Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Presentation of Ag bound to MHC class II (MHC II) molecules to CD4+ T cells is a key event in adaptive immune responses. Genetic differences in MHC II expression in the rat CNS were recently positioned to allelic variability in the CIITA gene (Mhc2ta), located within the Vra4 locus on rat chromosome 10. In this study, we have examined reciprocal Vra4-congenic strains on the DA and PVGav1 backgrounds, respectively. After experimental nerve injury the strain-specific MHC II expression on microglia was reversed in the congenic strains. Similar findings were obtained after intraparenchymal injection of IFN-gamma in the brain. Expression of MHC class II was also lower on B cells and dendritic cells from the DA.PVGav1-Vra4- congenic strain compared with DA rats after in vitro stimulation with IFN-gamma. We next explored whether Vra4 may affect the outcome of experimental autoimmune disease. In experimental autoimmune encephalomyelitis induced by immunization with myelin oligodendrocyte glycoprotein, DA.PVGav1-Vra4 rats displayed a lower disease incidence and milder disease course compared with DA, whereas both PVGav1 and PVGav1.DA-Vra4 rats were completely protected. These results demonstrate that naturally occurring allelic differences in Mhc2ta have profound effects on the quantity of MHC II expression in the CNS and on immune cells and that this genetic variability also modulates susceptibility to autoimmune neuroinflammation.
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PMID:Vra4 congenic rats with allelic differences in the class II transactivator gene display altered susceptibility to experimental autoimmune encephalomyelitis. 1829 53

Previous studies have found that a 95% reduction in TCR expression does not adversely affect response to foreign Ags, indicating that T cells have an excess of TCR for Ag recognition. Because self-reactive T cells may have low affinity for peptide:MHC, we investigated whether myelin-reactive T cells require these excess TCR for optimal response. To test this concept, mAb were used to effectively reduce the TCR of Valpha3.2 and Vbeta11 TCR transgenic mice (referred to as 2D2). After masking the TCR with either continuous or prepulsed anti-Valpha3.2 Ab, 2D2 cells were immediately stimulated with myelin oligodendrocyte glycoprotein (MOG)(35-55). These cells have a dramatic Ab dose-dependent reduction in proliferation, with a small reduction in TCR expression leading to a 50% reduction in proliferation in vitro. Additionally, 2D2 cells, treated with anti-Valpha3.2 Ab and peptide for 7 days, were re-stimulated with MOG and continue to have a dose-dependent reduction in proliferation. TCR quantitation identified the same amount of TCR on the Ab/peptide treatment compared with the peptide-only control. These results point out that the combination of reduced TCR and peptide challenge leads to a phenotypic change resulting in T cell anergy. Importantly, adoptive transfer of these anergic T cells upon autoimmune disease induction had a marked reduction in disease severity compared with untreated MOG-specific CD4(+) T cells, which had significant autoimmune disease manifested by optic neuritis and death. Thus, reduction of TCR expression may provide a potential therapy for self-reactive T cells involved in autoimmune diseases through the induction of anergy.
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PMID:Induction of anergy by antibody blockade of TCR in myelin oligodendrocyte glycoprotein-specific cells. 1849 Jul 25

Th17 cells have been recognized as the central effectors in organ-related autoimmune diseases. IL-6 is a key factor that reciprocally regulates Th17 and Foxp3(+) Treg differentiation by inhibition of TGF-beta induced Foxp3 and induction of RORgammat, a Th17 lineage-specific transcription factor. Recently IL-21 has been suggested to induce RORgammat and Th17 development in the absence of IL-6. However, the relevance of IL-21 for Th17-dependent inflammatory responses in vivo remains unclear. In this study, we demonstrate that differentiation of IL-17-producing CD4 T cells, their recruitment to inflamed organs, and the development of autoimmune disease was not affected in il21R(-/-) and il21(-/-) mice in models of myelin oligodendrocyte glycoprotein-induced autoimmune encephalitis and autoimmune myocarditis. IL-6 induced Th17 differentiation independent of and much more potently than IL-21 in vitro. These data suggest that IL-6 is sufficient to drive Th17 development and associated autoimmunity in vivo in the absence of IL-21 or IL-21R.
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PMID:IL-21 and IL-21R are not required for development of Th17 cells and autoimmunity in vivo. 1854 47

