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)

To investigate the development of HLA-DR-associated autoimmune diseases, we generated transgenic (Tg) mice with HLA-DRA-IE alpha and HLA-DRB1*0401-IE beta chimeric genes. The transgene-encoded proteins consisted of antigen-binding domains from HLA-DRA and HLA-DRB1*0401 molecules and the remaining domains from the IE(d)-alpha and IE(d)-beta chains. The chimeric molecules showed the same antigen-binding specificity as HLA-DRB1*0401 molecules, and were functional in presenting antigens to T cells. The Tg mice were backcrossed to MHC class II-deficient (IA beta-, IE alpha-) mice to eliminate any effect of endogenous MHC class II genes on the development of autoimmune diseases. As expected, IA alpha beta or IE alpha beta molecules were not expressed in Tg mice. Moreover, cell-surface expression of endogenous IE beta associated with HLA-DRA-IE alpha was not detectable in several Tg mouse lines by flow cytometric analysis. The HLA-DRA-IE alpha/HLA-DRB1*0401-IE beta molecules rescued the development of CD4+ T cells in MHC class II-deficient mice, but T cells expressing V beta 5, V beta 11, and V beta 12 were specifically deleted. Tg mice were immunized with peptides, myelin basic protein (MBP) 87-106 and proteolipid protein (PLP) 175-192, that are considered to be immunodominant epitopes in HLA-DR4 individuals. PLP175-192 provoked a strong proliferative response of lymph node T cells from Tg mice, and caused inflammatory lesions in white matter of the CNS and symptoms of experimental allergic encephalomyelitis (EAE). Immunization with MBP87-106 elicited a very weak proliferative T cell response and caused mild EAE. Non-Tg mice immunized with either PLP175-192 or MBP87-106 did not develop EAE. These results demonstrated that a human MHC class II binding site alone can confer susceptibility to an experimentally induced murine autoimmune disease.
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PMID:HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis. 867 84

Recently, it has been shown that the immunization of mice with an 18 amino acid synthetic peptide corresponding to the third hypervariable region of MHC class II beta chain can induce a specific antibody response against MHC class II molecules, and can be utilized in the prevention and treatment of experimental allergic encephalomyelitis (EAE) [Proc. Natl. Acad. Sci. 1994, 91, 8005-8009]. Based on this finding, a chemically-modified synthetic peptide with the amino acid sequence corresponding to residues of beta 57-76 from human HLA-DR4Dw4 (DR4/1 peptide) is being clinically investigated for the treatment of rheumatoid arthritis in human. The present study describes the development of a novel in vitro potency assay for human HLA-DR4/1 peptide using cloned murine T-T hybridoma cells. Several mouse strains were immunized with the DR4/1 peptide and their lymph node T cell proliferation was measured in the presence of syngeneic APCs and the DR4/1 peptide. T cells isolated from the peptide primed-B10. PL mouse strain, which showed the highest recall response in this assay, were fused with BW5147 lymphoma cells to generate DR4/1 peptide-specific T-T hybridoma clones. Cloned hybridoma cells were characterized for peptide specificity and MHC class II restriction, and used to monitor the biological activity of various DR4/1 peptide preparations. The potency of peptide batches were assessed by measuring the IL-2 secretion of cloned T-T hybridoma cells upon TCR engagement in an antigen-specific manner. The quantitative detection of IL-2 was performed by measuring [3H]thymidine incorporation of HT-2 cells or directly by ELISA. These results demonstrate that peptide-specific murine T-T hybridoma clones can be successfully utilized to monitor biological activity of synthetic peptides by measuring T cell-mediated immunological responses. Development of such in vitro potency assay for synthetic peptides may have broad applications for vaccines related to immunological disorders.
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PMID:Application of murine T-T hybridoma cells to in vitro potency assay of human synthetic peptide vaccines. 900 39

Myelin oligodendrocyte glycoprotein (MOG) is an Ag present in the myelin sheath of the CNS thought to be targeted by the autoimmune T cell response in multiple sclerosis (MS). In this study, we have for the first time characterized the T cell epitopes of human MOG restricted by HLA-DR4 (DRB1*0401), an MHC class II allele associated with MS in a subpopulation of patients. Using MHC binding algorithms, we have predicted MOG peptide binding to HLA-DR4 (DRB1*0401) and subsequently defined the in vivo T cell reactivity to overlapping MOG peptides by testing HLA-DR4 (DRB1*0401) transgenic mice immunized with recombinant human (rh)MOG. The data indicated that MOG peptide 97-108 (core 99-107, FFRDHSYQE) was the immunodominant HLA-DR4-restricted T cell epitope in vivo. This peptide has a high in vitro binding affinity for HLA-DR4 (DRB1*0401) and upon immunization induced severe experimental autoimmune encephalomyelitis in the HLA-DR4 transgenic mice. Interestingly, the same peptide was presented by human B cells expressing HLA-DR4 (DRB1*0401), suggesting a role for the identified MOG epitopes in the pathogenesis of human MS.
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PMID:T cell epitopes of human myelin oligodendrocyte glycoprotein identified in HLA-DR4 (DRB1*0401) transgenic mice are encephalitogenic and are presented by human B cells. 1173 34

