The Scientific World Journal: Immunology The latest articles from Hindawi © 2017 , Hindawi Limited . All rights reserved. Study of Natural Cytotoxicity Receptors in Patients with HIV/AIDS and Cancer: A Cross-Sectional Study Mon, 13 Jun 2016 06:25:25 +0000 The NCR receptors play a fundamental role in the cytotoxicity mediated by NK cells against tumor cells. In the current study, we investigated possible HIV/AIDS-related changes in the expression of the NCR receptors comparing healthy donors, HIV/AIDS patients, and HIV/AIDS patients with cancer (HIV/AIDSWC). The NCRs were quantified in NK cells ( and ) and T lymphocytes from peripheral blood samples by flow cytometry. We found a significant decrease in the frequency of NK cells expressing NKp46 in HIV/AIDS group (). There was a decrease in the frequency of NK cells expressing NKp46 in the HIV/AIDSWC group; however, this was not statistically significant. We found a significant decrease in the frequency of NK cells expressing NKp30 in the HIV/AIDS group (). There was a decrease in the frequency of NK cells expressing NKp30 and in the HIV/AIDSWC group, but this was not statistically significant. There were no changes in the distribution of NK cells and their subtypes in both groups. Orlando Nascimento Terra Junior, Gabriel de Carvalho Maldonado, Guilherme Rohem Alfradique, Vinicius da Cunha Lisboa, Adriano Arnóbio, Dirce Bonfim de Lima, Hilda Rachel Diamond, and Maria Helena Faria Ornellas de Souza Copyright © 2016 Orlando Nascimento Terra Junior et al. All rights reserved. Sex Hormones and Immune Dimorphism Mon, 17 Nov 2014 11:51:25 +0000 The functioning of the immune system of the body is regulated by many factors. The abnormal regulation of the immune system may result in some pathological conditions. Sex hormones of reproductive system are one of the major factors that regulate immune system due to the presence of hormone receptors on immune cells. The interaction of sex hormones and immune cells through the receptors on these cells effect the release of cytokines which determines the proliferation, differentiation, and maturation of different types of immunocytes and as a result the outcome of inflammatory or autoimmune diseases. The different regulations of sex hormones in both sexes result in immune dimorphism. In this review article the mechanism of regulation of immune system in different sexes and its impact are discussed. Aruna Bhatia, Harmandeep Kaur Sekhon, and Gurpreet Kaur Copyright © 2014 Aruna Bhatia et al. All rights reserved. Direct and Indirect Suppression of Interleukin-6 Gene Expression in Murine Macrophages by Nuclear Orphan Receptor REV-ERBα Tue, 14 Oct 2014 07:41:33 +0000 It is now evident that many nuclear hormone receptors can modulate target gene expression. REV-ERBα, one of the nuclear hormone receptors with the capacity to alter clock function, is critically involved in lipid metabolism, adipogenesis, and the inflammatory response. Recent studies suggest that REV-ERBα plays a key role in the mediation between clockwork and inflammation. The purpose of the current study was to investigate the role of REV-ERBα in the regulation of interleukin-6 (il6) gene expression in murine macrophages. REV-ERBα agonists, or overexpression of rev-erbα in the murine macrophage cell line RAW264 cells, suppressed the induction of il6 mRNA following a lipopolysaccharide (LPS) endotoxin challenge. Also, rev-erbα overexpression decreased LPS-stimulated nuclear factor κB (NFκB) activation in RAW264 cells. We showed that REV-ERBα represses il6 expression not only indirectly through an NFκB binding motif but also directly through a REV-ERBα binding motif in the murine il6 promoter region. Furthermore, peritoneal macrophages from mice lacking rev-erbα increased il6 mRNA expression. These data suggest that REV-ERBα regulates the inflammatory response of macrophages through the suppression of il6 expression. REV-ERBα may therefore be identified as a potent anti-inflammatory receptor and be a therapeutic target receptor of inflammatory diseases. Shogo Sato, Takuya Sakurai, Junetsu Ogasawara, Ken Shirato, Yoshinaga Ishibashi, Shuji Oh-ishi, Kazuhiko Imaizumi, Shukoh Haga, Yoshiaki Hitomi, Tetsuya Izawa, Yoshinobu Ohira, Hideki Ohno, and Takako Kizaki Copyright © 2014 Shogo Sato et al. All rights reserved. The Role of IL-33 in Host Response to Candida albicans Mon, 21 Jul 2014 09:07:44 +0000 Background. Interleukin (IL) 33 is a recently identified pleiotropic cytokine that influences the activity of multiple cell types and orchestrates complex innate and adaptive immune responses. Methods. We performed an extensive review of the literature published between 2005 and 2013 on IL-33 and related cytokines, their functions, and their regulation of the immune system following Candida albicans colonization. Our literature review included cross-references from retrieved articles and specific data from our own studies. Results. IL-33 (IL-1F11) is a recently identified member of the IL-1 family of cytokines. Accumulating evidence suggests a pivotal role of the IL-33/ST2 axis in host immune defense against fungal pathogens, including C. albicans. IL-33 induces a Th2-type inflammatory response and activates both innate and adaptive immunity. Studies in animal models have shown that Th2 inflammatory responses have a beneficial role in immunity against gastrointestinal and systemic infections by Candida spp. Conclusions. This review summarizes the most important clinical studies and case reports describing the beneficial role of IL-33 in immunity and host defense mechanisms against pathogenic fungi. The finding that the IL-33/ST2 axis is involved in therapeutic target has implications for the prevention and treatment of inflammatory diseases, including acute or chronic candidiasis. C. Rodríguez-Cerdeira, A. Lopez-Bárcenas, B. Sánchez-Blanco, and R. Arenas Copyright © 2014 C. Rodríguez-Cerdeira et al. All rights reserved. Mycoplasma pneumoniae Infection in Children Is a Risk Factor for Developing Allergic Diseases Mon, 07 Apr 2014 09:12:57 +0000 Mycoplasma pneumoniae (MP) infection is the dominant cause of pneumonia in children. We sought to determine the relationship between MP infection and secondary allergic disease and to clarify the associated mechanisms of inflammatory response. A prospective study was performed among 1330 patients diagnosed with pneumonia to investigate the patient immune status by determining the correlation between MP infection, immunoglobulin E (IgE) levels, and a spectrum of associated serum cytokines. Serum IgE, IL-4, IL-6, and IL-10 levels for MPP patients in the acute phase were obviously higher than those in the recovery phase (). MPP patients with allergic conditions had increased serum IgE levels and increased IL-4/INF-γ ratio, and IgE and Eosinophil Cationic Protein were further elevated in patients who eventually developed secondary asthma changes. Patients with severe pneumonia and high clinical pulmonary infection scores presented higher levels of IL-4 and IL-5 in serum than those with low scores (). The proportion of CD4+ and CD8+ T cells that secreted IL-4 was significantly increased in MPP patients with elevated IgE. Our data demonstrate a significant correlation between MP infection and IgE levels, which is associated with a Th1/Th2 cytokine imbalance. Qing Ye, Xiao-Jun Xu, Wen-Xia Shao, Yan-Xiang Pan, and Xue-Jun Chen Copyright © 2014 Qing Ye et al. All rights reserved. Hematology of Wild Caught Dubois’s Tree Frog Polypedates teraiensis, Dubois, 1986 (Anura: Rhacophoridae) Thu, 30 Jan 2014 09:08:09 +0000 Blood was analyzed from eighty (forty males and forty females) adult individuals of Polypedates teraiensis to establish reference ranges for its hematological and serum biochemical parameters. The peripheral blood cells were differentiated as erythrocytes, lymphocytes, eosinophils, neutrophils, monocytes, basophils, and thrombocytes, with similar morphology to other anurans. Morphology of blood cells did not vary according to sex. The hematological investigations included morphology and morphometry of erythrocytes, morphometry of leucocytes, packed cell volume (PCV), hemoglobin content (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), erythrocyte or red blood cell (RBC) count, leukocyte or white blood cell (WBC) count, differential leukocyte count, and neutrophil to lymphocyte (N/L) ratio. Besides, protein, cholesterol, glucose, urea, uric acid, and creatinine content of blood serum were assayed. Hematological parameters that differed significantly between sexes were RBC count, length and breadth of RBC, neutrophil %, N/L ratio, area occupied by basophils, and diameter of large lymphocyte and eosinophils. The level of glucose, urea, and creatinine in blood serum also significantly differed between sexes. Madhusmita Das and Pravati Kumari Mahapatra Copyright © 2014 Madhusmita Das and Pravati Kumari Mahapatra. All rights reserved. Transforming Growth Factor-Beta and Matrix Metalloproteinases: Functional Interactions in Tumor Stroma-Infiltrating Myeloid Cells Tue, 21 Jan 2014 08:04:58 +0000 Transforming growth factor-beta (TGF-β) is a pleiotropic factor with several different roles in health and disease. In tumorigenesis, it may act as a protumorigenic factor and have a profound impact on the regulation of the immune system response. Matrix metalloproteinases (MMPs) are a family that comprises more than 25 members, which have recently been proposed as important regulators acting in tumor stroma by regulating the response of noncellular and cellular microenvironment. Tumor stroma consists of several types of resident cells and infiltrating cells derived from bone marrow, which together play crucial roles in the promotion of tumor growth and metastasis. In cancer cells, TGF-β regulates MMPs expression, while MMPs, produced by either cancer cells or residents’ stroma cells, activate latent TGF-β in the extracellular matrix, together facilitating the enhancement of tumor progression. In this review we will focus on the compartment of myeloid stroma cells, such as tumor-associated macrophages, neutrophils, and dendritic and mast cells, which are potently regulated by TGF-β and produce large amounts of MMPs. Their interplay and mutual implications in the generation of pro-tumorigenic cancer microenvironment will be analyzed. Jelena Krstic and Juan F. Santibanez Copyright © 2014 Jelena Krstic and Juan F. Santibanez. All rights reserved. Effect of Cytokines on Osteoclast Formation and Bone Resorption during Mechanical Force Loading of the Periodontal Membrane Sun, 19 Jan 2014 13:00:38 +0000 Mechanical force loading exerts important effects on the skeleton by controlling bone mass and strength. Several in vivo experimental models evaluating the effects of mechanical loading on bone metabolism have been reported. Orthodontic tooth movement is a useful model for understanding the mechanism of bone remodeling induced by mechanical loading. In a mouse model of orthodontic tooth movement, TNF-α was expressed and osteoclasts appeared on the compressed side of the periodontal ligament. In TNF-receptor-deficient mice, there was less tooth movement and osteoclast numbers were lower than in wild-type mice. These results suggest that osteoclast formation and bone resorption caused by loading forces on the periodontal ligament depend on TNF-α. Several cytokines are expressed in the periodontal ligament during orthodontic tooth movement. Studies have found that inflammatory cytokines such as IL-12 and IFN-γ strongly inhibit osteoclast formation and tooth movement. Blocking macrophage colony-stimulating factor by using anti-c-Fms antibody also inhibited osteoclast formation and tooth movement. In this review we describe and discuss the effect of cytokines in the periodontal ligament on osteoclast formation and bone resorption during mechanical force loading. Hideki Kitaura, Keisuke Kimura, Masahiko Ishida, Haruki Sugisawa, Haruka Kohara, Masako Yoshimatsu, and Teruko Takano-Yamamoto Copyright © 2014 Hideki Kitaura et al. All rights reserved. Use of Heavy Water (D2O) in Developing Thermostable Recombinant p26 Protein Based Enzyme-Linked Immunosorbent Assay for Serodiagnosis of Equine Infectious Anemia Virus Infection Thu, 09 Jan 2014 14:15:39 +0000 Thermostabilizing effect of heavy water (D2O) or deuterium oxide has been demonstrated previously on several enzymes and vaccines like oral poliovirus vaccine and influenza virus vaccine. In view of the above observations, effect of heavy water on in situ thermostabilization of recombinant p26 protein on enzyme-linked immunosorbent assay (ELISA) for serodiagnosis of equine infectious anemia virus (EIAV) infection was investigated in the present study. The carbonate-bicarbonate coating buffer was prepared in 60% and 80% D2O for coating the p26 protein in 96-well ELISA plate and thermal stability was examined at 4°C, 37°C, 42°C, and 45°C over a storage time from 2 weeks to 10 months. A set of positive serum () consisting of strong, medium, and weak titer strength (4 samples in each category) and negative serum () were assessed in ELISA during the study period. At each time point, ELISA results were compared with fresh plate to assess thermal protective effect of D2O. Gradual increase in the stabilizing effect of 80% D2O at elevated temperature (37°C < 42°C < 45°C) was observed. The 80% D2O provides the thermal protection to rp26 protein in ELISA plate up to 2 months of incubation at 45°C. The findings of the present study have the future implication of adopting cost effective strategies for generating more heat tolerable ELISA reagents with extended shelf life. Harisankar Singha, Sachin K. Goyal, Praveen Malik, and Raj K. Singh Copyright © 2014 Harisankar Singha et al. All rights reserved. Association of Interleukin-6 Gene Promoter Polymorphism with Coronary Artery Disease in Pakistani Families Mon, 02 Dec 2013 14:41:47 +0000 Interleukin-6 (IL-6) is a well-known inflammatory cytokine and suggested to be involved in the development of coronary artery disease (CAD). IL-6 gene expression has been investigated with controversy in CAD patients. This study investigates the association of the IL-6 gene expression with CAD, the molecular basis for the regulation of interleukin-6 expression in a Pakistani population. Our data show that the serum IL-6 levels were increased in patients with CAD compared with healthy controls and that the IL-6 gene polymorphism at -174 was more prevalent in CAD cases. There was a