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)

In search of a phenotypic marker determining genetically controlled susceptibility to delayed-type hypersensitivity (DTH) reactions in the brain--in particular, experimental autoimmune encephalomyelitis (EAE)--we have compared the gamma-interferon (IFN-gamma) induction of Ia molecules on astrocytes and macrophages from rat and mouse strains that are susceptible or resistant to this disease. We focused on Ia expression because DTH reactions to self or foreign antigens are largely mediated by lymphocytes restricted by class II (Ia) antigens of the major histocompatibility complex (MHC). Our data demonstrate that Lewis (fully susceptible) and Brown Norway (BN) (fully resistant) rats are very different in that Lewis astrocytes express much higher levels of Ia than BN astrocytes. Similar data were obtained from an analysis of EAE-susceptible and -resistant mouse strains (SJL and BALB/c, respectively), which suggests that this phenomenon may be universal and not limited to only one mammalian species. At least one gene responsible for Ia hyperinduction is located outside the rat RT-1 or the mouse MHC locus. Animals congenic at the RT-1 or MHC locus of the resistant strain but with background genes of the susceptible strain exhibit intermediate levels of Ia compared to fully resistant and susceptible rodents, which fits well with the reduced EAE susceptibility of these congenic animals. Furthermore, hyperinduction of Ia is astrocyte specific, since peritoneal macrophages of susceptible and resistant strains exhibit identical profiles of Ia induction. Thus, astrocyte Ia hyperinducibility may be a major strain- and tissue-specific factor that contributes to Ia-restricted DTH reactions in the brain.
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PMID:Hyperinducibility of Ia antigen on astrocytes correlates with strain-specific susceptibility to experimental autoimmune encephalomyelitis. 349 2

Cell surface expression of Class II major histocompatibility complex (Ia) molecules is required for antigen recognition by T cells. To determine the ultrastructural cellular distribution of Ia molecules in the autoimmune disease model acute experimental allergic encephalomyelitis (EAE) we studied central nervous system (CNS) tissues from adult Strain 13 guinea pigs (GP). Experimental allergic encephalomyelitis was induced by sensitization with GP spinal cord homogenate in complete Freund's adjuvant (CFA). Nine of 11 sensitized GP had clinical and histologic EAE whereas unsensitized and CFA-sensitized controls were normal. Central nervous system tissues were reacted with monoclonal antibodies to either GP Ia or T cell surface antigen using an avidin-biotin immunoperoxidase technique and studied by electron microscopy; Ia was found on luminal but not abluminal surfaces of many meningeal and parenchymal vascular endothelial cells in GP with EAE. In EAE perivascular lymphocytes and macrophages and processes of unidentified cells in the parenchyma expressed surface Ia and Ia+ macrophages encircled and phagocytosed myelin. T cells were found predominantly in perivascular inflammatory cuffs. These observations indicate that following immunologic challenge Ia is expressed on luminal surfaces of vascular endothelium and on resident CNS cells, suggesting the possibility that these cells may have active antigen-presenting functions in CNS inflammatory reactions.
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PMID:The immunopathology of acute experimental allergic encephalomyelitis. IV. An ultrastructural immunocytochemical study of class II major histocompatibility complex molecule (Ia) expression. 354 82

One question in the pathogenesis of experimental allergic encephalomyelitis (EAE) is whether antigen-presenting cells exist in the central nervous system which help induce the development of the disease. Since EAE is a delayed-type hypersensitivity condition, and since T cells require major histocompatibility complex (MHC)-restricted antigen presentation, it is presumed that if antigen presentation occurs in CNS tissue, the presenting cell should express surface Ia molecules. Using immunofluorescent double labeling, the possibility that astrocytes express surface Ia during EAE evolution in the Lewis rat was examined. Very rare Ia-positive astrocytes were found (less than 0.1% of the astrocytes), but only in the spinal cords of clinically ill animals. In addition, endothelial cell Ia positivity was noted prior to the onset of clinical disease. The immunological significance of such low numbers of astrocytes expressing Ia during EAE is uncertain.
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PMID:Expression of Ia molecules by astrocytes during acute experimental allergic encephalomyelitis in the Lewis rat. 388 13

Genetic analysis of susceptibility to experimental allergic encephalomyelitis (EAE) was performed in guinea-pigs. The results indicate the existence of two Ir genes to EAE in susceptible strain 13 guinea-pigs. One gene is linked to the major histocompatibility complex (MHC) of this species, while the other one is located outside the MHC. The two genes segregate independently and both of them must be expressed to render the animal susceptible to EAE.
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PMID:Genetic analysis of susceptibility to experimental allergic encephalomyelitis in guinea-pigs. 616 34

