) in response to different F. psychrophilum bath vaccines, which is the first step in evaluating vaccine effectiveness and efficiency in fish. Results indicated that bacterins of the LM-02-Fp isolate were more immunogenic than those from the LM-13-Fp isolate. However, no differences were observed between the same bacteria inactivated by either formaldehyde or heat. Importantly, the same vaccine formulation without an adjuvant only triggered a mild neutrophil migration compared to the complete vaccine. Observations also found that, after a year of storage at 4°C, the activation of the innate immune system by the different vaccines was considerably decreased. Finally, new vaccine formulations prepared with heat and formaldehyde inactivated LM-02-Fp were significantly more efficient than the available commercial vaccine in regard to stimulating the innate immune system. Camila J. Solís, Matías Poblete-Morales, Sergio Cabral, Juan A. Valdés, Ariel E. Reyes, Ruben Avendaño-Herrera, and Carmen G. Feijóo Copyright © 2015 Camila J. Solís et al. All rights reserved. Connexin 43 Communication Channels in Follicular Dendritic Cell Development and in Follicular Lymphomas Thu, 26 Feb 2015 12:34:35 +0000 Follicular dendritic cells (FDC) show homo- and heterocellular metabolic coupling through connexin 43 (Cx43) gap junctions and support B cell selection and maturation in germinal centers. In follicular lymphomas B cells escape apoptosis while FDC develop abnormally. Here we tested Cx43 channels in reactive FDC development and follicular lymphomas. In culture, the treatment of FDC-B cell clusters (resembling to “ex vivo” germinal centers) with Gap27 peptide, mimicking the 2nd extracellular loop of Cx43 protein, significantly impaired FDC-B cell cluster formation and cell survival. In untreated cultures of intact clusters, cell proliferation showed a moderate reduction. In tissues, Cx43 protein levels run parallel with the density of FDC both in reactive germinal centers and in malformed follicles of follicular lymphomas and showed strong upregulation in newly generated and/or degrading bi-/multinuclear FDC of rudimentary processes. However, the inverse correlation between Cx43 expression and B cell proliferation seen in reactive germinal centers was not detected in follicular lymphomas. Furthermore, Cx43 levels were not associated with either lymphoma grade or bone marrow involvement. Our results suggest that Cx43 channels are critical in FDC and “ex vivo” germinal center development and in the persistence of FDC in follicular lymphomas but do not affect tumor progression. Hajnalka Rajnai, Ivett Teleki, Gergo Kiszner, Nora Meggyesházi, Peter Balla, Tamas Vancsik, Gyorgyi Muzes, Judit Csomor, Andras Matolcsy, and Tibor Krenacs Copyright © 2015 Hajnalka Rajnai et al. All rights reserved. The Value of a Panel of Autoantibodies for Predicting the Activity of Lupus Nephritis at Time of Renal Biopsy Thu, 26 Feb 2015 12:05:48 +0000 Few studies have correlated serum biomarkers with renal histology, the gold standard for renal activity, in lupus nephritis (LN). We tested a panel of autoantibodies and complement at the time of kidney biopsy and after treatment. Anti-dsDNA, anti-nucleosome, anti-ribosome P, and anti-C1q antibodies and C3/C4 were measured in 107 patients with LN at the time of renal biopsy and after 6–12 months and were correlated with clinical/histological parameters. At multivariate analysis, high titers of anti-C1q antibodies or of anti-dsDNA antibodies (, OR = 8.67, CI: 2.03–37.3) were the independent predictors that discriminate proliferative from nonproliferative LN. All the immunological parameters, except anti-ribosome, showed a significant correlation with activity index but not with chronicity index. Only anti-C1q showed a significant correlation with the amount of proteinuria (, ). None of the immunological parameters were predictive of remission at 6 and 12 months. We found that anti-C1q alone or in combination with anti-dsDNA emerged as the most reliable test in differentiating proliferative and nonproliferative LN. Anti-C1q was the only test correlated with the clinical presentation of LN. After treatment, the titre of the autoantibodies was significantly reduced, but none was predictive of remission. Gabriella Moroni, Silvana Quaglini, Antonella Radice, Barbara Trezzi, Francesca Raffiotta, Piergiorgio Messa, and Renato Alberto Sinico Copyright © 2015 Gabriella Moroni et al. All rights reserved. PGE2-Induced IDO1 Inhibits the Capacity of Fully Mature DCs to Elicit an In Vitro Antileukemic Immune Response Thu, 26 Feb 2015 08:49:55 +0000 In the last years, dendritic cells (DC) have been evaluated for antitumor vaccination. Although DC-based vaccines have raised great expectations, their clinical translation has been largely disappointing. For these results, several explanations have been proposed. In particular, the concomitant expression by DCs of tolerogenic pathways, such as the immunosuppressive agent indoleamine 2,3-dioxygenase-1 (IDO1), has been demonstrated. The aim of this study is to evaluate both the stimulatory and the tolerogenic feature of monocyte-derived DCs (Mo-DCs) after maturation with PGE2. In particular, the role of IDO1 expression in PGE2-matured Mo-DCs has been addressed. Here we show that PGE2, which is required for full maturation of DCs, is one mediator of DC tolerance by enhancing IDO1. PGE2-mediated expression of IDO1 results in the production of kynurenine, in the generation of Tregs, and in the inhibition of either the allogeneic