statistically significant association between the IL-6 gene polymorphism and CAD, which may be associated with an increased risk for the disease. Moreover, circulating IL-6 and hs-CRP levels were significantly higher in patients with CC genotype ( and , resp.). In a binary logistic-regression model, an independent association was found between CAD and increased serum IL-6 and hs-CRP levels and -174G>C polymorphism. This is the first report on the IL-6 expression and the IL-6 gene polymorphism in patients with CAD from Pakistan, and hence it highlights a novel risk factor for the disease. Humayoon Shafiq Satti, Sabir Hussain, and Qamar Javed Copyright © 2013 Humayoon Shafiq Satti et al. All rights reserved. In Astrocytes the Accumulation of the Immunity-Related GTPases Irga6 and Irgb6 at the Vacuole of Toxoplasma gondii Is Dependent on the Parasite Virulence Tue, 12 Nov 2013 11:44:12 +0000 Toxoplasma gondii is an obligate intracellular protozoan parasite responsible for a common infection of the central nervous system. Interferon (IFN)γ is the key cytokine of host defence against T. gondii. However, T. gondii strains differ in virulence and T. gondii factors determining virulence are still poorly understood. In astrocytes IFNγ primarily induces immunity-related GTPases (IRGs), providing a cell-autonomous resistance system. Here, we demonstrate that astrocytes prestimulated with IFNγ inhibit the proliferation of various avirulent, but not virulent, T. gondii strains. The two analyzed immunity-related GTPases Irga6 and Irgb6 accumulate at the PV only of avirulent T. gondii strains, whereas in virulent strains this accumulation is only detectable at very low levels. Both IRG proteins could temporarily be found at the same PV, but did only partially colocalize. Coinfection of avirulent and virulent parasites confirmed that the accumulation of the two analyzed IRGs was a characteristic of the individual PV and not determined by the presence of other strains of T. gondii in the same host cell. Thus, in astrocytes the accumulation of Irga6 and Irgb6 significantly differs between avirulent and virulent T. gondii strains correlating with the toxoplasmacidal properties suggesting a role for this process in parasite virulence. Felix P. Lubitz, Daniel Degrandi, Klaus Pfeffer, and Anne K. Mausberg Copyright © 2013 Felix P. Lubitz et al. All rights reserved. Influence of Physical Activity and Nutrition on Obesity-Related Immune Function Thu, 07 Nov 2013 13:08:39 +0000 Research examining immune function during obesity suggests that excessive adiposity is linked to impaired immune responses leading to pathology. The deleterious effects of obesity on immunity have been associated with the systemic proinflammatory profile generated by the secretory molecules derived from adipose cells. These include inflammatory peptides, such as TNF-α, CRP, and IL-6. Consequently, obesity is now characterized as a state of chronic low-grade systemic inflammation, a condition considerably linked to the development of comorbidity. Given the critical role of adipose tissue in the inflammatory process, especially in obese individuals, it becomes an important clinical objective to identify lifestyle factors that may affect the obesity-immune system relationship. For instance, stress, physical activity, and nutrition have each shown to be a significant lifestyle factor influencing the inflammatory profile associated with the state of obesity. Therefore, the purpose of this review is to comprehensively evaluate the impact of lifestyle factors, in particular psychological stress, physical activity, and nutrition, on obesity-related immune function with specific focus on inflammation. Chun-Jung Huang, Michael C. Zourdos, Edward Jo, and Michael J. Ormsbee Copyright © 2013 Chun-Jung Huang et al. All rights reserved. Effects of PARP-1 Deficiency on Th1 and Th2 Cell Differentiation Tue, 05 Nov 2013 08:42:17 +0000 T cell differentiation to effector Th cells such as Th1 and Th2 requires the integration of multiple synergic and antagonist signals. Poly(ADP-ribosy)lation is a posttranslational modification of proteins catalyzed by Poly(ADP-ribose) polymerases (PARPs). Recently, many reports showed that PARP-1, the prototypical member of the PARP family, plays a role in immune/inflammatory responses. Consistently, its enzymatic inhibition confers protection in several models of immune-mediated diseases, mainly through an inhibitory effect on NF-B (and NFAT) activation. PARP-1 regulates cell functions in many types of immune cells, including dendritic cells, macrophages, and T and B lymphocytes. Our results show that PARP-1KO cells displayed a reduced ability to differentiate in Th2 cells. Under both nonskewing and Th2-polarizing conditions, naïve CD4 cells from PARP-1KO mice generated a reduced frequency of IL-4+ cells, produced less IL-5, and expressed GATA-3 at lower levels compared with cells from wild type mice. Conversely, PARP-1 deficiency did not substantially affect differentiation to Th1 cells. Indeed, the frequency of IFN-+ cells as well as IFN- production, in nonskewing and Th1-polarizing conditions, was not affected by PARP-1 gene ablation. These findings demonstrate that PARP-1 plays a relevant role in Th2 cell differentiation and it might be a target to be exploited for the modulation of Th2-dependent immune-mediated diseases. M. Sambucci, F. Laudisi, F. Novelli, E. Bennici, M. M. Rosado, and C. Pioli Copyright © 2013 M. Sambucci et al. All rights reserved. The Paradox Role of Regulatory T Cells in Ischemic Stroke Thu, 31 Oct 2013 08:42:43 +0000 The underlying mechanism of ischemic stroke is not completely known. Regulatory T cells (Tregs), a subset of T cells, play a pivotal role in the pathophysiological process of ischemic stroke. However, there is also controversy over the role of Tregs in stroke. Hence, the function of Tregs in ischemic stroke has triggered a heated discussion recently. In this paper, we reviewed the current lines of evidence to describe the full view of Tregs in stroke. We would like to introduce the basic concepts of Tregs and then discuss their paradox function in ischemic stroke. On one side, Tregs could protect brain against ischemic injury via modulating the inflammation process. On the other side, they exaggerated the insult by causing microvascular dysfunction. They also interfered with the neurological function recovery. In addition, the reasons for this paradox role would be discussed in the review and the prospective of the clinical application of Tregs was also included. In conclusion, Tregs contributed to the outcome of ischemic stroke, while more lines of evidence are needed to understand how Tregs regulate the immune system and influence the outcome of stroke. Xiaomeng Xu, Min Li, and Yongjun Jiang Copyright © 2013 Xiaomeng Xu et al. All rights reserved. Possible Role of Human Herpesvirus 6 as a Trigger of Autoimmune Disease Thu, 24 Oct 2013 14:09:44 +0000 Human herpesvirus 6 (HHV-6) infection is common and has a worldwide distribution. Recently, HHV-6A and HHV-6B have been reclassified into two distinct species based on different biological features (genetic, antigenic, and cell tropism) and disease associations. A role for HHV-6A/B has been proposed in several autoimmune disorders (AD), including multiple sclerosis (MS), autoimmune connective tissue diseases, and Hashimoto's thyroiditis. The focus of this review is to discuss the above-mentioned AD associated with HHV-6 and the mechanisms proposed for HHV-6A/B-induced autoimmunity. HHV-6A/B could trigger autoimmunity by exposing high amounts of normally sequestered cell antigens, through lysis of infected cells. Another potential trigger is represented by molecular mimicry, with the synthesis of viral proteins that resemble cellular molecules, as a mechanism of immune escape. The virus could also induce aberrant expression of histocompatibility molecules thereby promoting the presentation of autoantigens. CD46-HHV-6A/B interaction is a new attractive mechanism proposed: HHV-6A/B (especially HHV-6A) could participate in neuroinflammation in the context of MS by promoting inflammatory processes through CD46 binding. Although HHV-6A/B has the ability to trigger all the above-mentioned mechanisms, more studies are required to fully elucidate the possible role of HHV-6A/B as a trigger of AD. Francesco Broccolo, Lisa Fusetti, and Luca Ceccherini-Nelli Copyright © 2013 Francesco Broccolo et al. All rights reserved. The Battle between Infection and Host Immune Responses of Dengue Virus and Its Implication in Dengue Disease Pathogenesis Sun, 10 Feb 2013 17:15:08 +0000 Dengue virus (DENV) is a mosquito-transmitted single stranded RNA virus belonging to genus Flavivirus. The virus is endemic in the tropical and subtropical countries of the world, causing diseases classified according to symptoms and severity (from mild to severe) as dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Among a variety of human cell types targeted by DENV, monocytes, macrophages, and dendritic cells are members of innate immunity, capable of mounting rapid inflammatory responses. These cells are also major antigen presenting cells, responsible for activating the adaptive immunity for long-term memory. This paper is an overview of the current understanding of the following mutually affected aspects: DENV structure, viral infectivity, cellular receptors, innate immune response, and adaptive immunity. Peifang Sun and Tadeusz J. Kochel Copyright © 2013 Peifang Sun and Tadeusz J. Kochel. All rights reserved. T Lymphocyte Autoreactivity in Inflammatory Mechanisms Regulating Atherosclerosis Mon, 10 Dec 2012 14:35:51 +0000 Atherosclerosis has been clearly demonstrated to be a chronic inflammatory disease of the arterial wall. Both cells of the innate and the acquired immune system, particularly monocytes and T lymphocytes, are implicated in the atherogenic process, producing different cytokines with pro- and anti-inflammatory effects. The majority of pathogenic T cells involved in atherosclerosis are of the Th1 profile, that has been correlated positively with coronary artery disease. Many studies conducted to evaluate the molecular factors responsible for the activation of T cells have demonstrated that the main antigenic targets in atherosclerosis are modified endogenous structures. These self-molecules activate autoimmune reactions mainly characterized by the production of Th1 cytokines, thus sustaining the inflammatory mechanisms involved in endothelial dysfunction and plaque development. In this paper we will summarize the different T-cell subsets involved in atherosclerosis and the best characterized autoantigens involved in cardiovascular inflammation. Elisabetta Profumo, Brigitta Buttari, Luciano Saso, Raffaele Capoano, Bruno Salvati, and Rachele Riganò Copyright © 2012 Elisabetta Profumo et al. All rights reserved. HER-2 Expression in Immunohistochemistry Has No Prognostic Significance in Gastric Cancer Patients Thu, 03 May 2012 09:06:50 +0000 The role of HER-2 expression as a prognostic factor in gastric cancer (GC) is still controversial. The aim of the study was to asses HER-2 status, its correlations with clinicopathological parameters, and prognostic impact in GC patients. Tumor samples were collected from 78 patients who had undergone curative surgery. In order to evaluate the intensity of immunohistochemical (IHC) reactions two scales were applied: the immunoreactive score according to Remmele modified by the authors and standardised Hercep test score modified for GC by Hofmann et al. The HER-2 overexpression was detected by IHC in 23 (29.5%) tumors in Hercep test (score 2+/3+) and in 24 (30.7%) in IRS scale (IRS 4–12). The overexpression of HER-2 was associated with poorly differentiated tumors, but this correlation was not significant (𝑃=0.064). No relationship was found between HER-2 expression and primary tumor size and degree of spread to regional lymph nodes. Both univariate and multivariate analyses revealed that TNM stage and patient’s age were the crucial negative prognostic factors. No correlation was observed between patient survival and expression of HER-2 estimated using both scales. This research did not confirm HER-2 expression (evaluated with immunohistochemistry) value as a prognostic tool in GC. Agnieszka Halon, Piotr Donizy, Przemyslaw Biecek, Julia Rudno-Rudzinska, Wojciech Kielan, and Rafal Matkowski Copyright © 2012 Agnieszka Halon et al. All rights reserved. DC-SIGN (CD209) Promoter −336 A/G (rs4804803) Polymorphism Associated with Susceptibility of Kawasaki Disease Wed, 02 May 2012 15:29:45 +0000 Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. High-dose intravenous immunoglobulin (IVIG) is the most effective therapy for KD to reduce the prevalence of coronary artery lesion (CAL) formation. Recently, the α2, 6 sialylated IgG was reported to interact with a lectin receptor, specific intracellular adhesion molecule-3 grabbing nonintegrin homolog-related 1 (SIGN-R1) in mice and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) in human, and to trigger an anti-inflammatory cascade. This study was conducted to investigate whether the polymorphism of DC-SIGN (CD209) promoter −336 A/G (rs4804803) is responsible for susceptibility and CAL formation in KD patients using Custom TaqMan SNP Genotyping Assays. A total of 521 subjects (278 KD patients and 243 controls) were investigated to identify an SNP of rs4804803, and they were studied and showed a significant association between the genotypes and allele frequency of rs4804803 in control subjects and KD patients (𝑃=0.004 under the dominant model). However, the promoter variant of DC-SIGN gene was not associated with the occurrence of IVIG resistance, CAL formation in KD. The G allele of DC-SIGN promoter −336 (rs4804803) is a risk allele in the development of KD. Hong-Ren Yu, Wei-Pin Chang, Lin Wang, Ying-Jui Lin, Chi-Di Liang, Kuender D. Yang, Chiu-Ming Kuo, Yi-Chuan Huang, Wei-Chiao Chang, and Ho-Chang Kuo Copyright © 2012 Hong-Ren Yu et al. All rights reserved. CD40 Gene Polymorphisms Associated with Susceptibility and Coronary Artery Lesions of Kawasaki Disease in the Taiwanese Population Wed, 02 May 2012 14:33:15 +0000 Background. Kawasaki disease (KD) is characterized by systemic vasculitis of unknown etiology. Our previous studies showed expression of CD40 ligand on CD4+ T cells correlated to the coronary artery lesion (CAL) and disease progress in KD. Other studies from Japan suggested the