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)

Myelin oligodendrocyte glycoprotein (MOG)-specific T cells mediate an autoimmune inflammatory response in the central nervous system (CNS) that differs radically from conventional models of T cell-mediated experimental allergic encephalomyelitis (EAE). Using synthetic peptides an encephalitogenic T cell epitope of MOG for the Lewis rat was identified within the extracellular IgG V-like domain of the protein, amino acids 44-53 (FSRVVHLYRN). The adoptive transfer of CD4+ T cells specific for this epitope induce an intense, dose-dependent inflammatory response in the CNS of naive syngeneic recipients. However, unlike the inflammatory response induced by myelin basic protein (MBP)-specific T cell lines, inflammation mediated by the MOG peptide-specific T cells failed to induce a gross neurological deficit. This unexpected observation was not due to a reduction in the overall inflammatory response in the CNS, but was specifically associated with a decrease in the extent of parenchymal (as opposed to perivascular) inflammation, a selective decrease in the number of ED1+ macrophages infiltrating the CNS, and a total lack of peripheral nerve inflammation. The decreased recruitment of macrophages into the CNS could not be ascribed to deficiencies in the synthesis of interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-6 or IL-2 by the T cell line. Moreover, this sub-clinical inflammatory response induced severe blood-brain barrier dysfunction as demonstrated by the induction of severe clinical disease following intravenous injection of a demyelinating MOG-specific monoclonal antibody. The neurological deficit in EAE thus exhibits an unexpected dependence on the identity of the target autoantigen, which determines the extent and nature of the local inflammatory response and ultimately the extent of the neurological deficit.
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PMID:T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. 768 87

Myelin/oligodendrocyte glycoprotein (MOG) is a CNS-specific protein that has been identified on the external myelin sheath and oligodendrocyte processes. MOG is the primary target autoantigen for demyelinating antibodies in experimental autoimmune encephalomyelitis, a widely used animal model for autoimmune demyelinating diseases such as multiple sclerosis. We have isolated a number of rat MOG cDNA clones as tools to begin studies to ascertain MOG function. A full-length cDNA clone (1.6 kb) was sequenced and the amino acid sequence for MOG deduced. This cDNA clone encodes a signal peptide of 27 amino acids, followed by 218 residues for mature MOG (24962 MW). A single site for N-glycosylation is found at Asn-31. The N-terminal half of mature MOG shares 52% identity with bovine butyrophilin, a possible lipid receptor, and 39% identity with chicken B-G antigen, a major histocompatibility complex antigen. This homology with Ig-like chicken MHC B-G antigens raises the issue of MOG involvement in autoimmune demyelination. Both MOG and butyrophilin meet criteria for inclusion in the immunoglobulin gene superfamily. Moreover, MOG appears to represent a novel member of this superfamily in that it possesses two potential transmembrane domains, in contrast to a single membrane-spanning domain or glycophospholipid anchor found in all other members of this superfamily. MOG mRNA expression is restricted to CNS tissue, and peak expression occurs during active myelination.
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PMID:Cloning and cDNA sequence analysis of myelin/oligodendrocyte glycoprotein: a novel member of the immunoglobulin gene superfamily. 768 65

A fundamental issue in the etiology of autoimmune diseases of the central nervous system such as multiple sclerosis and its animal counterpart experimental autoimmune encephalomyelitis (EAE) concerns the identity of cells capable of presenting autoantigen to the T cells that mediate these diseases. The prevailing dogma is that only bone marrow-derived cells function as APC during EAE induction. We have addressed this issue by studying EAE induction in mouse bone marrow chimeras, and have found that although bone marrow-derived APC such as macrophages and brain microglial cells are more efficient at presenting autoantigen, brain parenchymal cells such as astrocytes and endothelial cells are also capable of inducing disease. EAE was induced in these chimeras by the adoptive transfer of encephalitogenic T cell lines designed to be MHC-histocompatible with APC contained either within the hematopoietic system of the chimera or with APC resident to the brain of the chimera. The subsequent development of EAE in these chimeras then indicated which population of cells served as in vivo APC during EAE pathogenesis. Possible effects of alloreactivity between the host chimera and the adoptively transferred T cells were eliminated by using encephalitogenic T cell lines made tolerant to the haplotype(s) of the recipient chimera.
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PMID:In vivo antigen presentation by both brain parenchymal cells and hematopoietically derived cells during the induction of experimental autoimmune encephalomyelitis. 768 95