We have previously found that lines of activated T lymphocytes specifically autosensitized to the basic protein of myelin (BP), on intravenous inoculation into syngeneic rats, were able to penetrate blood vessels, accumulate in the nervous system and cause experimental autoimmune encephalomyelitis (EAE). An important question is how effector T cells reach such targets outside the walls of blood vessels. To investigate this we have studied in vitro the interaction of anti-BP effector T lymphocytes with the basement membrane-like extracellular matrix produced by vascular endothelial cells. We now report that activated but not resting T lymphocytes produce an endoglycosidase capable of degrading heparan sulphate side chains of the proteoglycan scaffold of the extracellular matrix. Moreover, the anti-BP T lymphocytes respond to BP presented by extracellular matrix by markedly enhanced elaboration of the endoglycosidase. These results suggest that tissue-specific antigens on blood vessel walls could direct lymphocyte homing by activating enzymes that facilitate penetration of the subendothelial basal lamina. They also suggest that effector T lymphocytes can recognize antigen which is not associated with a major histocompatibility complex signal.
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PMID:Activated T lymphocytes produce a matrix-degrading heparan sulphate endoglycosidase. 620 75

Polymorphism of the major histocompatibility complex (MHC) influences susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein (MBP) in rats. Current concepts relate such influences to the capacity of class II molecules to present relevant peptides to autoreactive T cells. We have here analyzed the MHC influence on the immune response and the development of EAE after immunization with the immunodominant peptide MBP-63-88. Analysis of MHC-congenic LEWIS strains showed that RT1a, RT1c and RT1(1) haplotypes are permissive for disease induction, whereas RT1d and RT1u are resistant. All EAE responding strains showed peptide-specific proliferation and interferon (IFN)-gamma secretion, but no early significant tendency to express interleukin (IL-4) or transforming growth factor (TGF)-beta mRNA in lymphocytes in response to the MBP 63-88, 7 days post immunization (p.i.). Later, 14 days p.i., peptide-specific induction of IL-4 and TGF-beta occurred in RT1(1) rats. Among the EAE non-responders strains, only the RT1u rats showed an immune response to MBP 63-88. This response, however, was qualitatively different from the immune response in the EAE-susceptible strains. Thus, there was no proliferation and only moderate IFN-gamma production in response to peptide, but in contrast, a significant and early peptide-induced IL-4 and TGF-beta response was observed. The data suggest that the MHC-associated susceptibility to EAE is partly related to the ability to mount a TH1-like immune response while the MHC-associated EAE resistance may either be related to MBP peptide non-responsiveness or to peptide recognition and induction of a qualitatively different and disease down-regulatory immune response.
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PMID:The major histocompatibility complex influences myelin basic protein 63-88-induced T cell cytokine profile and experimental autoimmune encephalomyelitis. 750 88

T-cell hybridomas specific for myelin basic protein (MBP) were used to assess regulation of co-stimulatory signals during remission of experimental autoimmune encephalomyelitis (EAE) in Lewis rats. Both THYB-1 and THYB-2 subsets of T-cell hybridomas recognize class II major histocompatibility complex-restricted determinants in the 72-86 encephalitogenic region of MBP. However, THYB-2 hybrids uniquely express additional requirements for co-stimulatory signals from radiosensitive splenocytes (SPL) to support the response of MBP-stimulated IL-2 production. Hence, this subset provides a means to study regulation of THYB-2 specific co-stimulatory signals during the course of EAE. This study revealed that sensitization of Lewis rats with MBP in complete Freund's adjuvant induced a radioresistant subpopulation of co-stimulatory SPL that emerged during the remission phase of EAE. These radioresistant SPL provided specific accessory cell activities that fulfilled the co-stimulatory requirements of THYB-2 hybrids. These findings support the hypothesis that in vivo activation events elicit radioresistance in an emergent clonally expanding population of antigen-specific lymphocytes. A central prediction of this hypothesis is that cellular activation should confer radioresistance to co-stimulatory lymphocytes. This prediction was verified by the observation that in vitro activation of naive SPL with different B- and T-cell mitogens conferred radioresistance to co-stimulatory SPL. Mitogenic activation not only induced radioresistance but also dramatically augmented co-stimulatory activity of purified B cells. In summary, the results of this study support the hypothesis that in vivo activation of co-stimulatory lymphocytes may regulate activities of encephalitogenic T-helper cells during progression and remission of EAE.
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PMID:Emergence of a radioresistant population of co-stimulatory splenocytes during remission of experimental autoimmune encephalomyelitis in Lewis rats. 751 Feb 67