role of CD40L in the pathogenesis of CAL, and this might help explain the excessive number of males affected with KD but cannot be reproduced by Taiwanese population. This study was conducted to investigate the CD40 polymorphism in KD and CAL formation. Methods. A total of 950 subjects (381 KD patients and 569 controls) were investigated to identify 2 tagging single-nucleotide polymorphisms (tSNPs) of CD40 (rs4810485 and rs1535045) by using the TaqMan allelic discrimination assay. Results. A significant association was noted with regards to CD40 tSNPs (rs1535045) between controls and KD patients (𝑃=0.0405, dominant model). In KD patients, polymorphisms of CD40 (rs4810485) showed significant association with CAL formation (𝑃=0.0436, recessive model). Haplotype analysis did not yield more significant results between polymorphisms of CD40 and susceptibility/disease activity of KD. Conclusions. This study showed for the first time that polymorphisms of CD40 are associated with susceptibility to KD and CAL formation, in the Taiwanese population. Ho-Chang Kuo, Mei-Chyn Chao, Yu-Wen Hsu, Ying-Chi Lin, Ying-Hsien Huang, Hong-Ren Yu, Ming-Feng Hou, Chi-Di Liang, Kuender D. Yang, Wei-Chiao Chang, and Chih-Lu Wang Copyright © 2012 Ho-Chang Kuo et al. All rights reserved. CD8+ T Cells: GITR Matters Mon, 30 Apr 2012 11:08:42 +0000 As many members of the tumor necrosis factor receptor superfamily, glucocorticoid-induced TNFR-related gene (GITR) plays multiple roles mostly in the cells of immune system. CD8+ T cells are key players in the immunity against viruses and tumors, and GITR has been demonstrated to be an essential molecule for these cells to mount an immune response. The aim of this paper is to focus on GITR function in CD8+ cells, paying particular attention to numerous and recent studies that suggest its crucial role in mouse disease models. Simona Ronchetti, Giuseppe Nocentini, Maria Grazia Petrillo, and Carlo Riccardi Copyright © 2012 Simona Ronchetti et al. All rights reserved. Natural Killer Cells and Their Role in Rheumatoid Arthritis: Friend or Foe? Sun, 01 Apr 2012 09:30:15 +0000 Rheumatoid arthritis (RA) is a long-term disease that leads to inflammation of the joints and surrounding tissues. Natural killer (NK) cells are an important part of the innate immune system and are responsible for the first line of defense against pathogens during the initial immune challenge before the adaptive immune system eventually eliminates the infectious burden. NK cells have the capacity to damage normal cells or through interaction with other cells such as dendritic cells, macrophages, and T cells cause autoimmune diseases, such as RA. NK cells isolated from the joints of patients with RA suggest that they may play a role in this disease. However, the involvement of NK cells in RA pathology is not fully elucidated. Both protective and detrimental roles of NK cells in RA have recently been reported. A better understanding of NK cells' role in RA might help to develop new therapeutic strategies for treatment of the RA or other autoimmune diseases. We have decided in this paper to focus on the NK cell biology, and attempt to bring the interested readership of this Journal up to date on the NK cell, specifically its possible relation to RA. Hamid Shegarfi, Fatemeh Naddafi, and Abbas Mirshafiey Copyright © 2012 Hamid Shegarfi et al. All rights reserved. Association between Levels of IgA Antibodies to Tissue Transglutaminase and Gliadin-Related Nonapeptides in Dermatitis Herpetiformis Sun, 01 Apr 2012 09:09:15 +0000 Dermatitis herpetiformis (DH) is an autoimmunity-driven inflammatory blistering dermatosis associated with a gluten-dependent enteropathy. Tissue transglutaminase (tTG) and nonapeptides of gliadin (npG) are considered in its pathomechanism/diagnostics. Here, the diagnostic accuracy of anti-tTG/anti-npG IgA ELISAs in Slavic DH patients with active skin rash was assessed through creating receiver operating characteristic (ROC) curves, determining cutoff values, and calculating correlations between levels of anti-tTG/anti-npG IgA in DH, IgA/neutrophil-mediated non-DH patients and healthy persons. Altogether, sera from 80 Slavic individuals were examined. There were negligible differences between cutoff points obtained by the ELISAs manufacturer and those in this study. There were statistically significant correlations between levels of anti-tTG/anti-npG IgA in both DH group and the group of IgA/neutrophil-mediated non-DH dermatoses. There was no such correlation in healthy controls. It seems that IgA autoantibodies to tTG and npG in the IgA/neutrophil-mediated DH are produced in the coordinated way implying their causal relationship. Justyna Gornowicz-Porowska, Monika Bowszyc-Dmochowska, Agnieszka Seraszek-Jaros, Elżbieta Kaczmarek, and Marian Dmochowski Copyright © 2012 Justyna Gornowicz-Porowska et al. All rights reserved. Evolution of the C-Type Lectin-Like Receptor Genes of the DECTIN-1 Cluster in the NK Gene Complex Sun, 01 Apr 2012 09:08:58 +0000 Pattern recognition receptors are crucial in initiating and shaping innate and adaptive immune responses and often belong to families of structurally and evolutionarily related proteins. The human C-type lectin-like receptors encoded in the DECTIN-1 cluster within the NK gene complex contain prominent receptors with pattern recognition function, such as DECTIN-1 and LOX-1. All members of this cluster share significant homology and are considered to have arisen from subsequent gene duplications. Recent developments in sequencing and the availability of comprehensive sequence data comprising many species showed that the receptors of the DECTIN-1 cluster are not only homologous to each other but also highly conserved between species. Even in Caenorhabditis elegans, genes displaying homology to the mammalian C-type lectin-like receptors have been detected. In this paper, we conduct a comprehensive phylogenetic survey and give an up-to-date overview of the currently available data on the evolutionary emergence of the DECTIN-1 cluster genes. Susanne Sattler, Hormas Ghadially, and Erhard Hofer Copyright © 2012 Susanne Sattler et al. All rights reserved. TNF-α Promotes IFN-γ-Induced CD40 Expression and Antigen Process in Myb-Transformed Hematological Cells Sun, 01 Apr 2012 08:40:20 +0000 Tumour necrosis factor-α, interferon-γ and interleukin-4 are critical cytokines in regulating the immune responses against infections and tumours. In this study, we investigated the effects of three cytokines on CD40 expression in Myb-transformed hematological cells and their regulatory roles in promoting these cells into dendritic cells. We observed that both interleukin-4 and interferon-γ increased CD40 expression in these hematological cells in a dose-dependent manner, although the concentration required for interleukin-4 was significantly higher than that for interferon-γ. We found that tumour necrosis factor-α promoted CD40 expression induced by interferon-γ, but not by interleukin-4. Our data showed that tumour necrosis factor-α plus interferon-γ-treated Myb-transformed hematological cells had the greatest ability to take up and process the model antigen DQ-Ovalbumin. Tumour necrosis factor-α also increased the ability of interferon-γ to produce the mixed lymphocyte reaction to allogenic T cells. Furthermore, only cotreatment with tumour necrosis factor-α and interferon-γ induced Myb-transformed hematological cells to express interleukin-6. These results suggest that tumour necrosis factor-α plays a key regulatory role in the development of dendritic cells from hematological progenitor cells induced by interferon-γ. Wenyi Gu, Jiezhong Chen, Lei Yang, and Kong-Nan Zhao Copyright © 2012 Wenyi Gu et al. All rights reserved. The Design of New Adjuvants for Mucosal Immunity to Neisseria meningitidis B in Nasally Primed Neonatal Mice for Adult Immune Response Sun, 01 Apr 2012 08:33:16 +0000 The aim of this study was to determine the value of detoxified Shiga toxins Stx1 and Stx2 (toxoids of Escherichia coli) as mucosal adjuvants in neonatal mice for immunogenicity against the outer membrane proteins (OMPs) of Neisseria meningitidis B. Mucosal immunization has been shown to be effective for the induction of antigen-specific immune responses in both the systemic and mucosal compartments. Systemic antibody levels (IgG, IgG1, IgG2a, IgG2b, IgM, and IgA) and mucosal IgM and IgA were measured by ELISA using an N. meningitidis as an antigen. In addition, IFN-γ and IL-6 production were measured after stimulated proliferation of immune cells. Intranasal administration elicited a higher anti-OMP IgA response in both saliva and vaginal fluids. Our results suggest that both Stx1 and Stx2 toxoids are effective mucosal adjuvants for the induction of Ag-specific IgG, IgM, and IgA antibodies. The toxoids significantly enhanced the IgG and IgM response against OMPs with a potency equivalent to CT, with the response being characterized by both IgG1 and IgG2a isotypes, and increased IFN-gamma production. Additionally, bactericidal activity was induced with IgG and IgM antibodies of high avidity. These results support the use of the new toxoids as potent inducing adjuvants that are particularly suitable for mucosal immunization. Tatiane Ferreira and Elizabeth De Gaspari Copyright © 2012 Tatiane Ferreira and Elizabeth De Gaspari. All rights reserved. Bacterial Infections, DNA Virus Infections, and RNA Virus Infections Manifest Differently in Neutrophil Receptor Expression Mon, 12 Mar 2012 14:28:26 +0000 Treating viral illnesses or noninfective causes of inflammation with antibiotics is ineffective and contributes to the development of antibiotic resistance, toxicity, and allergic reactions, leading to increasing medical costs. A major factor behind unnecessary use of antibiotics is, of course, incorrect diagnosis. For this reason, timely and accurate information on whether the infection is bacterial in origin would be highly beneficial. In this paper we will present our recent studies on the expression of opsonin receptors on phagocytes. The analysis of the expression levels of FcγRI, CR1, and CR3, along with CRP and ESR data, provides a novel application to the diagnosis of infectious and inflammatory diseases. The best clinical benefit will be obtained when the individual variables are combined to generate the CIS point method for a bacterial infection marker, DNAVS point for differentiating between DNA and RNA virus infections, and CRP/CD11b ratio for a marker of Gram-positive sepsis. Esa-Matti Lilius and Jari Nuutila Copyright © 2012 Esa-Matti Lilius and Jari Nuutila. All rights reserved. B Cell Responses to CpG Correlate with CXCL16 Expression Levels in Common Variable Immunodeficiency Wed, 01 Feb 2012 12:21:06 +0000 Broad Toll-like receptor 9 (TLR9) signalling defects after CpG in vitro stimulation have been described in common variable immunodeficiency (CVID). CXCL16, a surface receptor, was recently shown to influence cell responses to CpG. We evaluated the expression and function of CXCL16 on B cells from healthy controls and CVID patients. We report that CXCL16 is normally expressed on B cells throughout peripheral maturation. Decreased B cell expression of CXCL16 was observed in a subgroup of CVID patients that correlated with defective in vitro responses to CpG (such as upregulation of CD69, CD86, AICDA, IL-6, and TLR9). Our data suggest that expression levels of a surface receptor, namely, CXCL16, correlate with B cell responses mediated by TLR9 in common variable immunodeficiency. Vassilios Lougaris, Manuela Baronio, Massimiliano Vitali, Giacomo Tampella, Annarosa Soresina, Raffaele Badolato, and Alessandro Plebani Copyright © 2012 Vassilios Lougaris et al. All rights reserved. Regulatory Immunotherapy in Bone Marrow Transplantation Mon, 02 Jan 2012 00:00:00 +0000 Every year individuals receive hematopoietic stem cell transplantation (HSCT) to eradicate malignant and nonmalignant disease. The immunobiology of allotransplantation is an area of ongoing discovery, from the recipient's conditioning treatment prior to the transplant to the donor cell populations responsible for engraftment, graft-versus-host disease, and graft-versus-tumor effect. In this review, we focus on donor-type immunoregulatory T cells, namely, natural killer T cells (NKT) and regulatory T cells (Treg), and their current and potential roles in tolerance induction after allogeneic HSCT. Vanessa Morales-Tirado, Wioleta Luszczek, Marié van der Merwe, and Asha Pillai Copyright © 2011 Vanessa Morales-Tirado et al. All rights reserved. Macrophages, Meta-Inflammation, and Immuno-Metabolism Wed, 28 Dec 2011 00:00:00 +0000 Current research depicts specific modes of immunity and energy metabolism as being interrelated at the molecular, cellular, organ and organism level. Hence, whereas M2 (alternatively-activated) macrophages dominate insulin-sensitive adipose tissue in the lean, M1-skewed (classically-activated) macrophages accumulate in parallel to adiposity in the obese, and promote inflammation and insulin resistance, that is, meta-inflammation. The latest frontier of immuno-metabolism explores the coregulation of energy metabolism and immune function within hematopoietic cells. M1-skewed macrophages are sustained in edematous, hypoxic tissues by anaerobic glycolysis, whereas mitochondrial biogenesis and respiration dominates in M2 cells. We review the underlying mechanisms and the consequences of the transition from M2 to M1 predominance in adipose tissue, as well as the extracellular signals and transcription factors that control macrophage phenotypes and impose distinct metabolic modes. Haim Shapiro, Aviv Lutaty, and Amiram Ariel Copyright © 2011 Haim Shapiro et al. All rights reserved. Midkine in Inflammation Tue, 27 Dec 2011 00:00:00 +0000 The 13 kDa heparin-binding growth factor midkine (MK) was originally identified as a molecule involved in the orchestration of embryonic development. Recent studies provided evidence for a new role of MK in acute and chronic inflammatory processes. Accordingly, several inflammatory diseases including nephritis, arthritis, atherosclerosis, colitis, and autoimmune encephalitis have been shown to be alleviated in the absence of MK in animal models. Reduced leukocyte recruitment to the sites of inflammation was found to be one important mechanism attenuating chronic inflammation when MK was absent. Furthermore, MK was found to modulate expression of proinflammatory cytokines and the expansion