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 the present study we have investigated the influence of pregnancy on the induction and development of experimental autoimmune encephalomyelitis (EAE) in rabbits in relation to the time of gestation. Randomly bred rabbits were immunized with encephalitogenic bovine brain homogenate in complete Freund's adjuvant before or during pregnancy. The appearance of EAE was delayed and occurred only after delivery, abortion, or fetal resorption. The incidence of the disease was lower and the duration longer. The levels of antibodies to myelin basic protein, an autoantigen of EAE, as measured by solid phase radioimmunoassay, were lower in the pregnant rabbits as compared to the nonpregnant animals. The suppressive influence of pregnancy on the induction and the development of EAE confirms previous reports demonstrating amelioration of autoimmune diseases and other immunological reactions during the second half of human pregnancy. This effect might be partially attributed to the increased level of alpha-fetoprotein (AFP) and/or other pregnancy-associated factors in maternal serum.
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PMID:Suppressive effect of pregnancy on the development of experimental allergic encephalomyelitis in rabbits. 620 44

Major histocompatibility complex (MHC) class II genes are the strongest susceptibility markers for many human autoimmune diseases. A perplexing aspect of this is that HLA alleles can confer either susceptibility or dominant protection. In nonobese diabetic (NOD) mice, the strongest known diabetes susceptibility locus is within the MHC and is presumed to be the H-2Ag7 product. When NOD mice carry a transgenic E alpha d molecule allowing expression of an H-2E heterodimer, diabetes is prevented. We investigated whether, as in human autoimmunity, a single class II heterodimer might protect from some autoimmune diseases while predisposing to others. NOD mice are susceptible to experimental autoimmune encephalomyelitis (EAE) induced by the proteolipoprotein (PLP) epitope 56-70. Susceptibility to EAE was analyzed in NOD mice which either have or lack transgenic H-2E expression. We found that H-2E expression in NOD mice has converse effects on diabetes and EAE: while diabetes is prevented, EAE is greatly exacerbated and leads to demyelination. Although PLP 56-70 could be presented both in the context of H-2A and H-2E, increased disease severity in H-2E transgenic mice could not be attributed either to an enhanced T cell proliferative response to PLP or to differences in determinant spread. However, cytokine analysis of the response revealed important differences between NOD mice and their H-2E transgenic counterparts: H-2E expression was associated with reduced interleukin-4 secretion and enhanced interferon-gamma (IFN-gamma) secretion by lymph node cells, while the response of central nervous system infiltrating T cells displayed a markedly enhanced IFN-gamma response. Thus, whether a particular class II molecule confers resistance or susceptibility to an autoimmune disease may depend on differential cytokine profiles elicited by particular class II/autoantigen complexes.
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PMID:Exacerbated autoimmunity associated with a T helper-1 cytokine profile shift in H-2E-transgenic mice. 748 54

Encephalitogenic activity of myelin basic protein (MBP) isolated in a form retaining binding to all myelin lipids was tested in Lewis rats. Immunization with this new stable lipid-bound and native-like preparation (LB-MBP), induced experimental autoimmune encephalomyelitis (EAE) as intensively as the classical lipid free MBP (LF-MBP). During the course of the disease, high affinity specific response to LB-MBP and high frequency of LB-MBP specific precursors was observed in peripheral lymphoid organs, indicating that the disease occurred in presence of anti LB-MBP specific T-cell responsivity. Short term lines, generated from lymphocytes collected at the onset of the disease from LB-MBP immunized rats, showed a strong dose-dependent response to LB-MBP, but not to LF-MBP. The present data indicate that in rat, LB-MBP maintains encephalitogenic activity and induces expansion of a specific T-cell population. These data suggest also that LB-MBP is a new autoantigen that may be relevant in human diseases.
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PMID:Induction of experimental autoimmune encephalomyelitis in rats and immune response to myelin basic protein in lipid-bound form. 750 90

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

A combined role of a virus infection of the central nervous system (CNS) and an autoimmune response to myelin basic protein (MBP), an autoantigen of the CNS, is suggested in the pathogenesis of multiple sclerosis (MS). SJL mice are highly susceptible while B6 mice are less susceptible to the induction of experimental autoimmune encephalomyelitis (EAE), the autoimmune model of MS. Peripheral inoculation of Semliki forest virus (SFV) into SJL and B6 mice resulted in: (1) Higher viral titers, more severe clinical disease, and hence a stronger nonspecific and SFV-specific lymphoproliferation, and production of IFN-gamma and TNF/LT was observed by splenocytes (SPL) of B6 than by those of SJL mice, on Day 7 postinfection. (2) Following viral clearance, however, proliferation to SFV, and to MBP, and the production of IFN-gamma and TNF/LT by SPL of SFV-infected SJL mice were significantly higher, while the production of TGF-beta was significantly lower than by those of B6 mice. In conclusion, the immune responses to SFV, and to MBP, which were triggered by SFV infection were significantly higher and more prolonged in the SPL of SJL mice, the EAE-susceptible mice, than by those of B6 mice after the infection was cleared.
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PMID:Immune responses, and autoimmune outcome, during virus infection of the central nervous system. 751 51

