Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The existence of T cells restricted for the MHC I-like molecule CD1 is well established, but the function of these cells is still obscure; one implication is that CD1-dependent T cells regulate autoimmunity. In this study, we investigate their role in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, using CD1-deficient mice on a C57BL/6 background. We show that CD1-/- mice develop a clinically more severe and chronic EAE compared with CD1+/+ C57BL/6 mice, which was histopathologically confirmed with increased demyelination and CNS infiltration in CD1-/- mice. Autoantigen rechallenge in vitro revealed similar T cell proliferation in CD+/+ and CD1-/- mice but an amplified cytokine response in CD1-/- mice as measured by both the Th1 cytokine IFN-gamma and the Th2 cytokine IL-4. Investigation of cytokine production at the site of inflammation showed a CNS influx of TGF-beta1-producing cells early in the disease in CD1+/+ mice, which was absent in the CD1-/- mice. Passive transfer of EAE using an autoreactive T cell line induced equivalent disease in both groups, which suggested additional requirements for activation of the CD1-dependent regulatory pathway(s). When immunized with CFA before T cell transfer, the CD1-/- mice again developed an augmented EAE compared with CD1+/+ mice. We suggest that CD1 exerts its function during CFA-mediated activation, regulating development of EAE both through enhancing TGF-beta1 production and through limiting autoreactive T cell activation, but not necessarily via effects on the Th1/Th2 balance.
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PMID:CD1-dependent regulation of chronic central nervous system inflammation in experimental autoimmune encephalomyelitis. 1468 25

Most autoimmune diseases are associated with certain MHC class II haplotypes. Autoantigen-based specific immune therapy can lead either to beneficial or, in the context of inflammatory conditions, detrimental outcomes. Therefore, we designed a platform of peptides by combinatorial chemistry selected in a nonbiased Ag-independent approach for strong binding to the rat MHC class II isotype RT1.D(n) allelic product of the RT1(n) haplotype that is presenting autoantigen in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis in LEW.1N rats. Peptide p17 (Ac-FWFLDNAPL-NH(2)) was capable of suppressing the induction of and also ameliorated established experimental autoimmune encephalomyelitis. MHC class II isotype and allele specificity of the therapeutic principle were demonstrated in myelin basic protein-induced experimental autoimmune encephalomyelitis in LEW rats bearing the RT1(l) haplotype. A general immunosuppressive effect of the treatment was excluded by allogeneic heart transplantation studies. In vitro studies demonstrated the blocking effect of p17 on autoantigenic T cell responses. We thus demonstrate a rational design of strong MHC class II-binding peptides with absolute isotype and allele specificity able to compete for autoantigenic sequences presented on disease-associated MHC class II molecules.
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PMID:MHC class II isotype- and allele-specific attenuation of experimental autoimmune encephalomyelitis. 1529 98

For many years, CD4+ effector T cells were categorized into two subsets: T helper type 1 (Th1) and type 2 (Th2) cells. More recent research has refined this model, delineating further subsets; in particular, Th17 cells, activated CD4+ T cells characterised by the production of the cytokine IL-17. Autoantigen-specific Th17 cells are associated with pathology in a number of animal models of organ-specific autoimmune disease and evidence is mounting that Th17 cells are also critical in human autoimmunity. Retinoids, a family of compounds that bind to and activate retinoic acid receptors (RARs and RXRs), are able to alter CD4+ T cell differentiation in vitro though agonism and antagonism of a range of retinoid receptors. For example, all-trans retinoic acid (ATRA) inhibits Th17 differentiation and instead promotes the upregulation of Foxp3, a key transcription factor in regulatory T cells. Importantly, treatment with retinoids can modulate Th17-mediated autoimmunity: experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS), is ameliorated by ATRA administration due to suppression of both the differentiation and the function of Th17 cells. In this review, we discuss the unveiled molecular mechanism and the possible clinical application of retinoids for the treatment of human Th17-mediated autoimmune diseases.
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PMID:Retinoid signals and Th17-mediated pathology. 1925 74

The source, specificity, and plasticity of the forkhead box transcription factor 3 (Foxp3)(+) regulatory T (Treg) and conventional T (Tconv) cell populations active at sites of autoimmune pathology are not well characterized. To evaluate this, we combined global repertoire analyses and functional assessments of isolated T cell receptors (TCR) from TCRalpha retrogenic mice with autoimmune encephalomyelitis. Treg and Tconv cell TCR repertoires were distinct, and autoantigen-specific Treg and Tconv cells were enriched in diseased tissue. Autoantigen sensitivity and fine specificity of these cells intersected, implying that differences in responsiveness were not responsible for lineage specification. Notably, autoreactive Treg and Tconv cells could be fully distinguished by an acidic versus aliphatic variation at a single TCR CDR3 residue. Our results imply that ontogenically distinct Treg and Tconv cell repertoires with convergent specificities for autoantigen respond during autoimmunity and argue against more than limited plasticity between Treg and Tconv cells during autoimmune inflammation.
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PMID:T cell receptor CDR3 sequence but not recognition characteristics distinguish autoreactive effector and Foxp3(+) regulatory T cells. 2000 34