of regulatory T-cells. Here, we review the current understanding of the role of MK in different inflammatory disorders and summarize the knowledge of MK biology. Ludwig T. Weckbach, Takashi Muramatsu, and Barbara Walzog Copyright © 2011 Ludwig T. Weckbach et al. All rights reserved. Cytokines: Pulling the Body Together as a Whole Tue, 27 Dec 2011 00:00:00 +0000 Giamila Fantuzzi Copyright © 2011 Giamila Fantuzzi. All rights reserved. In Vivo Expression of Interleukin-37 Reduces Local and Systemic Inflammation in Concanavalin A-Induced Hepatitis Mon, 26 Dec 2011 00:00:00 +0000 We recently reported that after LPS stimulation, IL-37 translocates to the nucleus and reduces the expression of proinflammatory cytokines. The aim of this study was to investigate whether transiently expressed IL-37 in mice reduces inflammation in concanavalin A (ConA)-induced hepatitis and LPS-induced sepsis. Transgene IL-37 expression was detected in the liver lysate of mice injected with IL-37 plasmid-DNA after hydrodynamic tail vein injection. All mice developed severe acute hepatitis after ConA injection. No difference in the histological score and serum ALT was observed between the two groups that might be explained by patchy expression of IL-37 protein in the liver. However, 2 hrs after ConA injection, serum levels for IL-1α, IL-6, IL-5, and IL-9 were significantly reduced in IL-37-expressing mice as seen for the LPS model. In conclusion, in vivo expression of human IL-37 in mice reduces local and systemic inflammation in ConA-induced hepatitis and LPS challenge. Ana-Maria Bulau, Michaela Fink, Christof Maucksch, Roland Kappler, Doris Mayr, Kai Wagner, and Philip Bufler Copyright © 2011 Ana-Maria Bulau et al. All rights reserved. New Role for L-Arginine in Regulation of Inducible Nitric-Oxide-Synthase-Derived Superoxide Anion Production in Raw 264.7 Macrophages Sun, 18 Dec 2011 00:00:00 +0000 Dietary supplementation with L-arginine was shown to improve immune responses in various inflammatory models. However, the molecular mechanisms underlying L-arginine effects on immune cells remain unrecognized. Herein, we tested the hypothesis that a limitation of L-arginine could lead to the uncoupled state of murine macrophage inducible nitric oxide synthase and, therefore, increase inducible nitric-oxide-synthase-derived superoxide anion formation. Importantly, we demonstrated that L-arginine dose- and time dependently potentiated superoxide anion production in bacterial endotoxin-stimulated macrophages, although it did not influence NADPH oxidase expression and activity. Detailed analysis of macrophage activation showed the time dependence between LPS-induced iNOS expression and increased O2•− formation. Moreover, downregulation of macrophage iNOS expression, as well as the inhibition of iNOS activity by NOS inhibitors, unveiled an important role of this enzyme in controlling O2•− and peroxynitrite formation during macrophage stimulation. In conclusion, our data demonstrated that simultaneous induction of NADPH oxidase, together with the iNOS enzyme, can result in the uncoupled state of iNOS resulting in the production of functionally important levels of O2•− soon after macrophage activation with LPS. Moreover, we demonstrated, for the first time that increased concentrations of L-arginine further potentiate iNOS-dependent O2•− formation in inflammatory macrophages. Michaela Pekarova, Antonin Lojek, Hana Martiskova, Ondrej Vasicek, Lucia Bino, A. Klinke, D. Lau, Radek Kuchta, Jaroslav Kadlec, Radimir Vrba, and Lukas Kubala Copyright © 2011 Michaela Pekarova et al. All rights reserved. Cell Intrinsic Roles of Apoptosis-Associated Speck-Like Protein in Regulating Innate and Adaptive Immune Responses Thu, 08 Dec 2011 00:00:00 +0000 The role of apoptosis-associated speck-Like protein (ASC) in the assembly of the inflammasome complex within macrophages has been elucidated in several studies. In this particular role, ASC functions as an adaptor protein by linking nod-like receptors (NLRs) and procaspase-1, thereby leading to the activation of caspase-1 to cleave inflammatory cytokines IL-1β and IL-18 and inducing pyroptosis. It has been noted that ASC maintains inflammasome-independent roles, including but not limited to controlling the expression of Dock2 and mitogen-activated protein kinases (MAPK/ERK2) and regulating the NF-κB pathway. This paper will emphasize the major roles of ASC during pathogen infection, the mechanisms by which it mediates inflammation, and discuss its more recently discovered functions. Hoda Hassan and Amal O. Amer Copyright © 2011 Hoda Hassan and Amal O. Amer. All rights reserved. Macrophage Polarization in Health and Disease Mon, 05 Dec 2011 00:00:00 +0000 Macrophages are terminally differentiated cells of the mononuclear phagocyte system that also encompasses dendritic cells, circulating blood monocytes, and committed myeloid progenitor cells in the bone marrow. Both macrophages and their monocytic precursors can change their functional state in response to microenvironmental cues exhibiting a marked heterogeneity. However, there are still uncertainties regarding distinct expression patterns of surface markers that clearly define macrophage subsets, particularly in the case of human macrophages. In addition to their tissue distribution, macrophages can be functionally polarized into M1 (proinflammatory) and M2 (alternatively activated) as well as regulatory cells in response to both exogenous infections and solid tumors as well as by systems biology approaches. Luca Cassetta, Edana Cassol, and Guido Poli Copyright © 2011 Luca Cassetta et al. All rights reserved. Proinflammatory Stimuli Enhance Phagocytosis of Apoptotic Cells by Neutrophil Granulocytes Tue, 15 Nov 2011 00:00:00 +0000 Recently, we have reported that, in addition to macrophages, also neutrophil granulocytes can phagocytose apoptotic neutrophils. Based on this finding, we hypothesized that “cannibalistic” neutrophils at sites of acute infection/inflammation play a major role in the clearance of apoptotic neutrophils. Since at sites of infection/inflammation neutrophils are exposed to microbial constituents and proinflammatory cytokines, in the present study we analyzed the effect of TLR-ligands and cytokines on the ability of neutrophils to phagocytose apoptotic cells in vitro. We observed that exposure to ligands of TLR2 (Malp2, Pam3CSK4), TLR4 (LPS), TLR7/TLR8 (R848), and TLR9 (ODN 2006) led to increased phagocytosis of apoptotic cells by neutrophils. In addition, proinflammatory cytokines such as TNF and GM-CSF strongly enhanced the uptake of apoptotic cells by neutrophils. These results support the hypothesis that neutrophils acquire the ability to phagocytose apoptotic cells at sites of acute infection/inflammation and thereby can contribute to the resolution of inflammation. Lars Hellberg, Sabrina Fuchs, Christoph Gericke, Arup Sarkar, Martina Behnen, Werner Solbach, and Tamás Laskay Copyright © 2011 Lars Hellberg et al. All rights reserved. Overlapping, Additive and Counterregulatory Effects of Type II and I Interferons on Myeloid Dendritic Cell Functions Tue, 01 Nov 2011 00:00:00 +0000 Dendritic cells (DCs) are central player in immunity by bridging the innate and adaptive arms of the immune system (IS). Interferons (IFNs) are one of the most important factors that regulate both innate and adaptive immunity too. Thus, the understanding of how type II and I IFNs modulate the immune-regulatory properties of DCs is a central issue in immunology. In this paper, we will address this point in the light of the most recent literature, also highlighting the controversial data reported in the field. According to the wide literature available, type II as well as type I IFNs appear, at the same time, to collaborate, to induce additive effects or overlapping functions, as well as to counterregulate each one's effects on DC biology and, in general, the immune response. The knowledge of these effects has important therapeutic implications in the treatment of infectious/autoimmune diseases and cancer and indicates strategies for using IFNs as vaccine adjuvants and in DC-based immune therapeutic approaches. Loredana Frasca and Roberto Lande Copyright © 2011 Loredana Frasca and Roberto Lande. All rights reserved. The Role of CD40/CD40 Ligand Interactions in Bone Marrow Granulopoiesis Wed, 26 Oct 2011 00:00:00 +0000 The CD40 ligand (CD40L) and CD40 are two molecules belonging to the TNF/TNF receptor superfamily, and their role in adaptive immune system has widely been explored. However, the wide range of expression of these molecules on hematopoietic as well as nonhematopoietic cells has revealed multiple functions of the CD40/CD40L interactions on different cell types and processes such as granulopoiesis. CD40 triggering on stromal cells has been documented to enhance the expression of granulopoiesis growth factors such as granulocyte-colony-stimulating factor (G-CSF) and granulocyte/monocyte-colony-stimulating factor (GM-CSF), and upon disruption of the CD40/CD40L-signaling pathway, as in the case of X-linked hyperimmunoglobulin M (IgM) syndrome (XHIGM), it can lead to neutropenia. In chronic idiopathic neutropenia (CIN) of adults, however, under the influence of an inflammatory microenvironment, CD40L plays a role in granulocytic progenitor cell depletion, providing thus a pathogenetic cause of CIN. Irene Mavroudi and Helen A. Papadaki Copyright © 2011 Irene Mavroudi and Helen A. Papadaki. All rights reserved. Regulation of Neutrophil Survival/Apoptosis by Mcl-1 Wed, 26 Oct 2011 00:00:00 +0000 Neutrophil granulocytes have the shortest lifespan among leukocytes in the circulation and die via apoptosis. At sites of infection or tissue injury, prolongation of neutrophil lifespan is critical for effective host defense. Apoptosis of inflammatory neutrophils and their clearance are critical control points for termination of the inflammatory response. Evasion of neutrophil apoptosis aggravates local injury and leads to persistent tissue damage. The short-lived prosurvival Bcl-2 family protein, Mcl-1 (myeloid cell leukemia-1), is instrumental in controlling apoptosis and consequently neutrophil lifespan in response to rapidly changing environmental cues during inflammation. This paper will focus on multiple levels of control of Mcl-1 expression and function and will discuss targeting Mcl-1 as a potential therapeutic strategy to enhance the resolution of inflammation through accelerating neutrophil apoptosis. Eric Milot and János G. Filep Copyright © 2011 Eric Milot and János G. Filep. All rights reserved. Role of the Inflammasome, IL-1𝛽, and IL-18 in Bacterial Infections Sat, 01 Oct 2011 00:00:00 +0000 The inflammasome is an important innate immune pathway that regulates at least two host responses protective against infections: (1) secretion of the proinflammatory cytokines IL-1β and IL-18 and (2) induction of pyroptosis, a form of cell death. Inflammasomes, of which different types have been identified, are multiprotein complexes containing pattern recognition receptors belonging to the Nod-like receptor family or the PYHIN family and the protease caspase-1. The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized. Production of IL-1β and IL-18 and induction of pyroptosis of the infected cell have been shown to be protective against many infectious agents. Here, we review the recent literature concerning inflammasome activation in the context of bacterial infections and identify important questions to be answered in the future. Manoranjan Sahoo, Ivonne Ceballos-Olvera, Laura del Barrio, and Fabio Re Copyright © 2011 Manoranjan Sahoo et al. All rights reserved. Role of Neutrophil Apoptosis in the Resolution of Inflammation Mon, 01 Jan 1900 00:00:00 +0000 Neutrophil granulocytes play a central role in host defense to infection and tissue injury. Their timely removal is essential for resolution of inflammation. Increasing evidence identified neutrophil apoptosis as an important control point in the development and resolution of inflammation. Delayed apoptosis and/or impaired clearance of neutrophils aggravate and prolong tissue injury. This review will focus on outside-in signals that provide survival cues for neutrophils, the hierarchy of pro- and antiapoptotic signals, and molecular targets in the antiapoptotic signaling network that can be exploited by endogenously produced bioactive lipids, such as lipoxins or pharmacological inhibitors, including cyclin-dependent kinase inhibitors, to redirect neutrophils to apoptosis in vivo, thus promoting resolution of inflammation. Driss El Kebir and János G. Filep Copyright © 2010 Driss El Kebir and János G. Filep. All rights reserved. A Novel Tool for High-Throughput Screening of Granulocyte-Specific Antibodies Using the Automated Flow Cytometric Granulocyte Immunofluorescence Test (Flow-GIFT) Mon, 01 Jan 1900 00:00:00 +0000 Transfusion-related acute lung injury (TRALI) is a severe complication related with blood transfusion. TRALI has usually been associated with antibodies against leukocytes. The flow cytometric granulocyte immunofluorescence test (Flow-GIFT) has been introduced for routine use when investigating patients and healthy blood donors. Here we describe a novel tool in the automation of the Flow-GIFT that enables a rapid screening of blood donations. We analyzed 440 sera from healthy female blood donors for the presence of granulocyte antibodies. As positive controls, 12 sera with known antibodies against anti-HNA-1a, -b, -2a; and -3a were additionally investigated. Whole-blood samples from HNA-typed donors were collected and the test cells isolated using cell sedimentation in a Ficoll density gradient. Subsequently, leukocytes were incubated with the respective serum and binding of antibodies was detected using FITC-conjugated antihuman antibody. 