The pathogenic potential of autoimmune T cell responses to nonmyelin autoantigens was investigated in the Lewis rat using the astrocyte-derived calcium binding protein S100 beta, as a model nonmyelin autoantigen. The Lewis rat mounts a vigorous RT1B1 (major histocompatibility complex class II) restricted autoimmune response to an immunodominant S100 beta epitope (amino acid residues 76-91). The adoptive transfer of S100 beta-specific T cell lines induced a severe inflammatory response in the nervous system, but only minimal neurological dysfunction in naive syngeneic recipients. The inability of S100 beta-specific T cell transfer to induce severe disease was associated with a decreased recruitment of ED1+ macrophages into the central nervous system (CNS) in comparison with that seen in severe experimental autoimmune encephalomyelitis (EAE) induced by the adoptive transfer of myelin basic protein (MBP)-specific T line cells. Moreover, unlike encephalitogenic MBP-specific T cell lines, S100 beta-specific T cell lines exhibited no cytotoxic activity in vitro. Histopathological analysis also revealed striking differences in the distribution of inflammatory lesions in MBP- and S100 beta-specific T cell-mediated disease. In contrast to the MBP paradigm, S100 beta-specific T cell transfer induces intense inflammation not only in the spinal cord, but throughout the entire CNS and also in the uvea and retina of the eye. In view of the distribution of lesions throughout the grey and white matter of the CNS we propose to term this new model experimental autoimmune panencephalomyelitis (EAP) to differentiate it from EAE. These experiments demonstrate for the first time that nonmyelin CNS autoantigens can initiate a pathogenic autoimmune T cell response, although the nature of the target autoantigen profoundly influences the clinical and histopathological characteristics of the resulting autoimmune disease. This is not simply a consequence of the distribution of the autoantigen, as both MBP and S100 beta are coexpressed in many areas of the CNS, but reflects differences in the capacity of different regions of the CNS to process and present specific autoantigens. This new model of T cell-mediated autoimmune CNS disease exhibits a number of similarities to multiple sclerosis (MS), such as its mild clinical course and the involvement of areas of the brain and eye, which are absent in myelin-mediated models of EAE. Nonmyelin autoantigens may therefore play an unexpectedly important role in the immunopathogenesis of inflammatory diseases of the CNS.
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PMID:Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100 beta molecule, a calcium binding protein of astroglia. 752 Apr 74

Immunomodulatory treatment paradigms have been applied to animal models of T cell-mediated autoimmune diseases in an attempt to develop an immunospecific and non-toxic form of therapy which can be applied to humans. These treatment paradigms are often directed to T cells with a restricted T cell receptor repertoire or that react with dominant peptide determinants. Experimental data, however, suggests that even if the initial T cell response is restricted to a specific self-protein in the target organ, spreading autoimmunity may develop with broadening of T cell autoreactivity to additional epitopes of the same autoantigen or to different autoantigens in the target organ. Thus, multiple autoantigens may become targets of the autoimmune response. This makes immunotherapeutic strategies based on suppressing responses to restricted proteins or clones of cells problematic. We have previously shown that suppression of experimental autoimmune encephalomyelitis (EAE) in the Lewis rat by oral myelin basic protein (MBP) is mediated by the release of transforming growth factor-beta after triggering by the oral tolerogen. Here, we report that in the SJL model of EAE oral administration of an autoantigen from the target tissue suppresses disease independent of whether it is or is not the inciting antigen. Thus, orally administered MBP or MBP peptides suppress proteolipid protein (PLP)-induced EAE, whereas intravenously administered MBP does not. Both oral and intravenous PLP, however, suppressed PLP disease. These findings have important implications for the use of oral tolerance as a therapeutic approach for the treatment of T cell-mediated inflammatory autoimmune diseases in man in which the inciting autoantigen is unknown or in which there is autoreactivity to multiple autoantigens in the target tissue.
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PMID:Antigen-driven tissue-specific suppression following oral tolerance: orally administered myelin basic protein suppresses proteolipid protein-induced experimental autoimmune encephalomyelitis in the SJL mouse. 752 60