Multiple sclerosis (MS) is widely accepted as an autoimmune disease with myelin basic protein (MBP) a candidate autoantigen. In the current report, human T cell lines specific for an immunodominant region of MBP were shown to have a functional phenotype similar to T helper 1 (Th1) inflammatory cells of the mouse on the basis of their antigen-specific cytotoxic activity and production of interferon-gamma and lymphotoxin/tumor necrosis factor-alpha, but not interleukin-4. In experimental allergic encephalomyelitis (EAE), a proposed animal model for MS, MBP-specific T cell lines which mediate disease are of the Th1 subtype. Thus, MBP-specific T cells in humans exist which are phenotypically similar to MBP-specific encephalitogenic T cells in murine EAE.
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PMID:T helper 1 (Th1) functional phenotype of human myelin basic protein-specific T lymphocytes. 769 95

The cytokine effector status of CD4+ T cells from lymph nodes (LN) and the central nervous system (CNS) of SJL/J mice immunized with autoantigen in adjuvant for the induction of experimental allergic encephalomyelitis (EAE) was compared. CD4+ T cells were FACS sorted based on the levels of expression of the activation marker CD45RB. Low levels of expression of this surface marker are induced by antigen recognition and are associated with 'effector' T cell function. Reverse transcriptase polymerase chain reaction (PCR) was used to analyze the expression of different T cell cytokine genes in the sorted populations. CD45RBlow cells constituted a minority of CD4+ cells in the LN and expressed elevated levels of IL-2, IFN-gamma, and IL-4 mRNA, whereas the CD45RBlow CD4+ population did not express detectable message for these cytokines under linear PCR conditions. By contrast to the LN, CD4+ cells from the CNS were predominantly CD45RBlow and expressed readily detectable levels of IL-2 and IFN-gamma mRNA, but almost no IL-4 transcription could be detected. IL-4 mRNA levels in CNS were 100- to 250-fold lower than in LN. Also, IL-4 message could not be detected in the CNS 1 week after remission. A cytokine-specific immunocytochemical single cell staining technique was used to enumerate cytokine-producing cells in LN cell populations and in CNS infiltrates. Between 1 and 5% cells in isolated LN cells produced detectable IL-2 and IFN-gamma. By contrast, the frequency of cytokine-producing cells stained in perivascular infiltrates in frozen sections from the brains of animals with active EAE was 10-fold higher.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective enrichment of Th1 CD45RBlow CD4+ T cells in autoimmune infiltrates in experimental allergic encephalomyelitis. 791 Apr 82

Susceptible strains of mice infected intracerebrally with Theiler's murine encephalomyelitis virus develop a chronic, progressive, immune-mediated CNS demyelinating disease similar both pathologically and clinically to multiple sclerosis. Previous reports indicated that polyclonal immunoglobulins from mice injected with homogenized spinal cord promote CNS remyelination when given to SJL/J mice chronically infected with Theiler's virus. To explore further both the mechanism(s) and potential therapeutic usefulness of antibodies in the treatment of CNS demyelinating diseases, we made a panel of monoclonal antibodies derived from splenocytes of SJL/J mice injected with homogenized spinal cord, and screened them for their autoantigen-binding capability. Monoclonal IgM autoantibodies from two clones, designated SCH94.03 and SCH94.32, promoted fourfold more CNS remyelination than controls when given to chronically infected SJL/J mice. CNS remyelination, assessed morphologically by the presence of abnormally thin myelin sheaths relative to axonal diameter, correlated with the absence of clinical disease progression. In titration experiments, treatment with SCH94.03 and remyelination had a positive dose-response relationship, and as little as 10 micrograms of antibody promoted remyelination. Both SCH94.03 and SCH94.32 showed multiorgan autoreactivity, and recognized both surface and cytoplasmic determinants on glial cells. We propose that this model provides a unique system to elucidate the mechanism(s) and test the reparative potential of autoantibodies in the treatment of CNS injury.
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PMID:Monoclonal autoantibodies promote central nervous system repair in an animal model of multiple sclerosis. 793 75