7-AAD was used to exclude dead cells. Pipetting steps were automated using the Biomek NXp Multichannel Automation Workstation. All samples were prepared in the 96-deep well plates and analyzed by flow cytometry. The standard granulocyte immunofluorescence test (GIFT) and granulocyte agglutination test (GAT) were also performed as reference methods. Sixteen sera were positive in the automated Flow-GIFT, while five of these sera were negative in the standard GIFT (anti—HNA 3a, n = 3; anti—HNA-1b, n = 1) and GAT (anti—HNA-2a, n = 1). The automated Flow-GIFT was able to detect all granulocyte antibodies, which could be only detected in GIFT in combination with GAT. In serial dilution tests, the automated Flow-GIFT detected the antibodies at higher dilutions than the reference methods GIFT and GAT. The Flow-GIFT proved to be feasible for automation. This novel high-throughput system allows an effective antigranulocyte antibody detection in a large donor population in order to prevent TRALI due to transfusion of blood products. Xuan Duc Nguyen, Thomas Dengler, Monika Schulz-Linkholt, and Harald Klüter Copyright © 2011 Xuan Duc Nguyen et al. All rights reserved. Multiple Myeloma and B Cell Lymphoma. Investigation of IL-6, IL-6 Receptor Antagonist (IL-6RA), and GP130 Antagonist (GP130A) Using Various Parameters in an In Vitro Model Mon, 01 Jan 1900 00:00:00 +0000 Interleukin-6 (IL-6) affects the survival and proliferation of myeloma cells via autocrine and/or paracrine mechanisms. In this study, we investigated the effects of IL-6, IL-6 receptor antagonist (IL-6RA), and gp130 antagonist (gp130A) on the membrane expressions of IL-6R and gp130, on the viability, on the proliferation, on the DNA synthesis, and on the cell cycle phases in several multiple myeloma (MM) cell lines and B cell lymphoma cell lines. Our results showed that (1) all five MM cell lines (OPM-2, RPMI-8226, U-266, KMS-12-BM, MOLP-8) expressed surface IL-6R and gp130, the B cell lymphomas (WSU-1, DOHH-2, U-698) expressed only gp130; (2) exogenous IL-6 markedly up-regulated the expression of membrane IL-6R (up to 186%) and down-regulated the gp130 receptor (down to 4%) in MM cell lines, the membrane expression of gp130 in B cell lymphomas was not altered; (3) IL-6 markedly increased the spontaneous proliferation (up to 151%) in all MM cell lines, that of B cell lymphomas was not affected; (4) IL-6 increased the DNA synthesis in the S cell cycle phase of MM cells and arrested the stage G2/M, IL-6 was ineffective in any cell cycle phase of B cell lymphoma; (5) IL-6RA inhibited the membrane IL-6R partially, the proliferation was decreased only slightly; and (6) although gp130A inhibited the membrane gp130 completely, the proliferation was decreased 81—78% in MM and B cell lymphoma cell lines. This means that gp130 is not absolutely necessary for the cellular signalling cascade via JAK/STAT and RAS/MAPK pathways involved in proliferation and viability. Our results give an indication in the therapy of MM: IL-6 antibody (IL-6A) alone or in combination with IL-6RA. The latter could be more effective. This kind of therapy is not recommended for B cell lymphoma, as these cells have no IL-6R. Eva Kovacs Copyright © 2006 Eva Kovacs. All rights reserved. Castleman's Disease: An Intrapulmonary Form with Intrafissural Development Mon, 01 Jan 1900 00:00:00 +0000 Castleman's disease (CD) is an uncommon, mainly benign, lymphoproliferative disorder of unknown etiology, mostly involving the mediastinum. Parenchymal lung involvement of the disease is exceedingly rare. We describe a case of CD in a 23-year-old woman with a 4-year history of recurring dyspnea and nonproductive cough, whose chest X-ray showed an abnormal shadow of the right hilum. Chest computed tomography confirmed the presence of a tissue-density mass of the right lower lobe, demonstrating poor contrast enhancement, associated with multiple laterotracheal and mediastinal lymphadenopathies. The patient underwent curative surgery, revealing a right hilar compressive mass, with an intrafissural development between the superior and middle lobes. Pneumonectomy was performed due to profuse bleeding. This case of CD is particular because of its unusual intrapulmonary location and its intrafissural development. Poor contrast enhancement is atypical in CD. Hajer Racil, Sana Cheikh Rouhou, Olfa Ismail, Saoussen Hantous-Zannad, Nawel Chaouch, Mourad Zarrouk, Belhassen Smati, Faouzi Mezni, and Abdellatif Chabbou Copyright © 2009 Hajer Racil et al. All rights reserved. Hypothesis: Ran GTPase-Based Potential Therapeutic Interventions Against Lethal Microbial Infections Mon, 01 Jan 1900 00:00:00 +0000 Host innate immune response represents a vital immediate defense against infections by a diverse group of microorganisms that include bacteria, viruses, and fungi. Many types of cell surface receptors in mammalian cells specifically recognize particular groups of microorganisms and transmit response signals to the nuclei via multiple signal transduction pathways. These signaling pathways must merge at some point and are likely to be redundant, as the host innate immune response to many microorganisms is remarkably similar; it is characterized by the production of proinflammatory cytokines such as TNFα, IL-1, and IL-6 by the principal cell types – macrophages and dendritic cells. Since these cytokines influence greatly the magnitude of the cascade of inflammatory events, the proportion and the actual amount of each among the cytokine group may be a characteristic of each type of infections. Immune modulation by systematically up-regulate or down-modulate these cytokines would conceivably have major therapeutic potential. We have recently shown that two alleles of Ran cDNAs – RanT/n and RanC/d – may possess these characteristics. Thus the applica-tion of Ran to the treatment of septic shock, lethal anthrax shock, or adenovirus-induced toxicities may open up many interesting possibilities in the future. Peter M.C. Wong Copyright © 2002 Peter M.C.�Wong. All rights reserved. New Antibody Conjugates in Cancer Therapy Mon, 01 Jan 1900 00:00:00 +0000 Targeting of radiation, drugs, and protein toxins to cancers selectively with monoclonal antibodies (MAbs) has been a topic of considerable interest and an area of continued development. Radioimmunotherapy (RAIT) of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti-CD22 MAb, 90Y-epratuzumab. The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and preclinically. The area of drug-conjugated antibodies is progressing with encouraging data published for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The Dock-and-Lock platform technology has contributed to the design and the evaluation of complex antibody-cytokine and antibody-toxin conjugates. This review describes the advances made in these areas, with illustrations taken from advances made in the authors' institutions. Serengulam V. Govindan and David M. Goldenberg Copyright © 2010 Serengulam V. Govindan and David M. Goldenberg. All rights reserved. Mediation of Immunoregulation by Dendritic Cells Mon, 01 Jan 1900 00:00:00 +0000 Suryasarathi Dasgupta Copyright © 2011 Suryasarathi Dasgupta. All rights reserved. Toll-Like Receptors, Their Ligands, and Atherosclerosis Mon, 01 Jan 1900 00:00:00 +0000 Atherosclerosis is a disease characterized by inflammation in the arterial wall. Atherogenesis is dependent on the innate immune response involving activation of Toll-like receptors (TLRs) and the expression of inflammatory proteins. TLRs, which recognize various pathogen-associated molecular patterns, are expressed in various cell types within the atherosclerotic plaque. Microbial agents are associated with an increased risk of atherosclerosis and this is, in part, due to activation of TLRs. Recently considerable evidence has been provided suggesting that endogenous proteins promote atherosclerosis by binding to TLRs. In this review, we describe the role of TLRs in atherosclerosis with particular emphasis on those atherogenic endogenous proteins that have been implicated as TLR ligands. Conrad P. Hodgkinson and Shu Ye Copyright © 2011 Conrad Hodgkinson and Shu Ye. All rights reserved. Role of Polymorphonuclear Leukocytes in the Pathophysiology of Typical Hemolytic Uremic Syndrome Mon, 01 Jan 1900 00:00:00 +0000 Thrombotic microangiopathy and acute renal failure are cardinal features of post-diarrheal hemolytic uremic syndrome (HUS). These conditions are related to endothelial and epithelial cell damage induced by Shiga toxin (Stx), through an interaction with its globotriaosylceramide (Gb3) receptor. Although, Stx is the main pathogenic factor and necessary for HUS development, clinical and experimental evidence suggest that the inflammatory response is able to potentiate Stx toxicity. Lipopolysaccharides (LPS) and neutrophils (PMN) represent two central components of inflammation during a Gram-negative infection. In this regard, patients with high peripheral PMN counts at presentation have a poor prognosis. In the present review, we discuss the contribution of experimental models and patient's studies in an attempt to elucidate the pathogenic mechanisms of HUS. Ramón A. Exeni, Gabriela C. Fernández, and Marina S. Palermo Copyright © 2007 Ramón A. Exeni et al. All rights reserved. Investigation of the Association between Metabolic Syndrome and Disease Activity in Rheumatoid Arthritis Mon, 01 Jan 1900 00:00:00 +0000 Rheumatoid arthritis (RA) is the most common form of autoimmune arthritis. Increased prevalence of metabolic syndrome (MetS) in RA may occur secondary to specific drug treatment and reduced physical activity associated with this condition. However, some recent studies suggest contradictory theories about the association of RA with MetS. This study was designed to evaluate the frequency of MetS in RA patients and the relationship between MetS with RA disease activity and body mass index (BMI). The study was conducted on 120 RA patients and 431 age- and sex-matched apparently healthy controls. A considerable proportion of patients were being treated with prednisolone and/or methotrexate and/or hydroxychloroquine. Disease activity was measured by the 28 joint count of disease activity score-Cerythrocyte sedimentation rate (DAS28ESR). MetS was evaluated according to International Diabetic Federation (IDF) and Adult Treatment Panel III (ATP III) criteria. The prevalence of MetS was significantly higher in the control group (p = 0.005). We did not find any difference in the prevalence of MetS between the patients with DAS < 3.2 and DAS ≥ 3.2. There was no association between the DAS28 score and the presence of MetS components by either definition. Multiple logistic regression analysis showed that the odds of a DAS > 3.2 in patients with BMI between 25 and 30 kg/m2 (OR = 0.1, p = 0.01) and BMI > 30 kg/m2 (OR = 0.3, p = 0.1), in comparison to BMI < 25 kg/m2, was 1/5 and 1/3, respectively. RA was not found to increase the risk of MetS. In addition, disease activity in RA patients was not influenced by the presence of MetS. Maryam Sahebari, Ladan Goshayeshi, Zahra Mirfeizi, Zahra Rezaieyazdi, Mohammad R. Hatef, Majid Ghayour-Mobarhan, Saeed Akhlaghi, Amirhossein Sahebkar, and Gordon A. Ferns Copyright © 2011 Maryam Sahebari et al. All rights reserved. Development of Hematopoietic and Endothelial Cells from Human Embryonic Stem Cells: Lessons from the Studies using Mouse as a Model Mon, 01 Jan 1900 00:00:00 +0000 The current progress using the human embryonic stem cell (hESC) model system has provided much insight into the early origins of the hematopoietic and endothelial lineages, particularly the elusive hemangioblast. Recently, the cellular hierarchy and molecular regulation controlling hematopoietic commitment have been further elucidated. These findings not only provide new insights into early human development, but also advance the knowledge required to develop techniques capable of generating a given cell type for potential clinical applications. This review will focus on the latest advances using the hESC model system, capitalizing on the well-established mouse embryonic stem cell model system, as a means to investigate the lineage commitment events underlying the early embryonic development of human hematopoietic and endothelial cells. Anna Jezierski, Albert Swedani, and Lisheng Wang Copyright © 2007 Anna Jezierski et al. All rights reserved. A Potential Concept In The Management of Tumors With Modulation of Prostaglandin, Nitric Oxide and Antioxidants Mon, 01 Jan 1900 00:00:00 +0000 Prostaglandins (PGs), nitric oxide (NO), free radicals and chronic inflammation play a major role in tumorogenesis. We have found in vivo that PGs suppress antibody production; reduce serum iron, and modulate bone marrow function. Tumors are associated with immunosuppression and anemia. We have hypothesized that the over-production of PGs is responsible for immunosuppression and anemia in conditions associated with increased production of PG such as tumor, and that PG inhibitors might help reversing immunosuppression and anemia, and play a role in eradication and prevention of tumors. This is supported by reports that demonstrate the immunosuppressive effects of PGs in tumors. PG inhibitors have also been shown to be crucial in the prevention of tumors such as esophageal and colon cancers. Others and we have found that high NO production was encountered in patients with cancer while antioxidants are decreased. Evidence supports the efficacy of PG inhibition in malignancies, and the concept of PG inhibition, NO modulation, anti-oxidants, immunotherapy with antibody or immune cells, and anti-inflammatory agents when used in the prevention and management of malignancies are discussed. Noori S. Al-Waili Copyright © 2007 Noori S. Al-Waili. All rights reserved. A Case of Immunotactoid Glomerulopathy with Rapid Progression to End-Stage Renal Disease Mon, 01 Jan 1900 00:00:00 +0000 Immunotactoid glomerulopathy (IGN) is a rare immunoglobulin deposition disease. It is often mistaken for cryoglobulinemia or amyloidosis due to the similarities on biopsy findings. The disease progresses to end-stage renal disease (ESRD) within 7 months to 10 years. This is the first case reported of a patient with a diagnosis of IGN who developed acute kidney injury (AKI) and ESRD within 1 week of initial presentation. Shikha Jain and Darshika Chhabra Copyright © 2009 Shikha Jain and Darshika Chhabra. All rights reserved. The Role and Therapeutic Potential of Endothelial Progenitor Cells in Tumor Neovascularization Mon, 01 Jan 1900 00:00:00 +0000 Although the cellular and molecular mechanisms of tumor growth and metastasis are not completely understood, it is established that formation and growth of new blood vessels is a conditio sine qua non for tumor survival, growth, and expansion. Numerous studies over the past decades demonstrated that neovascularization associated with tumor growth occurs via angiogenic and vasculogenic mechanisms that involve sprouting angiogenesis, intussusceptive angiogenesis, vessel co-option, vasculogenic mimicry, lymphangiogenesis, and the recruitment of endothelial progenitor