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

Recruitment of inflammatory cells into the CNS during pathological processes associated with neurodegeneration, trauma, autoimmune disease, and infection involves the generation of signaling molecules that are both cell-associated and soluble. Alteration in the permeability of the blood brain barrier, adhesion of blood-borne leukocytes to cerebral vessels, activation of chemoattractants and their receptors, and migration of inflammatory cells into the CNS are events that have been proposed to be regulated by cytokines and reactive oxygen and nitrogen species. In this review we propose associative connections between these events and the molecules involved as they may relate to CNS inflammation, placing illustrative emphasis on multiple sclerosis and the animal model for MS, experimental allergic encephalomyelitis.
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PMID:Inflammatory events at the blood brain barrier: regulation of adhesion molecules, cytokines, and chemokines by reactive nitrogen and oxygen species. 951 13

T-cell activation requires clustering of a threshold number of T-cell receptors (TCRs) at the site of antigen presentation, a number that is reduced by CD28 co-receptor recruitment of signalling proteins to TCRs. Here we demonstrate that a deficiency in beta1,6 N-acetylglucosaminyltransferase V (Mgat5), an enzyme in the N-glycosylation pathway, lowers T-cell activation thresholds by directly enhancing TCR clustering. Mgat5-deficient mice showed kidney autoimmune disease, enhanced delayed-type hypersensitivity, and increased susceptibility to experimental autoimmune encephalomyelitis. Recruitment of TCRs to agonist-coated beads, TCR signalling, actin microfilament re-organization, and agonist-induced proliferation were all enhanced in Mgat5-/- T cells. Mgat5 initiates GlcNAc beta1,6 branching on N-glycans, thereby increasing N-acetyllactosamine, the ligand for galectins, which are proteins known to modulate T-cell proliferation and apoptosis. Indeed, galectin-3 was associated with the TCR complex at the cell surface, an interaction dependent on Mgat5. Pre-treatment of wild-type T cells with lactose to compete for galectin binding produced a phenocopy of Mgat5-/- TCR clustering. These data indicate that a galectin-glycoprotein lattice strengthened by Mgat5-modified glycans restricts TCR recruitment to the site of antigen presentation. Dysregulation of Mgat5 in humans may increase susceptibility to autoimmune diseases, such as multiple sclerosis.
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PMID:Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. 1121 64

An important event in the pathogenesis of the autoimmune disease multiple sclerosis (MS) is the recruitment of lymphocytes and inflammatory macrophages to the central nervous system (CNS). Recruitment requires adhesive interactions between the leukocytes and the microvascular endothelium, perivascular cells, and astrocytes in the CNS parenchyma. Previous studies using an animal model of MS, experimental allergic encephalomyelitis (EAE), have shown the involvement of the alpha4 integrin VLA-4 (beta4beta1). In the present study, the effect of a modified peptide inhibitor of alpha4 integrins on the clinical course and leukocyte infiltration during EAE is investigated. EAE was either induced actively, by immunizing Lewis rats with whole guinea pig MBP, or passively, by transfer of an MBP-specific T cell line. Treatment with the inhibitor (CS1 ligand mimic) completely prevented both clinical signs and cellular infiltration in passively induced EAE. Peptide treatment of actively induced EAE, which has a more severe disease course than the transfer model, significantly reduced clinical signs although the recruitment of inflammatory cells and induction of MHC class II expression was not prevented. The alpha4 inhibitor did inhibit the adhesion of lymphocytes to primary astrocytes in vitro suggesting a role for astrocyte-leukocyte interactions in the pathogenesis of induced EAE. Astrocytes were found to express an extracellular matrix protein distinct from fibronectin, which shows immune cross-reactivity with the CS1 domain of fibronectin. Our results show that small-molecule inhibitors of alpha4 integrins act therapeutically in EAE possibly by interfering with cell adhesion events involved in this autoimmune disease.
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PMID:Beneficial effect of modified peptide inhibitor of alpha4 integrins on experimental allergic encephalomyelitis in Lewis rats. 1178 63

Recruitment of naturally occurring CD4+ CD25+ regulatory T (T(reg)) cells is a highly promising approach for the treatment of experimental autoimmune encephalomyelitis (EAE), a widely used model of multiple sclerosis. Here, we studied the in vivo interaction of T(reg) cells, induced by the monoclonal anti-CD28 antibody JJ316, with encephalitogenic T cell lines established from eGFP-transgenic rats. By tracking these fluorescent cells using flow cytometry and confocal microscopy, we found that the activation and expansion of T(reg) cells inhibited infiltration of the CNS by pathogenic T cells. Interference with effector cell migration occured within the secondary lymphoid organs, since the early therapeutic effects were achieved despite the absence of T(reg) cells in the spinal cord. However, the delayed homing to the CNS seen after prophylactic JJ316 administration indicates that T(reg) cells may play an additional role within the target tissue. In addition, the blood-brain barrier remained largely intact after JJ316 treatment, the secretion of T(H)2 cytokines was augmented and the encephalitogenic T cells exhibited a reduced secretion of IFN-gamma. This in turn resulted in a reduced expression of the chemokine receptor CXCR-3 on effector T cells which may interfere with their capacity to infiltrate the CNS. Importantly, these effects were not achieved by direct action of JJ316 on the encephalitogenic cells. Our data rather suggest that polyclonal activation of T(reg) cells in the secondary lymphoid organs is instrumental in preventing the pathological transmigration of encephalitogenic T cells into the CNS. We anticipate that these results may help to better understand the role of T(reg) cells in controlling autoimmunity in the CNS.
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PMID:Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of multiple sclerosis. 1692 Nov 76