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Autoimmune Inflammation (autoimmune + inflammation)
Selected AbstractsIL-23-driven encephalo-tropism and Th17 polarization during CNS-inflammation in vivoEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2009Gabor Gyülvészi Abstract IL-23 but not IL-12 is essential for the development of autoimmune tissue inflammation in mice. Conversely, IL-12 and IL-23 impact on the polarization of Th1 and Th17 cells, respectively. While both polarized T helper populations can mediate autoimmune inflammation, their redundancy in the pathogenesis of EAE indicates that IL-23 exerts its crucial influence on the disease independent of its T helper polarizing capacity. To study the impact of IL-23 and IL-12 on the behavior of encephalitogenic T cells in vivo, we generated BM-chimeric mice in which we can trace individual populations of IL-23 or IL-12 responsive T helper cells during EAE. We observed that T cells, which lack IL-12R,1 (no IL-12 and IL-23 signaling), fail to invade the CNS and do not acquire a Th17 phenotype. In contrast, loss of IL-12 signaling prevents Th1 polarization but does not prevent T-cell entry into the CNS. The loss of IL-12R engagement does not appear to alter T-cell expansion but leads to their accumulation in secondary lymphoid organs. We found that IL-23 licenses T cells to invade the target tissue and to exert their effector function, whereas IL-12 is critical for Th1 differentiation, but does not influence the pathogenic capacity of auto-reactive T helper cells in vivo. [source] Impaired activation-induced cell death promotes spontaneous arthritis in antigen (cartilage proteoglycan),specific T cell receptor,transgenic miceARTHRITIS & RHEUMATISM, Issue 10 2010Ferenc Boldizsar Objective To investigate whether genetic preponderance of a T cell receptor (TCR) recognizing an arthritogenic peptide of human cartilage proteoglycan (PG) is sufficient for development of arthritis. Methods We performed a longitudinal study using BALB/c mice expressing a TCR that recognizes the arthritogenic ATEGRVRVNSAYQDK peptide of human cartilage PG. PG-specific TCR,transgenic (PG-TCR,Tg) mice were inspected weekly for peripheral arthritis until 12 months of age. Peripheral joints were examined histologically, and T cell responses, T cell activation markers, serum cytokines, and autoantibodies were measured. Apoptosis and signaling studies were performed in vitro on T cells from aged PG-TCR,Tg mice. Results Spontaneous arthritis developed as early as 5,6 months of age, and the incidence increased to 40,50% by 12 months of age. Progressive inflammation began with cartilage and bone erosions in the interphalangeal joints, and later expanded to the proximal joints of the front and hind paws. Spontaneous arthritis was associated with a high proportion of activated CD4+ T cells, enhanced interferon-, and interleukin-17 (IL-17) production, and elevated levels of serum autoantibodies. PG-TCR,Tg mice lacking IL-4 developed arthritis earlier and at a higher incidence than IL-4,sufficient mice. Antigen-specific activation,induced cell death was diminished in vitro in CD4+ T cells of PG-TCR,Tg mice with spontaneous arthritis, especially in those lacking IL-4. Conclusion The presence of CD4+ T cells expressing a TCR specific for an arthritogenic PG epitope is sufficient to trigger spontaneous autoimmune inflammation in the joints of BALB/c mice. IL-4 appears to be a negative regulator of this disease, through attenuation of activation-induced cell death. [source] Activation of AMP-activated protein kinase by adiponectin rescues salivary gland epithelial cells from spontaneous and interferon-,,induced apoptosisARTHRITIS & RHEUMATISM, Issue 2 2010Stergios Katsiougiannis Objective Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltrates associated with destruction of salivary gland epithelial cells (SGECs) induced mainly by apoptosis. Adiponectin is an immunoregulatory hormone. We have previously shown that SGECs from patients with primary SS as well as from controls differentially express adiponectin. SGECs derived from patients with primary SS constitutively produce and secrete adiponectin in higher quantities. The aim of this study was to investigate the effect of adiponectin on the proliferation and apoptosis of SGECs. Methods Cultured, non-neoplastic SGECs were treated with recombinant human adiponectin, and the rate of cell proliferation was assessed. Spontaneous and interferon-, (IFN,),induced apoptosis was evaluated with a specific single-stranded DNA enzyme-linked immunosorbent assay. The AMP-activated protein kinase (AMPK) inhibitor Compound C was used to test the involvement of AMPK in adiponectin effects. Western blotting was applied to detect the phosphorylation levels of AMPK after adiponectin treatment. Results Adiponectin treatment resulted in a dose-dependent suppression of proliferation of SGECs from patients with primary SS and control donors. Adiponectin protected cells from spontaneous as well as from IFN,-induced apoptosis. Furthermore, the antiapoptotic effects of adiponectin were dependent upon AMPK phosphorylation at Thr172, since pretreatment of SGECs with Compound C abolished the adiponectin protective effect. Conclusion Adiponectin exerted antiproliferative effects on SGECs without inducing apoptosis and protected SGECs from spontaneous as well as from IFN,-induced apoptosis through an AMPK-dependent pathway. Our observations suggest that adiponectin may protect SGECs in this specific inflammatory milieu, providing a potential pathway through which AMPK may regulate cell survival under energy stress conditions