cells (EPCs). Due to their ability to self-renew, circulate, home to the ischemic sites, and differentiate into mature endothelial cells, EPCs hold enormous potential to be used as a diagnostic and/or therapeutic agent in antitumor therapies. Hence, this review focuses on EPCs and their role in tumor angiogenesis with the emphasis on EPC recruitment/migration, and the potential use of EPCs as a therapeutic tool and imaging probe. Branislava Janic and Ali S. Arbab Copyright © 2010 Branislava Janic and Ali S. Arbab. All rights reserved. Breaking Immunological Tolerance through OX40 (CD134) Mon, 01 Jan 1900 00:00:00 +0000 Immunological tolerance represents a mechanism by which cells of the host remain protected from the immune system. Breaking of immunological tolerance can result in a variety of autoimmune diseases such as rheumatoid arthritis, diabetes, and multiple sclerosis. The reasons for tolerance breaking down and autoimmune processes arising are largely unknown but of obvious interest for therapeutic intervention of these diseases. Although reversal of the tolerant state is generally unwanted, there are instances where this may be of benefit to the host. In particular, one way a cancerous cell escapes being targeted by the immune system is through tolerance mechanisms that in effect turn off the reactivity of T lymphocytes that can respond to tumor-associated peptides. Thus tolerance represents a major obstacle in developing effective immunotherapy against tumors. The molecules that are involved in regulating immunological tolerance are then of interest as they may be great targets for positively or negatively manipulating the tolerance process. Pratima Bansal-Pakala and Michael Croft Copyright © 2001 Pratima Bansal-Pakala and Michael Croft. All rights reserved. Clinical Holistic Medicine: A Pilot Study on HIV and Quality of Life and a Suggested Cure for HIV and AIDS Mon, 01 Jan 1900 00:00:00 +0000 This study was undertaken to examine the association between the immunological impact of HIV (measured by CD4 count) and global self-assessed quality of life (QOL) (measured with QOL1) for people suffering from HIV, to see if the connection was large and statistically strong enough to support our hypothesis of a strong QOL-immunological connection through the nonspecific, nonreceptor-mediated immune system, and thus to give a rationale for a holistic cure for HIV. This cross-sectional population study in Uganda included 20 HIV infected persons with no symptoms of AIDS and a CD4 count above 200 mill./liter. The main outcome measures were CD4 count, global QOL measured with the validated questionnaire QOL1, translated to Luganda and translated back to English. We found a large, clinically significant correlation between the number of T-helper cells (CD4) and global self-assessed quality of life (QOL1) (r = 0.57, p = 0.021), when controlled for age, gender, and years of infection. Together with other studies and holistic medicine theory, the results have given rationale for a holistic cure for HIV. We suggest, based on our findings and theoretical considerations, that HIV patients who improve their global QOL, also will improve their CD4 counts. Using the technique of holistic medicine based on the life mission theory and the holistic process theory of healing, we hypothesize that the improvement of QOL can have sufficient biological effect on the CD4, which could avoid or postpone the development of AIDS. A holistic HIV/AIDS cure improving the QOL draws on hidden resources in the person and is thus affordable for everybody. Improving global QOL also means a higher consciousness and a more ethical attitude, making it more difficult for the HIV-infected person to pass on the infection. Søren Ventegodt, Trine Flensborg-Madsen, Niels Jørgen Andersen, Mohammed Morad, and Joav Merrick Copyright © 2004 Soren Ventegodt et al. All rights reserved. A Case of Simultaneous, Biopsy-Proven, Classic, ANCA-Positive Wegener's Granulomatosis and Anti-GBM Disease, but without Detectible Circulating Anti-GBM Antibodies Mon, 01 Jan 1900 00:00:00 +0000 Wegener's granulomatosis (WG) is a systemic, necrotizing, granulomatous vasculitis of unknown etiology. Approximately 75% of cases present as classic WG with both pulmonary and renal involvement, while the remaining 25% of patients present with a limited form with either predominantly upper or lower respiratory tract symptoms. Ninety percent of WG patients have circulating anti–neutrophil cytoplasmic antibodies (ANCA), and approximately 10% have both circulating ANCA antibodies and concomitant anti–glomerular basement membrane (anti-GBM) disease on renal biopsy. Virtually all of these patients also have circulating anti-GBM antibodies. While it has been reported that some patients with ANCA vasculitis have circulating anti-GBM antibodies, and patients with anti-GBM disease may have positive ANCA, review of the literature does not demonstrate other cases of biopsy-proven, simultaneous, ANCA-associated vasculitis and anti-GBM disease. We report a case of simultaneous, biopsy-proven, classic, ANCA-positive WG and anti-GBM disease, but without detectible circulating anti-GBM antibodies. We present findings characteristic of both WG and linear IgG deposition along the GBM suggesting concurrent anti-GBM disease, in the absence of detectable circulating anti-GBM antibodies. Possible theories to explain the absence of these antibodies are discussed. Aleksandra Gmurczyk, Shubhada N. Ahya, Robert Goldschmidt, George Kim, L. Tammy Ho, and Kevin Nash Copyright © 2010 Aleksandra Gmurczyk et al. All rights reserved. Clinical Holistic Medicine: Chronic Infections and Autoimmune Diseases Mon, 01 Jan 1900 00:00:00 +0000 The consciousness-based (holistic) medical toolbox might be useful in general practice and in cases of recurrent infections and chronic infection or inflammation. From our clinical experiences, there is hope for improvement from a number of diseases caused by disorders affecting the regulation of the immune system when the physician includes the holistic medical approach.Our scientific understanding of the connection between consciousness and cellular order is still limited. Consciousness-based holistic medicine removes (as explained by the holistic process theory of healing) the “blockages” in the tissues of the body and facilitates function and informational exchange of the cells of the body. Many blockages and repressed feelings in an area would imply “noise and disturbances”” on the level of intercellular communications, which in turn means major difficulties for the cells of the immune system. For this they are totally dependent on the body information system, which the holistic treatment aims to recover. Processing the blockages increases the coherence of the cells and organism, thus increasing the intercellular flow of information in the area and thus strengthening the immune defense and healing the disease. The area of clinical holistic medicine is going through a rapid development and the toolbox of consciousness-based medicine is available for dealing with many diseases arising from disturbances in the regulation of the immune system. Holistic medicine has yet to be better explained scientifically and our proposed holistic cures have yet to be documented clinically. We invite the medical community to cooperate on this important challenge. Søren Ventegodt and Joav Merrick Copyright © 2005 Søren Ventegodt and Joav Merrick. All rights reserved. Immunotherapeutic Strategies for Alzheimer's Disease Treatment Mon, 01 Jan 1900 00:00:00 +0000 Naturally occurring antibodies against amyloid-β peptides have been found in human cerebrospinal fluid and in the plasma of healthy individuals, but were significantly lower in Alzheimer's disease (AD) patients, suggesting that AD may be an immunodeficient disorder. The performance of anti-amyloid-β antibodies in transgenic mice models of AD showed that they are delivered to the central nervous system, preventing and dissolving amyloid-β plaques. Moreover, these antibodies protected the mice from learning and age-related memory deficits. Active and/or passive immunization against the amyloid-β peptide has been proposed as a method for preventing and/or treating AD. Immunotherapy represents fascinating ways to test the amyloid hypothesis and offers genuine opportunities for AD treatment, but requires careful antigen and antibody selection to maximize efficacy and minimize adverse events. Beka Solomon Copyright © 2009 Beka Solomon. All rights reserved. New Therapeutic Approaches for the Treatment of Rheumatoid Arthritis may Rise from the Cholinergic Anti-Inflammatory Pathway and Antinociceptive Pathway Mon, 01 Jan 1900 00:00:00 +0000 Due to the complex etiology of rheumatoid arthritis (RA), it is difficult to be completely cured at the current stage although many approaches have been applied in clinics, especially the wide application of nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). New drug discovery and development via the recently discovered cholinergic anti-inflammatory and antinociceptive pathways should be promising. Based on the above, the nicotinic acetylcholine receptor agonists maintain the potential for the treatment of RA. Therefore, new therapeutic approaches may rise from these two newly discovered pathways. More preclinical experiments and clinical trials are required to confirm our viewpoint. Xiao Hua Pan, Jianxin Zhang, Xiaowei Yu, Ling Qin, Ligeng Kang, and Peng Zhang Copyright © 2010 Xiao Hua Pan et al. All rights reserved. Anaplastic, T-Cell, Non-Hodgkin's Lymphoma Presenting with Haematuria Mon, 01 Jan 1900 00:00:00 +0000 Non-Hodgkin's lymphoma (NHL) represents about 3% of new cancer cases[1]. Bladder involvement has been found in approximately 3-13% of NHL patients when studied at postmortem[2]. Although accounting for only 0.2% of all primary bladder tumours, the majority of bladder lymphomas are B-cell lymphomas. T-cell lymphoma of the bladder is incredibly rare. We describe a case of anaplastic, T-cell lymphoma presenting with haematuria and loin pain, with unilateral upper tract obstruction. C. Blick, S. Abdelhadi, D. Bailey, and A. Muneer Copyright © 2008 C. Blick et al. All rights reserved. New Frontiers in the Treatment of Multiple Myeloma Mon, 01 Jan 1900 00:00:00 +0000 Recent leaps in elucidating the biology of myeloma, particularly the intracellular pathways and the complex interaction with the bone marrow microenvironment, have resulted in an unprecedented surge of novel, targeted therapies and therapeutic regimens. There are currently over 30 new agents being tested in the treatment of multiple myeloma (MM). Many of these are novel, targeted agents that have demonstrated significant efficacy and prolonged survival. In this review, we summarize the current understanding of the mechanisms of action of novel therapies being tested in the preclinical and clinical settings in MM. These include agents that act directly on the intracellular signaling pathways, cell maintenance processes, and cell surface receptors. Finally, we present the clinical responses to some of these agents when used alone or in combination in clinical trials of patients with MM. Indeed, MM has become a model disease for the development of novel, therapeutic agents. Janice Jin Hwang, Irene M. Ghobrial, and Kenneth C. Anderson Copyright © 2006 Janice Jin Hwang et al. All rights reserved. Low-Avidity Antibodies to Carbonic Anhydrase-I and -II in Autoimmune Chronic Pancreatitise Mon, 01 Jan 1900 00:00:00 +0000 Antibodies (Abs) to carbonic anhydrase (isoforms CA-I and CA-II) have been considered pathogenic factors in the development of autoimmune pancreatitis. Besides, such autoAbs might accelerate the pancreatic damage in alcoholic chronic pancreatitis (CP). The aim of the present study was to evaluate the presence of serum Abs to CA-I and CA-II in CP and the relative affinity of these Abs. Maria J. Bartolomé, Gonzalo de las Heras, and Marcos López-Hoyos Copyright © 2002 Maria J. Bartolome et al. All rights reserved. Selective Inhibitors of Kv11.1 Regulate IL-6 Expression by Macrophages in Response to TLR/IL-1R Ligands Mon, 01 Jan 1900 00:00:00 +0000 The mechanism by which the platelet-endothelial cell adhesion molecule PECAM-1 regulates leukodiapedesis, vascular endothelial integrity, and proinflammatory cytokine expression in vivo is not known. We recently identified PECAM-1 as a negative regulator of Kv11.1, a specific voltage-gated potassium channel that functioned in human macrophages to reset a resting membrane potential following depolarization. We demonstrate here that dofetilide (DOF), a selective inhibitor of the Kv11.1 current, had a profound inhibitory effect on neutrophil recruitment in mice following TLR/IL-1R–elicited peritonitis or intrascrotal injection of IL-1β, but had no effect on responses seen with TNFα. Furthermore, inhibitors of Kv11.1 (DOF, E4031, and astemizole), but not Kv1.3 (margatoxin), suppressed the expression of IL-6 and MCP-1 cytokines by murine resident peritoneal macrophages, while again having no effect on TNFα. In contrast, IL-6 expression by peritoneal mesothelial cells was unaffected. Using murine P388 cells, which lack endogenous C/EBPβexpression and are unresponsive to LPS for the expression of both IL-6 and MCP-1, we observed that DOF inhibited LPS-induced expression of IL-6 mRNA following ectopic expression of wild-type C/EBPβ, but not a serine-64 point mutant. Finally, DOF inhibited the constitutive activation of cdk2 in murine peritoneal macrophages; cdk2 is known to phosphorylate C/EBPβ at serine-64. Taken together, our results implicate a potential role for Kv11.1 in regulating cdk2 and C/EBPβ activity, where robust transactivation of both IL-6 and MCP-1 transcription is known to be dependent on serine-64 of C/EBPβ. Our data might also explain the altered phenotypes displayed by PECAM-1 knockout mice in several disease models. Cheryl Hunter, Tejas B. Kadakia, Dianne Cooper, Mauro Perretti, Richard C. Schwartz, and Simon B. Brown Copyright © 2010 Cheryl Hunter et al. All rights reserved. TCR-Engineered, Customized, Antitumor T Cells for Cancer Immunotherapy: Advantages and Limitations Mon, 01 Jan 1900 00:00:00 +0000 The clinical outcome of the traditional adoptive cancer immunotherapy approaches involving the administration of donor-derived immune effectors, expanded ex vivo, has not met expectations. This could be attributed, in part, to the lack of sufficient high-avidity antitumor