or the autologous antigen-specific stimulatory capacity of DCs. When pulsed with leukemic lysates and matured with PGE2, DCs are impaired in the induction of IFN-γ secreting CD4+ and CD8+ T cells due to IDO1 upregulation. Moreover, the inhibition of IDO1 enhances the antileukemic response. Overall, these results point toward the use of IDO1 inhibitors to enhance the vaccination capacity of DCs, matured with PGE2. Sara Trabanelli, Mariangela Lecciso, Valentina Salvestrini, Michele Cavo, Darina Očadlíková, Roberto M. Lemoli, and Antonio Curti Copyright © 2015 Sara Trabanelli et al. All rights reserved. Correlation between Genetic Variations and Serum Level of Interleukin 28B with Virus Genotypes and Disease Progression in Chronic Hepatitis C Virus Infection Wed, 25 Feb 2015 14:00:40 +0000 Recent studies have demonstrated that polymorphisms near the interleukin-28B (IL-28B) gene could predict the response to Peg-IFN-a/RBV combination therapy in HCV-infected patients. The aim of the study was to correlate the serum level of IL28B in HCV-infected patients with virus genotype/subgenotype and disease progression. IL28B serum level was detected and variations at five single nucleotide polymorphisms (SNPs) in IL28B gene region were genotyped and analyzed. The variation of IL28B genetic polymorphisms was found to be strongly associated with HCV infection when healthy control group was compared to HCV-infected patients with all values <0.0001. Functional analysis revealed that subjects carrying rs8099917-GG genotype had higher serum level of IL28B than those with GT or TT genotypes . Also, patients who were presented with cirrhosis (Cirr) only or with cirrhosis plus hepatocellular carcinoma (Cirr+HCC) had higher levels of serum IL28B when compared to chronic HCV-infected patients ( and 0.003, resp.). No significant association was found when serum levels of IL28B were compared to virus genotypes/subgenotypes. This study indicates that variation at SNP rs8099917 could predict the serum levels of IL28B in HCV-infected patients. Furthermore, IL28B serum level may serve as a useful marker for the development of HCV-associated sequelae. Ahmed Al-Qahtani, Mashael Al-Anazi, Ayman A. Abdo, Faisal M. Sanai, Waleed Al-Hamoudi, Khalid A. Alswat, Hamad I. Al-Ashgar, Mohammed Q. Khan, Ali Albenmousa, Nisreen Khalaf, Nisha Viswan, and Mohammed N. Al-Ahdal Copyright © 2015 Ahmed Al-Qahtani et al. All rights reserved. Impact of Kefir Derived Lactobacillus kefiri on the Mucosal Immune Response and Gut Microbiota Tue, 24 Feb 2015 10:02:25 +0000 The evaluation of the impact of probiotics on host health could help to understand how they can be used in the prevention of diseases. On the basis of our previous studies and in vitro assays on PBMC and Caco-2 ccl20:luc reporter system presented in this work, the strain Lactobacillus kefiri CIDCA 8348 was selected and administrated to healthy Swiss mice daily for 21 days. The probiotic treatment increased IgA in feces and reduced expression of proinflammatory mediators in Peyer Patches and mesenteric lymph nodes, where it also increased IL-10. In ileum IL-10, CXCL-1 and mucin 6 genes were upregulated; meanwhile in colon mucin 4 was induced whereas IFN-γ, GM-CSF, and IL-1β genes were downregulated. Moreover, ileum and colon explants showed the anti-inflammatory effect of L. kefiri since the LPS-induced increment of IL-6 and GM-CSF levels in control mice was significantly attenuated in L. kefiri treated mice. Regarding fecal microbiota, DGGE profiles allowed differentiation of experimental groups in two separated clusters. Quantitative PCR analysis of different bacterial groups revealed only significant changes in Lactobacillus population. In conclusion, L. kefiri is a good candidate to be used in gut inflammatory disorders. P. Carasi, S. M. Racedo, C. Jacquot, D. E. Romanin, M. A. Serradell, and M. C. Urdaci Copyright © 2015 P. Carasi et al. All rights reserved. Toll-Like Receptor Mediated Modulation of T Cell Response by Commensal Intestinal Microbiota as a Trigger for Autoimmune Arthritis Mon, 23 Feb 2015 06:51:35 +0000 In autoimmune diseases, a disturbance of the balance between T helper 17 (Th17) and regulatory T cells (Tregs) is often observed. This disturbed balance is also the case in rheumatoid arthritis (RA). Genetic predisposition to RA confers the presence of several polymorphisms mainly regulating activation of T lymphocytes. However, the presence of susceptibility factors is neither necessary nor sufficient to explain the disease development, emphasizing the importance of environmental factors. Multiple studies have shown that commensal gut microbiota is of great influence on immune homeostasis and can trigger the development of autoimmune diseases by favoring induction of Th17 cells over Tregs. However the mechanism by which intestinal microbiota influences the Th cell balance is not completely understood. Here we review the current evidence supporting the involvement of commensal intestinal microbiota in rheumatoid arthritis, along with a potential role of Toll-like receptors (TLRs) in modulating the relevant Th cell responses to trigger autoimmunity. A better understanding of TLR triggering by intestinal microbiota and subsequent T cell activation might offer new perspectives for manipulating the T cell response in RA patients and may lead to the discovery of new therapeutic targets or even preventive measures. Rebecca Rogier, Marije I. Koenders, and Shahla Abdollahi-Roodsaz Copyright © 2015 Rebecca Rogier et al. All rights reserved.