Models of T cell recognition suggest that amino acid residues in the CDR3 region of the T cell receptor (TCR) alpha or beta chain directly contact the major histocompatibility complex-bound peptide, and thus are crucial for providing peptide specificity. T cells derived from B10.PL or PL/J mice of H-2u haplotype, use only D beta 2 and J beta 2 gene segments in the recognition of the dominant determinant, Ac1-9/Au, of myelin basic protein (MBP). New Zealand White (NZW) mice, with identical class II H-2u genes (I-A and I-E), carry an 8.8-kb deletion in their TCR beta chain locus encompassing D beta 2 and J beta 2 gene segments. How does this deletion of the crucial D beta 2-J beta 2 region in NZW mice influence specific responses to Ac1-9/Au as well as to other known Au or Eu determinants of MBP? We found that these mice respond very poorly to the dominant Ac1-9/Au and to the subdominant 31-50/Eu determinant in in vitro proliferation assays as well as in their in vivo capacity to induce experimental autoimmune encephalomyelitis. This loss of response is apparently owing to the absence of high avidity TCRs with essential CDR3 residues contributed by D beta 2 or J beta 2 gene segments. These data reveal constraints in the recognition of certain antigenic structures, and further support a TCR-recognition model in which CDR3 residues of the TCR alpha and beta chains constitute the antigenic peptide-binding sites on the TCR molecule. Implications for autoimmune manifestations contributed by NZW genes in (NZB x NZW)F1 disease are also discussed.
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PMID:Holes in the T cell repertoire to myelin basic protein owing to the absence of the D beta 2-J beta 2 gene cluster: implications for T cell receptor recognition and autoimmunity. 751 12

Previous studies have shown that major histocompatibility complex (MHC) blockade by competitor peptides with high MHC class II binding affinity can prevent peptide-induced experimental autoimmune encephalomyelitis (EAE). However, none of these studies addressed the question whether this approach could also be used to prevent EAE induced with a multivalent antigen. In this report we show the effect of competitor peptides co-immunized during EAE induction with entire guinea pig myelin basic protein (MBP) in Lewis rats. As MHC class II binding competitor peptides we used one nonimmunogenic disease-nonrelated peptide, and two immunogenic peptides, one EAE-related and one non-EAE-related. The respective efficacy of these three competitor peptides to inhibit MBP-induced proliferation of an encephalitogenic T cell line in vitro correlated with their respective MHC binding affinity. Co-immunization of the competitor peptides during disease induction with entire MBP resulted in a competitor concentration-dependent inhibition of clinical signs of EAE. These results demonstrate that, although polyclonal T cell responses to MBP were not completely inhibited, co-administration of immunogenic or nonimmunogenic either EAE-related or non-EAE-related MHC class II binding competitor peptides can inhibit the development of EAE induced with entire MBP.
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PMID:Inhibition of entire myelin basic protein-induced experimental autoimmune encephalomyelitis in Lewis rats by major histocompatibility complex class II-binding competitor peptides. 751 28

Copolymer 1 (Cop 1) is a synthetic basic random copolymer of amino acids that has been shown to be effective in suppression of experimental allergic encephalomyelitis and is being tested as a candidate drug for multiple sclerosis. It has been previously demonstrated that Cop 1 is immunologically cross-reactive with the autoantigen myelin basic protein (BP) and competitively inhibits the response to BP of T-cell lines and clones of different major histocompatibility complex (MHC) restrictions, of both mouse and human origin. In the present study we demonstrated the direct binding of Cop 1, using its biotinylated derivative, to MHC molecules on living antigen-presenting cells. Binding of biotinylated BP and peptide p84-102 (an immunodominant epitope of BP) was also demonstrated. Cop 1 and BP bound in a promiscuous manner to different types of antigen-presenting cells of various H-2 and HLA haplotypes. The specificity of the binding was confirmed by its inhibition with either the relevant anti-MHC class II antibodies or unlabeled analogs. Cop 1 exhibited the most extensive and fast binding to antigen-presenting cells. In addition, Cop 1 inhibited the binding of biotinylated derivatives of BP and of p84-102 to the MHC class II molecules and even displaced these antigens when already bound. Thus, these results suggest that Cop 1 indeed competes with BP for MHC binding and, thereby, inhibits T-cell responses to BP. The binding of Cop 1 to different DR alleles, probably because of its multiple MHC binding motifs, may indicate its potential as a broad-spectrum drug for multiple sclerosis.
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PMID:Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity and promiscuity. 751 81


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