T-cell precursors in most cancer patients, poor immunogenicity of cancer cells, and the technological limitations to generate a sufficiently large number of tumor antigen-specific T cells. In addition, the host immune regulatory mechanisms and immune homeostasis mechanisms, such as activation-induced cell death (AICD), could further limit the clinical efficacy of the adoptively administered antitumor T cells. Since generation of a sufficiently large number of potent antitumor immune effectors for adoptive administration is critical for the clinical success of this approach, recent advances towards generating customized donor-specific antitumor-effector T cells by engrafting human peripheral blood-derived T cells with a tumor-associated antigen-specific transgenic T-cell receptor (TCR) are quite interesting. This manuscript provides a brief overview of the TCR engineering-based cancer immunotherapy approach, its advantages, and the current limitations. Arvind Chhabra Copyright © 2011 Arvind Chhabra. All rights reserved. Cytokine-Based Immunotherapy for Advanced Kidney Cancer: Past Results and Future Perspectives in the Era of Molecularly Targeted Agents Mon, 01 Jan 1900 00:00:00 +0000 Until recently, immunotherapy has been the only therapeutic option available for patients with advanced kidney cancer, even though different choices were often made on the two sides of the Atlantic Ocean. The absence of alternatives made different immunotherapeutic approaches common practice, even with few adequate randomized studies that addressed key questions, such as the best treatment and schedule, and so on. The recent registration of the first two, molecularly targeted, agents Sorafenib and Sunitinib could (and will) render many therapeutic approaches, e.g., single-agent Interferon, obsolete. In this review, we shall cover the past achievements obtained so far with cytokine-based immunotherapy and discuss the present role of immunotherapy in the era of molecularly targeted agents. In particular, specific indications for immunotherapy are emerging (e.g., the use of Interleukin-2 in patients with high CAIX expression), while new trials are ongoing to test immunotherapy in combination with molecularly targeted agents, such as Sorafenib, Sunitinib, or Bevacizumab. Camillo Porta, Chiara Paglino, Ilaria Imarisio, and Lucia Bonomi Copyright © 2007 Camillo Porta et al. All rights reserved. Anti-Inflammatory Prostanoids: Focus on the Interactions between Electrophile Signaling and Resolution of Inflammation Mon, 01 Jan 1900 00:00:00 +0000 Prostanoids are products of cyclooxygenase biosynthetic pathways and constitute a family of lipidic mediators of widely diverse structures and biological actions. Besides their known proinflammatory role, numerous works have revealed the anti-inflammatory effects of various prostanoids and established their role in the resolution of inflammation. Among these, prostaglandins with cyclopentenone structure (cyPG) are electrophilic lipids that may act through various mechanisms, including the activation of nuclear and membrane receptors and, importantly, direct addition to protein cysteine residues and modification of protein function. Due to their ability to influence cysteine modification–mediated signaling, cyPG may play a critical role in the interplay between redox and inflammatory signaling pathways. Moreover, cellular redox status modulates cyPG addition to proteins; thus, a reciprocal regulation exists between these two factors. After initial controversy, it is becoming clear that endogenous cyPG are generated at concentrations sufficient to promote inflammatory resolution. As for other prostanoids, cyPG effects are highly dependent on context factors and they may exert pro- or anti-inflammatory actions in a cell type–dependent manner, or even biphasic or dual actions in a given cell type or tissue. In light of the growing number of cyPG protein targets identified, cyPG resemble other pleiotropic mediators acting through protein modification. However, their complex structure results in an inter- and intramolecular selectivity of the residues being modified, thus opening the way for structure-activity and drug discovery studies. Detailed characterization of cyPG interactions with cellular proteins will help us to understand their mechanism of action fully and establish their therapeutic potential in inflammation. Beatriz Díez-Dacal and Dolores Pérez-Sala Copyright © 2010 Beatriz Díez-Dacal and Dolores Pérez-Sala. All rights reserved. Transepithelial Migration Process Induced by Interleukin-8 Delays Polymorphonuclear Leukocytes (PMNL) Apoptosis Mon, 01 Jan 1900 00:00:00 +0000 Gaëlle Le'Negrate, Phillippe Rostagno, Bernard Rossi, and Paul Hofman Copyright © 2001 Phillippe Rostagno et al. All rights reserved. A Lesson in Survival, by Giardia lamblia Mon, 01 Jan 1900 00:00:00 +0000 In the relationships between host and parasites, there is a cross-talk that involves diverse mechanisms developed by two different genetic systems during years of evolution. On the one hand, immunocompetent hosts have developed effective innate and acquired immune responses that are used to restrict or avoid parasitism. On the other hand, parasites evade the immune response, expressing different antigens on their surface or by using other specific mechanisms, such as nutrient depletion. In this review, we analyze the survival mechanisms used by the protozoan parasite Giardia lamblia during infection. In particular, we examine the multiple roles played by the enzyme arginine deiminase during colonization of the gut, also involving the parasite's mechanism of antigenic variation. Potential drug targets for the treatment of giardiasis are also discussed. Andrea A. S. Rópolo and Maria C. Touz Copyright © 2010 Andrea A. S. Rópolo and Maria M. C. Touz. All rights reserved. Effects of Hyperbaric Oxygen on Inflammatory Response to Wound and Trauma: Possible Mechanism of Action Mon, 01 Jan 1900 00:00:00 +0000 There is growing interest in expanding the clinical applications for HBO2 (hyperbaric oxygen therapy) into new medical and surgical fields. The pathophysiology of response towards wounds, infection, trauma, or surgery involves various chemical mediators that include cytokines, prostaglandins (PGs), and nitric oxide (NO). The beneficial role played by HBO2 in wound healing, carbon monoxide poisoning, decompression sickness, and other indications is well documented. However, the exact mechanism of action is still poorly understood. This review addresses the effects of HBO2 on PGs, NO, and cytokines involved in wound pathophysiology and inflammation in particular. The results of this review indicate that HBO2 has important effects on the biology of cytokines and other mediators of inflammation. HBO2 causes cytokine down-regulation and growth factor up-regulation. HBO2 transiently suppresses stimulus-induced proinflammatory cytokine production and affects the liberation of TNFα (tumor necrosis factor alpha) and endothelins. VEGF (vascular endothelial growth factor) levels are significantly increased with HBO2, whereas the value of PGE2 and COX-2 mRNA are markedly reduced. The effect of HBO2 on NO production is not well established and more studies are required. In conclusion, cytokines, PGs, and NO may play a major role in the mechanism of action of HBO2 and further research could pave the way for new clinical applications for HBO2 to be established. It could be proposed that chronic wounds persist due to an uncontrolled pathological inflammatory response in the wound bed and that HBO2 enhances wound healing by damping pathological inflammation (anti-inflammatory effects); this hypothetical proposal remains to be substantiated with experimental results. Noori S. Al-Waili and Glenn J. Butler Copyright © 2006 Noori S. Al-Waili and Glenn J. Butler. All rights reserved. Activation and Genetic Modification of Human Monocyte-Derived Dendritic Cells using Attenuated Salmonella typhimurium Mon, 01 Jan 1900 00:00:00 +0000 Live attenuated bacterial vectors, such as Salmonella typhimurium, have shown promise as delivery vehicles for DNA. We have examined two new strains of S. typhimurium and their impact on dendritic cell maturation (CD12-sifA/aroC mutant and WT05-ssaV/aroC, both in TML background). Strain WT05 matured dendritic cells in a more efficient way; caused higher release of cytokines TNF-α, IL-12, IL-1β; and was efficient for gene transfer. These findings suggest that the genetic background of the attenuation can influence the pattern of inflammatory immune response to Salmonella infection. Agnieszka Michael, Justin John, Brendan Meyer, and Hardev Pandha Copyright © 2010 Agnieszka Michael et al. All rights reserved. Chemokines Mon, 01 Jan 1900 00:00:00 +0000 Chemokines are a family of polypeptides that direct the migration of leukocytestoward a site of infection. They play a major role in autoimmune disease and chemokine receptors have recently been found to mediate HIV-1 fusion. In this short review we examine the role of chemokines in host defence and in the pathophysiology of autoimmune diseases. We conclude by discussing various therapeutic approaches that target chemokine receptors and that could be beneficial in disease. Richard Horuk Copyright © 2007 Richard Horuk. All rights reserved. Natural Cytotoxicity Receptors: Pattern Recognition and Involvement of Carbohydrates Mon, 01 Jan 1900 00:00:00 +0000 Natural cytotoxicity receptors (NCRs), expressed by natural killer (NK) cells, trigger NK lysis of tumor and virus-infected cells on interaction with cell-surface ligands of these target cells. We have determined that viral hemagglutinins expressed on the surface of virus-infected cells are involved in the recognition by the NCRs, NKp44 and NKp46. Recognition of tumor cells by the NCRs NKp30 and NKp46 involves heparan sulfate epitopes expressed on the tumor cell membrane. Our studies provide new evidence for the identity of the ligands for NCRs and indicate that a broader definition should be applied to pathological patterns recognized by innate immune receptors. Since nonmicrobial endogenous carbohydrate structures contribute significantly to this recognition, there is an imperative need to develop appropriate tools for the facile sequencing of carbohydrate moieties. Angel Porgador Copyright © 2005 Angel Porgador. All rights reserved. New Perspectives on Aspirin and the Endogenous Control of Acute Inflammatory Resolution Mon, 01 Jan 1900 00:00:00 +0000 Aspirin is unique among the nonsteroidal anti-inflammatory drugs in that it has both anti-inflammatory as well as cardio-protective properties. The cardio-protective properties arise form its judicious inhibition of platelet-derived thromboxane A2 over prostacyclin, while its anti-inflammatory effects of aspirin stem from its well-established inhibition of prostaglandin (PG) synthesis within inflamed tissues. Thus aspirin and the other NSAIDs have popularised the notion of inhibiting PG biosynthesis as a common anti-inflammatory strategy based on the erroneous premise that all eicosanoids are generally detrimental to inflammation. However, our fascination with aspirin has shown a more affable side to lipid mediators based on our increasing interest in the endogenous control of acute inflammation and in factors that mediate its resolution. Epi-lipoxins (epi-LXs), for instance, are produced from aspirin’s acetylation of inducible cyclooxygenase 2 (COX-2) and together with Resolvins represent an increasingly important family of immuno-regulatory and potentially cardio-protective lipid mediators. Aspirin is beginning to teach us what nature knew all along – that not all lipid mediators are bad. It seems that while some eicosanoids are pathogenic in a variety of diseases, others are unarguable protective. In this review we will re-count aspirin’s colorful history, discuss its traditional mode of action and the controversies associated therewith, as well as highlight some of the new pathways in inflammation and the cardiovascular systems that aspirin has recently revealed. Thea Morris, Melanie Stables, and Derek W. Gilroy Copyright © 2006 Thea Morris et al. All rights reserved. Dissociated Steroids Mon, 01 Jan 1900 00:00:00 +0000 Glucocorticoids (GCs) are some of the most important drugs in clinical use today. They are mainly used to suppress disease-related inflammation and are widely used for the treatment of many inflammatory diseases including asthma and arthritis. However, GCs are also associated with debilitating side effects that place limitations on the long-term use of these drugs. The development of a GC with reduced side effects would allow more effective treatments for patients who require long-term suppression of inflammation. GCs exert their effects by binding and activating the GC receptor (GR). The activated receptor then binds GC response elements (GREs) in the promoter of genes, and activates transcription (transactivation) or interferes with the activation of transcription by inhibiting the transactivating function of other transcription factors, such as AP-1 and NF-ĸB (transrepression). Transrepression is believed to be responsible for the majority of the beneficial anti-inflammatory effects of GCs, whereas transactivation is believed to play a bigger role in the unwanted side effects of GCs. Compounds that can dissociate the transactivation function of GCs from the transrepression function may, therefore, have an improved therapeutic index. A number of these dissociated corticosteroids have been developed. In vitro assays using these compounds appear to show good dissociation. However, in vivo, the dissociation appears to be lost and these compounds still produce many of the side effects associated with conventional GCs. A better understanding of the molecular mechanisms behind GC-induced effects would allow the design of novel selective GR modulators with an improved therapeutic index. Matthew C. Catley Copyright © 2007 Matthew Catley. All rights reserved. Biological Functions of Interleukin-21 and Its Role in Inflammation Mon, 01 Jan 1900 00:00:00 +0000 Interleukin-21 (IL-21), the most recently discovered CD132-dependent cytokine, is mainly produced by activated T lymphocytes, particularly the inflammatory Th17 subset, and is believed to be a key factor in the transition between innate and acquired immunity. In the last few years, this cytokine has been shown to modulate the functions of T, B, and NK cells, as well as cells of myeloid origin. In