such as autoimmune inflammation. [source] Epitope-specific immunotherapy of rheumatoid arthritis: Clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial,ARTHRITIS & RHEUMATISM, Issue 11 2009Eva C. Koffeman Objective Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement. Methods One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months. Results The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor , and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo. Conclusion Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity. [source] PAN,DR-Binding Hsp60 self epitopes induce an interleukin-10,mediated immune response in rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 7 2009Huib de Jong Objective Human Hsp60 is expressed in the joints of patients with rheumatoid arthritis (RA) and can elicit a regulatory T cell response in the peripheral blood and synovial fluid. However, Hsp60 can also trigger strong proinflammatory pathways. Thus, to understand the nature of these Hsp60-directed responses in RA, it is necessary to study such responses at the molecular, epitope-specific level. This study was undertaken to characterize the disease specificity and function of pan,DR-binding Hsp60,derived epitopes as possible modulators of autoimmune inflammation in RA. Methods Lymphocyte proliferation assays (using 3H-thymidine incorporation and carboxyfluorescein diacetate succinimidyl ester [CFSE] staining) and measurement of cytokine production (using multiplex immunoassay and intracellular staining) were performed after in vitro activation of peripheral blood mononuclear cells from patients with RA, compared with healthy controls. Results A disease (RA),specific immune recognition, characterized by T cell proliferation as well as increased production of tumor necrosis factor , (TNF,), interleukin-1, (IL-1,), and IL-10, was found for 3 of the 8 selected peptides in patients with RA as compared with healthy controls (P < 0.05). Intracellular cytokine staining and CFSE labeling showed that CD4+ T cells were the subset primarily responsible for both the T cell proliferation and the cytokine production in RA. Interestingly, the human peptides had a remarkably different phenotype, with a 5,10-fold higher IL-10:TNF, ratio, compared with that of the microbial peptides. Conclusion These results suggest a disease-specific immune-modulatory role of epitope-specific T cells in the inflammatory processes of RA. Therefore, these pan,DR-binding epitopes could be used as a tool to study the autoreactive T cell response in RA and might be suitable candidates for use in immunotherapy. [source] From the Background to the Spotlight: TASK Channels in Pathological ConditionsBRAIN PATHOLOGY, Issue 6 2010Stefan Bittner Abstract TWIK-related acid-sensitive potassium channels (TASK1,3) belong to the family of two-pore domain (K2P) potassium channels. Emerging knowledge about an involvement of TASK channels in cancer development, inflammation, ischemia and epilepsy puts the spotlight on a leading role of TASK channels under these conditions. TASK3 has been especially linked to cancer development. The pro-oncogenic potential of TASK3 could be shown in cell lines and in various tumor entities. Pathophysiological hallmarks in solid tumors (e.g. low pH and oxygen deprivation) regulate TASK3 channels. These conditions can also be found in (autoimmune) inflammation. Inhibition of TASK1,2,3 leads to a reduction of T cell effector function. It could be demonstrated that TASK1,/, mice are protected from experimental autoimmune inflammation while the same animals display increased infarct volumes after cerebral ischemia. Furthermore, TASK channels have both an anti-epileptic as well as a pro-epileptic potential. The relative contribution of these opposing influences depends on their cell type-specific expression and the conditions of the cellular environment. This indicates that TASK channels are per se neither protective nor detrimental but their functional impact depends on the "pathophysiological" scenario. Based on these findings TASK channels have evolved from "mere background" channels to key modulators in pathophysiological conditions. [source] Direct suppression of autoreactive lymphocytes in the central nervous system via the CB2 receptorBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2008B N Dittel The cannabinoid system is now recognized as a regulator of both the nervous and immune systems. Although marijuana has been used for centuries for the treatment of a variety of disorders, its therapeutic mechanisms are only now being understood. The best-studied plant cannabinoid, ,9 -tetrahydrocannabinol (THC), produced by Cannabis sativa and found in marijuana, has shown evidence of being immunosuppressive in both in vivo and in vitro. Since THC binds to at least two receptors that are differentially expressed by the immune and nervous systems, it has not been possible to clearly discriminate the biological effects it exerts in the two systems. In addition, endogenous cannabinoids have also been described that bind to both receptors and exert both neuronal and immune modulatory activity. The generation of mice deficient in specific cannabinoid receptors has facilitated studies to discriminate cannabinoid-specific functions. This review focuses on the function of the cannabinoid receptor 2 (CB2), primarily expressed in the immune system, in regulating T cell effector functions associated with autoimmune inflammation in the central nervous system (CNS). British Journal of Pharmacology (2008) 153, 271,276; doi:10.1038/sj.bjp.0707493; published online 8 October 2007 [source] | ||||||||||