Immunization with the multideterminant autoantigen myelin basic protein (MBP) causes experimental allergic encephalomyelitis (EAE), a T-cell-mediated autoimmune disease that serves as a model for multiple sclerosis (MS). MBP peptides Ac1-11 and p35-47 induce potent EAE in mice of the H-2u haplotype. T cells specific for Ac1-11 predominantly utilize one T-cell receptor (TCR) V beta gene segment, V beta 8.2. All T-cell clones and hybridomas analyzed, regardless of TCR V beta usage, utilize D beta 2 and J beta 2 elements. The NZW mouse strain (H-2z), which contributes to the spontaneous 'lupus-like' illness in (NZB x NZW)F1 mice, has a genomic deletion encompassing D beta 2 and J beta 2 gene segments. The NZW strain expresses class II (I-A and I-E) genes which share identical sequences with H-2u class II. We investigated whether these strains are susceptible to EAE induced with intact MBP and known encephalitogenic MBP peptides. In vitro analysis demonstrated that NZW antigen-presenting cells (APC) can present MBP and MBP peptide Ac1-11 to an encephalitogenic T-cell clone derived from an H-2u mouse, confirming the functional identity of NZW class-II (I-A) molecules with their respective H-2u class-II gene products. In vivo results demonstrated that NZW and (NZB x NZW)F1 mice are susceptible to EAE induced with intact MBP and Ac1-11. MBP p35-47 caused EAE in (NZB x NZW)F1 mice, which express alleles for both the normal (NZB) TCR beta-gene locus, and the abnormal (NZW) TCR beta-gene locus containing the J beta 2 deletion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:'Lupus-prone' mice are susceptible to organ-specific autoimmune disease, experimental allergic encephalomyelitis. 752 28

Remission of experimental autoimmune encephalomyelitis (EAE) in Lewis rats may involve mediators such as prostaglandins (PG) that are produced within demyelinating lesions and are known to potently inhibit T cell responses. In support, this study shows that PGE2 inhibited myelin basic protein (MBP)-specific responses of proliferation and IL-2 production by continuously propagated lines of T-helper cells. Simultaneous exposure to PGE2 and immunogenic MBP rendered T cells profoundly anergic. Even after several weeks of propagation in IL-2-containing medium, anergic T cells exhibited marked reductions in MBP-stimulated proliferation and IL-2 production responses when restimulated with optimal concentrations of MBP and irradiated splenocytes (SPL). PGE2 did not block other measures of MBP-dependent activation, including induction of postactivation refractoriness in IL-2 production pathways, activation-dependent decreases in MBP reactivity, and activation-dependent increases in PGE2 sensitivity. Proliferative responses by anergic T cells were reduced in magnitude but were not altered in their sensitivity to MBP. PGE2-mediated anergy was manifest as an intrinsic deficit rather than an acquired suppressive activity and was associated with reduced mitogenic responsiveness and a block in IL-2 production pathways. Anergic T cells were responsive to IL-2 and eventually regained full antigenic reactivity after extended propagation in IL-2-supplemented medium. In summary, a limited exposure to PG had long-lasting inhibitory effects on subsequent T cell responsiveness to the target autoantigen MBP. These findings support the hypothesis that PG may promote disease remission by inducing anergy in helper T cells.
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PMID:Prostaglandin E2 promotes the induction of anergy during T helper cell recognition of myelin basic protein. 753 Nov 17

The role of myelin basic protein (MBP) T cell recognition in the induction of experimental allergic encephalomyelitis (EAE) has been well established in mice and rats. A remarkable restriction has been observed in T cell receptor (TCR) genes utilized by encephalitogenic T cell lines (TCLs) specific for immunodominant epitopes in these species. Pathological similarities between this animal model and multiple sclerosis (MS) has led to consider MBP as a major candidate autoantigen in this human disorder. Unlike in inbred strains of animals, the T cell response to MBP in humans is quite heterogenous with regard to fine epitope specificity. The existence of V alpha and/or V beta restriction in MBP-specific T cells, from MS patients and healthy controls, is still a matter of debate. In this study we generated 77 MBP-specific TCLs from nine healthy donors and showed that peptide 7-27 is one of the most frequently recognized epitopes. 37% of all epitope-specific TCLs recognized this peptide and p7-27 specific TCLs were generated from seven out of the nine subjects studied. A high level of in vivo clonal expansion was observed in p7-27-specific TCLs in several subjects, which however is not specific of this epitope since this phenomenon was also observed in p85-104- and 149-162-specific TCLs.
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PMID:In vivo clonal expression of T lymphocytes specific for an immunodominant N-terminal myelin basic protein epitope in healthy individuals. 754 Oct 53


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