addition, it was demonstrated that IL-21 is a potent antitumor agent, making it a promising candidate for the development of therapeutic tools. IL-21 has also been associated with different autoimmune and inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review will summarize the biological functions of IL-21 and its potential role in inflammation. Martin Pelletier and Denis Girard Copyright © 2007 Martin Pelletier and Denis Girard. All rights reserved. Probing Single Icam-1/Lfa-1 Interaction under External Force Mon, 01 Jan 1900 00:00:00 +0000 Xiaohui Zhang, Ewa Wojcikiewicz, and Vincent T. Moy Copyright © 2002 Xiaohui Zhang et al. All rights reserved. Anti-Inflammatory and Immunosuppressive Effects of the A2A Adenosine Receptor Mon, 01 Jan 1900 00:00:00 +0000 The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A1, A2A, A2B, and A3, of which the A2A adenosine receptor (A2AAR) is recognised as a major mediator of anti-inflammatory responses. The A2AAR is widely expressed on cells of the immune system and numerous in vitro studies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings from in vivo studies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions. Gillian R. Milne and Timothy M. Palmer Copyright © 2011 Gillian R. Milne and Timothy M. Palmer. All rights reserved. Cytokines and Myelination in the Central Nervous System Mon, 01 Jan 1900 00:00:00 +0000 Myelin abnormalities that reflect damage to developing and mature brains are often found in neurological diseases with evidence of inflammatory infiltration and microglial activation. Many cytokines are virtually undetectable in the uninflamed central nervous system (CNS), so that their rapid induction and sustained elevation in immune and glial cells contributes to dysregulation of the inflammatory response and neural cell homeostasis. This results in aberrant neural cell development, cytotoxicity, and loss of the primary myelin-producing cells of the CNS, the oligodendrocytes. This article provides an overview of cytokine and chemokine activity in the CNS with relevance to clinical conditions of neonatal and adult demyelinating disease, brain trauma, and mental disorders with observed white matter defects. Experimental models that mimic human disease have been developed in order to study pathogenic and therapeutic mechanisms, but have shown mixed success in clinical application. However, genetically altered animals, and models of CNS inflammation and demyelination, have offered great insight into the complexities of neuroimmune interactions that impact oligodendrocyte function. The intracellular signaling pathways of selected cytokines have also been highlighted to illustrate current knowledge of receptor-mediated events. By learning to interpret the actions of cytokines and by improving methods to target appropriate predictors of disease risk selectively, a more comprehensive understanding of altered immunoregulation will aid in the development of advanced treatment options for patients with inflammatory white matter disorders. Thomas Schmitz and Li-Jin Chew Copyright © 2008 Thomas Schmitz and Li-Jin Chew. All rights reserved. Functional Decline in Human Neutrophils with Age Mon, 01 Jan 1900 00:00:00 +0000 Stephen Butcher, Hema Chahal, Elizabeth Savey, V. V. Killampalli, E. K. Alpar, and Janet M. Lord Copyright © 2001 Janet, M. Lord et al. All rights reserved. Therapeutic Antibodies for the Treatment of Pancreatic Cancer Mon, 01 Jan 1900 00:00:00 +0000 Pancreatic cancer is a devastating disease with the worst mortality rate and an overall 5-year survival rate lower than 5%. In the U.S., this disease is the fourth leading cause of death and represents 6% of all cancer-related deaths. Gemcitabine, the current standard first-line treatment, offers marginal benefits to patients in terms of symptom control and prolongation of life. Since 1996, about 20 randomized phase III trials have been performed to improve the efficacy of gemcitabine, with little success regarding a significant improvement in survival outcomes. The need for novel therapeutic strategies, such as target therapy, is obvious. Monoclonal antibodies have finally come of age as therapeutics and several molecules are now approved for cancer therapies. This review aims to give a general view on the clinical results obtained so far by antibodies for the treatment of pancreatic cancer and describes the most promising avenues toward a significant improvement in the treatment of this frustrating disease. Patrick Chames, Brigitte Kerfelec, and Daniel Baty Copyright © 2010 Patrick Chames et al. All rights reserved. Urinary Exosomes Mon, 01 Jan 1900 00:00:00 +0000 Exosomes are nanovesicles of endocytic origin that are secreted into the extracellular space or body fluids when a multivesicular body (MVB) fuses with the cell membrane. Interest in exosomes intensified after their description in antigen-presenting cells and the observation that they can significantly moderate immune responses in vivo. In the past few years, several groups have reported on the secretion of exosomes by almost all cell types in an organism. In addition to a common set of membrane and cytosolic molecules, exosomes harbor unique subsets of proteins, reflecting their cellular source. Major research efforts were put into their surprisingly various biological functions and in translating knowledge into clinical practice. Urine provides an exciting noninvasive alternative to blood or tissue samples as a potential source of disease biomarkers. Urinary exosomes (UE) became the subject of serious studies just a few years ago. A recent large-scale proteomics-based study of normal UE revealed a myriad of proteins, including disease-related gene products. Thus, UE have valuable potential as a source of biomarkers for early detection of various types of diseases, monitoring the disease evolution and/or response to therapy. As a relatively new field of research, it still faces many challenges, but UE have already shown some straightforward potential. Irena Dimov, Ljubinka Jankovic Velickovic, and Vladisav Stefanovic Copyright © 2009 Irena Dimov et al. All rights reserved. Immunoglobulin Free Light Chain Dimers in Human Diseases Mon, 01 Jan 1900 00:00:00 +0000 Immunoglobulin free light chain (FLC) kappa (κ) and lambda (λ) isotypes exist mainly in monomeric and dimeric forms. Under pathological conditions, the level of FLCs as well as the structure of monomeric and dimeric FLCs and their dimerization properties might be significantly altered. The abnormally high fractions of dimeric FLCs were demonstrated in the serum of patients with multiple myeloma (MM) and primary systemic amyloidosis (AL), as well as in the serum of anephric patients. The presence of tetra- and trimolecular complexes formed due to dimer-dimer and dimer-monomer interactions was detected in the myeloma serum. Analysis of the amyloidogenic light chains demonstrated mutations within the dimer interface, thus raising the possibility that these mutations are responsible for amyloidogenicity. Increased κ monomer and dimer levels, as well as a high κ/λ monomer ratio, were typically found in the cerebrospinal fluid from patients with multiple sclerosis (MS). In many MS cases, the elevation of κ FLCs was accompanied by an abnormally high proportion of λ dimers. This review focuses on the disease-related changes of the structure and level of dimeric FLCs, and raises the questions regarding their formation, function, and role in the pathogenesis and diagnosis of human diseases. Batia Kaplan, Avi Livneh, and Ben-Ami Sela Copyright © 2011 Batia Kaplan et al. All rights reserved. Role of C5 Activation Products in Sepsis Mon, 01 Jan 1900 00:00:00 +0000 Complement activation products are known to be generated in the setting of both experimental and human sepsis. C5 activation products (C5a anaphylatoxin and the membrane attack complex [MAC] C5b-9) are generated during sepsis following infusion of endotoxin, or after cecal ligation and puncture (CLP), which produces polymicrobial sepsis. C5a reacts with its receptors C5aR and C5L2 in a manner that creates the “cytokine storm”, and is associated with development of multiorgan failure (MOF). A number of other complications arising from the interaction of C5a with its receptors include apoptosis of lymphoid cells, loss of innate immune functions of neutrophils (PMNs, polymorphonuclear leukocytes), cardiomyopathy, disseminated intravascular coagulation, and complications associated with MOF. Neutralization of C5a in vivo or absence/blockade of C5a receptors greatly reduces the adverse events in the setting of sepsis, markedly attenuates MOF, and greatly improves survival. Regarding the possible role of C5b-9 in sepsis, the literature is conflicting. Some studies suggest that C5b-9 is protective, while other studies suggest the contrary. Clearly, in human sepsis, C5a and its receptors may be logical targets for interception. Peter A. Ward Copyright © 2010 Peter A. Ward. All rights reserved. Localization of T and B Lymphocytes to the White Pulp of the Spleen is Independent of L-, E-, and P-Selectin Mon, 01 Jan 1900 00:00:00 +0000 T and B cell interactions are thought to be of prime importance in the generation of a humoral immune response. These interactions are thought to take place in the secondary lymphoid organs. The largest of which is the spleen. While the pathways involved in lymphocyte migration into other secondary lymphoid organs have been unraveled, very little is understood about T and B cell migration to the spleen. We report that adoptively transferred T lymphocytes appear more rapidly within the lymphoid compartment of the spleen than do B lymphocytes. Indeed, half of the transferred T lymphocytes in the spleen appear within the white pulp by 1.4 hours. B lymphocytes take nearly 4.3 hours to achieve the same level of accumulation. In addition, T lymphocyte arrival is fucoidan sensitive, while B cells are not affected by this polysaccharide. Finally, we show that neither L-, E-, or P-selectin appears to play a significant role in the accumulation of lymphocytes in the white pulp.) Mitchell H. Grayson and David D. Chaplin Copyright © 2003 Mitchell H. Grayson and David D. Chaplin. All rights reserved. Cysteinyl-Leukotriene Receptors and Cellular Signals Mon, 01 Jan 1900 00:00:00 +0000 Cysteinyl-leukotrienes (cysteinyl-LTs) exert a range of proinflammatory effects, such as constriction of airways and vascular smooth muscle, increase of endothelial cell permeability leading to plasma exudation and edema, and enhanced mucus secretion. They have proved to be important mediators in asthma, allergic rhinitis, and other inflammatory conditions, including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. The classification into subtypes of the cysteinyl-LT receptors (CysLTRs) was based initially on binding and functional data, obtained using the natural agonists and a wide range of antagonists. CysLTRs have proved remarkably resistant to cloning. However, in 1999 and 2000, the CysLT1R and CysLT2R were successfully cloned and both shown to be members of the G-protein coupled receptors (GPCRs) superfamily. Molecular cloning has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Recombinant CysLTRs couple to the Gq/11 pathway that modulates inositol phospholipids hydrolysis and calcium mobilization, whereas in native systems, they often activate a pertussis toxin-insensitive Gi/o-protein, or are coupled promiscuously to both G-proteins. Interestingly, recent data provide evidence for the existence of an additional receptor subtype that seems to respond to both cysteinyl-LTs and uracil nucleosides, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Finally, a cross-talk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize recent data derived from studies on the molecular and cellular pharmacology of CysLTRs. G. Enrico Rovati and Valérie Capra Copyright © 2007 G. Enrico Rovati and Valérie Capra. All rights reserved. The Role of Leukotriene Receptor Signaling in Inflammation and Cancer Mon, 01 Jan 1900 00:00:00 +0000 Leukotrienes (LTs) and prostaglandins (PGs) are metabolites of arachidonic acid that play major roles in various inflammatory conditions. The release of these mediators, by cells recruited to or present at the site of inflammation, modulate/influence the magnitude of the inflammatory response. A better understanding of eicosanoids and how their receptors trigger intracellular signaling during inflammatory conditions is helping to elucidate the well-known connection between chronic inflammatory disease and neoplastic transformation. In the current review, we summarize the role of LTs and PGs in chronic inflammation and, in particular, we focus on recent insights into the role of CysLT1 receptor signaling pathway. In addition, we delineate how continuous CysLT1 receptor activation and signaling can increase cell survival and proliferation as important early steps toward oncogenicity. Ramin Massoumi and Anita Sjölander Copyright © 2007 Ramin Massoumi and Anita Sjölander. All rights reserved. The Origins, Specificity, and Potential Biological Relevance of Human Anti-IgG Hinge Autoantibodies Mon, 01 Jan 1900 00:00:00 +0000 Human anti-IgG hinge (HAH) autoantibodies constitute a class of immunoglobulins that recognize cryptic epitopes in the hinge region of antibodies exposed after proteolytic cleavage, but do not bind to the intact IgG counterpart. Detailed molecular characterizations of HAH autoantibodies suggest that they are, in some cases, distinct from natural autoantibodies that arise independent of antigenic challenge. Multiple studies have attempted to define the specificity of HAH autoantibodies, which were originally detected as binding to fragments possessing C-terminal amino acid residues exposed in either the upper or lower hinge regions of IgGs. Numerous investigators have provided information on the isotype profiles of the HAH autoantibodies, as well as correlations among protease cleavage patterns and HAH autoantibody reactivity. Several biological functions have been attributed to HAH autoantibodies, ranging from house-cleaning functions to an immunosuppressive role to restoring function to cleaved IgGs. In this review, we discuss both the historic and current literature regarding HAH autoantibodies in terms of their origins, specificity, and proposed biological relevance. Randall J. Brezski, David M. Knight, and Robert E. Jordan Copyright © 2011 Randall J. Brezski et al. All rights reserved.