Multiple sclerosis (MS) is the most common non-traumatic, disabling neurological human inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) models MS and is characterized as a CD4+ T-helper type 1 (Th1) cell-mediated autoimmune disease. It is characterized by an influx of activated leukocytes into the CNS. Genistein, occurring abundantly in soy products, has apoptotic, antioxidant, and anti-inflammatory properties. In the present report, we investigated the use of genistein for the treatment of the murine model of MS. After induction of EAE with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG(35-55)), we observed that genistein treatment ameliorated significantly the clinical symptoms, modulating pro- and anti-inflammatory cytokines. Moreover, we analyzed the leukocyte rolling and adherence in the CNS by performing intravital microscopy. Genistein treatment resulted in decreased rolling and adhering of leukocytes as compared to the untreated group. Our data suggest that genistein might be a potential therapy for MS.
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PMID:Genistein down-modulates pro-inflammatory cytokines and reverses clinical signs of experimental autoimmune encephalomyelitis. 1860 76

Relapsing-remitting multiple sclerosis (RRMS) is a complex autoimmune disease of the central nervous system with oscillating phases of relapse and remission. RRMS has been considered to be driven by T helper type 1 (Th1) lymphocytes but new data indicate the involvement of Th17 responses. In the present study, blood samples from patients (n=48) and healthy individuals (n=44) were evaluated for their immunological status. T cells from patients with RRMS expressed high levels of the activation marker CD28 (P<0.05) and secreted both interferon-gamma (CD8: P<0.05) and interleukin-17 upon polyclonal mitogen or myelin oligodendrocyte glycoprotein antigen stimulation. However, T cells from patients with RRMS in remission, in contrast to relapse, had poor proliferative capacity (P<0.05) suggesting that they are controlled and kept in anergy. This anergy could be broken with CD28 stimulation that restored the T-cell replication. Furthermore, the patients with RRMS had normal levels of CD4(+) Foxp3(+) T regulatory cells but the frequency of Foxp3(+) cells lacking CD127 (interleukin-7 receptor) was lower in patients with MS (mean 12%) compared to healthy controls (mean 29%). Still, regulatory cells (CD25(+) sorted cells) from patients with RRMS displayed no difference in suppressive capacity. In conclusion, patients in relapse/remission demonstrate in vitro T-cell responses that are both Th1 and Th17 that, while in remission, appear to be controlled by tolerogenic mechanisms yet to be investigated.
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PMID:The T-cell pool is anergized in patients with multiple sclerosis in remission. 1862 27

Multiple sclerosis (MS) is an autoimmune disease characterized by central nervous system (CNS) inflammation and leukocyte infiltration, demyelination of neurons, and blood-brain barrier breakdown. The development of experimental autoimmune encephalomyelitis (EAE), the animal model for MS is dependent on a number of components of the immune system including complement and adhesion molecules. Previous studies in our lab have examined the role of C3, the central complement component, and intercellular adhesion molecule-1 (ICAM-1) a key cell adhesion molecule involved in leukocyte trafficking to sites of inflammation including the CNS. In these studies we demonstrated that myelin oligodendrocyte glycoprotein (MOG)-induced EAE is markedly attenuated in both ICAM-1(-/-) and C3(-/-) mice. Given the pivotal role that these proteins play in EAE, we hypothesized that EAE in ICAM-1(-/-) and C3(-/-) double mutant mice would likely fail to develop. Unexpectedly, EAE in ICAM-1(-/-)xC3(-/-) mice was only modestly attenuated compared to wild type mice and significantly worse than C3(-/-) mice. Leukocyte infiltration was commensurate with disease severity between the three groups of mice. Spinal cord T cells from ICAM-1(-/-)xC3(-/-) mice produced the highest levels of IFN-gamma and TNF-alpha, despite reduced disease severity compared to wild type mice. The mechanisms behind the elevated EAE severity in ICAM-1(-/-)xC3(-/-) mice may relate to altered homing of leukocytes or processing of self-antigens in the double mutant background.
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PMID:Deletion of both ICAM-1 and C3 enhances severity of experimental autoimmune encephalomyelitis compared to C3-deficient mice. 1863 51