Oral tolerance is a long recognized method to induce peripheral immune tolerance. The primary mechanisms by which orally administered antigen induces tolerance are via the generation of active suppression or clonal anergy. Low doses of orally administered antigen favor active suppression whereas higher doses favor clonal anergy. The regulatory cells that mediate active suppression act via the secretion of suppressive cytokines such as TGF beta and IL-4 after being triggered by the oral tolerogen. Furthermore, antigen that stimulates the gut-associated lymphoid tissue preferentially generates a Th2 type response. Because the regulatory cells generated following oral tolerization are triggered in an antigen-specific fashion but suppress in an antigen nonspecific fashion, they mediate "bystander suppression" when they encounter the fed autoantigen at the target organ. Thus it may not be necessary to identify the target autoantigen to suppress an organ-specific autoimmune disease via oral tolerance; it is necessary only to administer orally a protein capable of inducing regulatory cells that secrete suppressive cytokines. Orally administered autoantigens suppress several experimental autoimmune models in a disease- and antigen-specific fashion; the diseases include experimental autoimmune encephalomyelitis (EAE), uveitis, and myasthenia, collagen- and adjuvant-induced arthritis, and diabetes in the NOD mouse. In addition, orally administered alloantigen suppresses alloreactivity and prolongs graft survival. Initial clinical trials of oral tolerance in multiple sclerosis, rheumatoid arthritis, and uveitis have demonstrated positive clinical effects with no apparent toxicity and decreases in T cell autoreactivity.
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PMID:Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. 801 Dec 98

Experimental allergic encephalomyelitis (EAE), an antigen induced autoimmune disease, is mediated by V beta 8+ CD4+ T cells in PL/J mice after injection with the autoantigen, myelin basic protein (MBP). Recently the superantigen, staphylococcal enterotoxin B (SEB), has been shown to peripherally anergize and delete T cells in a V beta specific manner. By treatment of PL/J mice with SEB, we have been able to protect PL/J mice from the development of EAE. Two-color FACS analysis of the spleens of SEB treated mice showed depletion of V beta 8+ CD4+ T cells. Consistent with this observation, spleen cells of SEB treated mice that did not show signs of EAE could not be stimulated in vitro with SEB but did respond to SEA. Thus, V beta specific superantigens may prove to be a preventative therapy for autoimmune diseases mediated by V beta specific T lymphocytes.
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PMID:Treatment of PL/J mice with the superantigen, staphylococcal enterotoxin B, prevents development of experimental allergic encephalomyelitis. 809 23

Oral administration of acetylcholine receptor (AChR) or myelin basic protein (MBP) to Lewis rat prior to immunization with AChr or MBP and complete Freund's adjuvant (CFA) has previously been shown to prevent or delay the onset of experimental autoimmune myasthenia gravis (EAMG) or experimental allergic encephalomyelitis (EAE), which represent animal models of myasthenia gravis and multiple sclerosis, respectively. Here we show that Lewis rats immunized with AChr+MBP+CFA developed both signs of muscular weakness seen in EAMG and paresis characteristic for EAE. This disease was associated with high levels of anti-AChR and anti-MBP antibody secreting cells and of AChR- and MBP-reactive INF-gamma secreting Th1-like cells in lymph nodes. The diseased rats also showed upregulation of AChR- and MBP-induced mRNA expression of IFN-gamma in lymph node cells. Oral tolerization with AChR and MBP in combination prior to immunization with AChR+MBP+CFA alleviated clinical disease as well as AChR- and MBP-specific B cell node cells. The results implicate that oral tolerization simultaneously to more than one autoimmune disease-related autoantigen is feasible, and that suppression of autoantigen-induced IFN-gamma and augmentation of TGF-beta are pivotal in tolerance induction.
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PMID:Suppression of experimental autoimmune myasthenia gravis and experimental allergic encephalomyelitis by oral administration of acetylcholine receptor and myelin basic protein: double tolerance. 855 28

Myelin basic protein (MBP) is highly immunogenic and a known autoantigen capable of inducing experimental allergic encephalomyelitis (EAE), the animal model of multiple sclerosis. We have previously described a murine monoclonal antibody (mAb), F28C4, directed against the encephalitogenic MBP peptide acetyl (Ac) 1-9, which contains a V lambda x light chain. Considering the rarity of V lambda x usage, we determined whether other Abs having V lambda x light chains shared similar antigen (Ag) specificity. We screened a panel of V lambda x-containing monoclonal and polyclonal Abs, of unknown specificity for reactivity with MBP. All such Ab, but not heavy chain isotype matched controls, bound MBP but were not polyreactive with other potential self Ags. The binding of a recombinant form of V lambda x alone to MBP demonstrated the important contribution of the V lambda x light chain to the reaction. With the exception of mAb F28C4 which recognizes MBP Ac1-9, the epitope specificity of all other V lambda x-bearing Abs was localized to MBP residues 25-34. These results demonstrate a unique association between V lambda x expression and MBP reactivity. Given that V lambda x shares sequence homology with T cell receptors (TCR) from encephalitogenic T lymphocytes, these results imply a potential role for V lambda x in the pathogenesis of EAE.
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PMID:Murine V lambda x and V lambda x-containing antibodies bind human myelin basic protein. 856 71


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