Multiple sclerosis (MS) is a chronic, debilitating disease, which manifests itself by de-myelination of the central nervous system (CNS). MS is predominantly found in Caucasians of European decent and is more prominent in females than males. MS is one of the most prevalent causes of disability of young adults in the world. The exact cause of MS is not known, however genetic susceptibility to MS is linked to the major histocompability complex (MHC). Self reactive CD4+ T cells, specific for CNS antigens, such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and proteolipid protein (PLP), are detectable in MS patients along with pathogenic autoantibodies specific to these CNS antigens produced by B cells. These observations suggest that MS is an autoimmune disease. Epidemiology of MS along with the analysis of sibling pairs and twins suggest that the multiple genetic factors and their interaction with environment contribute to disease susceptibility. Recent developments and advancements in genetic analysis may aid in accurate determination of genetic risk factors for the development of MS. We review these developments, advances in technology and discuss recent results in this article.
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PMID:Strategies for the identification of loci responsible for the pathogenesis of multiple sclerosis. 1872 92

To elucidate the role of antibodies in development of chronic non-remitting experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, which is a well-established Th1-mediated autoimmune disease, and the involvement of activation-induced cytidine deaminase (AID) in Th1-mediated function, we have investigated the myelin oligodendrocyte glycoprotein (MOG)-induced EAE in mice deficient of AID, which is absolutely required for class switching and somatic hypermutation. Following immunization with MOG, AID(-/-) had completely same levels of clinical and pathological severity of EAE when compared with AID(+/-) and AID(+/+), although AID(-/-) did not produce IgG and anti-MOG IgG. Similar levels of T cell proliferation and a modest increase of anti-MOG IgM synthesis were found in spleen cells of AID(-/-) stimulated with MOG. These results indicate that antibodies are not involved in development of EAE in C57BL/6 mice.
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PMID:Antibodies to myelin oligodendrocyte glycoprotein are not involved in the severity of chronic non-remitting experimental autoimmune encephalomyelitis. 1882 98

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model of multiple sclerosis. Signal transducer and activator of transcription 4 (Stat4) is a transcription factor activated by IL-12 and IL-23, two cytokines known to play important roles in the pathogenesis of EAE by inducing T cells to secrete IFN-gamma and IL-17, respectively. We and others have previously shown that therapeutic intervention or targeted disruption of Stat4 was effective in ameliorating EAE. Recently, a splice variant of Stat4 termed Stat4beta has been characterized that lacks 44 amino acids at the C terminus of the full-length Stat4alpha. In this study we examined whether T cells expressing either isoform could affect the pathogenesis of EAE. We found that transgenic mice expressing Stat4beta on a Stat4-deficient background develop an exacerbated EAE compared with wild-type mice following immunization with myelin oligodendrocyte glycoprotein peptide 35-55, while Stat4alpha transgenic mice have greatly attenuated disease. The differential development of EAE in transgenic mice correlates with increased IFN-gamma and IL-17 in Stat4beta-expressing cells in situ, contrasting increased IL-10 production by Stat4alpha-expressing cells. This study demonstrates that Stat4 isoforms differentially regulate inflammatory cytokines in association with distinct effects on the onset and severity of EAE.
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PMID:Stat4 isoforms differentially regulate inflammation and demyelination in experimental allergic encephalomyelitis. 1883 27

Autoimmune diseases are incurable. We have hypothesized that these diseases can be cured by the transplantation of bone marrow (BM) stem cells that have been genetically engineered to express self-Ag. Here we have tested this hypothesis in experimental autoimmune encephalomyelitis (EAE) induced by the self-Ag myelin oligodendrocyte glycoprotein (MOG). We show that, in mice, transplantation of BM genetically modified to express MOG prevented the induction and progression of EAE, and combined with antecedent corticosteroid treatment, induced long-term remission of established disease. Mice remained resistant to EAE development upon subsequent rechallenge with MOG. Transfer of BM from these mice rendered recipients resistant to EAE. Splenocytes from these mice failed to proliferate or produce IL-17, IFN-gamma, and GM-CSF in response to MOG(35-55) peptide stimulation and they failed to produce MOG autoantibody. Mechanistically, we demonstrated in vivo reduction in development of CD4(+) MOG(35-55)-specific thymocytes, indicative of clonal deletion with no evidence for selection of Ag-specific regulatory T cells. These findings validate our hypothesis that transplantation of genetically modified BM expressing disease-causative self-Ag provides a curative approach by clonal deletion of disease-causative self-reactive T cells.
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PMID:Transplantation of bone marrow transduced to express self-antigen establishes deletional tolerance and permanently remits autoimmune disease. 1901 46


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