Epitope spreading has been implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS). T cell epitope spreading has been demonstrated in rodents for myelin basic protein (MBP) and proteolipid protein (PLP) determinants, but not for myelin oligodendrocyte glycoprotein (MOG), another important myelin antigen. Moreover, the role of human autoimmunity-associated MHC molecules in epitope spreading, including HLA-DR2 and DR4, has not been formally examined. To address these questions, we investigated epitope spreading to MOG determinants in HLA-DR4 (DRB1*0401) transgenic mice during EAE. The data show that upon induction of EAE in HLA-DR4 transgenic mice with the immunodominant HLA-DR4-restricted MOG peptide 97-108 (MOG(97-108); TCFFRDHSYQEE), the T cell response diversifies over time to MOG(181-200) (core: MOG(183-191); FVIVPVLGP) and MBP. The spreading epitope MOG(181-200) binds with high affinity to HLA-DRB1*0401 and is presented by human HLA-DRB1*0401+antigen presenting cells. Moreover, this epitope is encephalitogenic in HLA-DRB1*0401 transgenic mice. This study demonstrates intra- and intermolecular epitope spreading to MOG and MBP in "humanized" HLA-DR4 transgenic mice.
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PMID:T cell epitope spreading to myelin oligodendrocyte glycoprotein in HLA-DR4 transgenic mice during experimental autoimmune encephalomyelitis. 1509 52

A cyclic analogue, [cyclo(87-99)MBP(87)(-)(99)], of the human immunodominant MBP(87)(-)(99) epitope, was designed based on ROESY/NMR distance information and modeling data for linear epitope 87-99, taking into account T-cell (Phe(89), Lys(91), Pro(96)) and HLA (His(88), Phe(90), Ile(93)) contact side-chain information. The cyclic analogue was found to induce experimental allergic encephalomyelitis (EAE), to bind HLA-DR4, and to increase CD4 T-cell line proliferation, like that of the conformationally related linear MBP(87)(-)(99) epitope peptide. The mutant cyclic peptides, the cyclo(91-99)[Ala(96)]MBP(87)(-)(99) and the cyclo(87-99)[Arg(91)Ala(96)]MBP(87)(-)(99), reported previously for suppressing, to a varying degree, autoimmune encephalomyelitis in a rat animal model, were found in this study to possess the following immunomodulatory properties: (i) they suppressed the proliferation of a CD4 T-cell line raised from a multiple sclerosis patient, (ii) they scored the best in vitro TH2/TH1 cytokine ratio in peripheral blood mononuclear cell cultures derived from 13 multiple sclerosis patients, inducing IL-10 selectively, and (iii) they bound to HLA-DR4, first to be reported for cyclic MBP peptides. In addition, cyclic peptides were found to be more stable to lysosomal enzymes and Cathepsin B, D, and H, compared to their linear counterparts. Taken together, these data render cyclic mimics as putative drugs for treating multiple sclerosis and potentially other Th1-mediated autoimmune diseases.
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PMID:Design and synthesis of a novel potent myelin basic protein epitope 87-99 cyclic analogue: enhanced stability and biological properties of mimics render them a potentially new class of immunomodulators. 1574 89

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS. The numbers of autoimmune T cells and Abs specific for proteins of CNS myelin are increased in the blood in some patients with MS. The aim of this study was to investigate whether there are correlations between the specificity of the autoimmune responses in the blood, the HLA molecules carried by the patient, and the clinical features of MS, because studies on experimental autoimmune encephalomyelitis, an animal model of MS, indicate that autoimmune responses targeting particular myelin proteins and the genetic background of the animal play a role in determining the pattern of lesion distribution. We tested blood T cell immunoreactivity to myelin proteins in 100 MS patients, 70 healthy controls, and 48 patients with other neurological disorders. Forty MS patients had strongly increased T cell reactivity to one or more myelin Ags. In these 40 patients, the most robust correlation was between CD4(+) T cell reactivity to myelin proteolipid protein residues 184-209 (PLP(184-209)) and development of lesions in the brainstem and cerebellum. Furthermore, carriage of HLA-DR4, -DR7, or -DR13 molecules by MS patients correlated with increased blood T cell immunoreactivity to PLP(184-209), as well as the development of lesions in the brainstem and cerebellum. Levels of PLP(190-209)-specific Abs in the blood also correlated with the presence of cerebellar lesions. These findings show that circulating T cells and Abs reactive against specific myelin Ags can correlate with lesion distribution in MS and suggest that they are of pathogenic relevance.
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PMID:Correlation of blood T cell and antibody reactivity to myelin proteins with HLA type and lesion localization in multiple sclerosis. 1842 64

The human autoimmune disease-associated HLA alleles HLA-DR2b (DRB1*1501) and HLA-DR4 (DRB1*0401) are strongly linked to increased susceptibility for multiple sclerosis (MS) and rheumatoid arthritis (RA), respectively. The underlying mechanisms are not fully understood, but these MHC alleles may shape the repertoire of pathogenic T cells via central tolerance. The transcription factor autoimmune regulator (AIRE) promotes central T cell tolerance via ectopic expression of tissue-specific antigens (TSAs). Aire deficiency in humans causes autoimmune polyendocrinopathy syndrome type 1 (APS1), and Aire knockout mice (Aire-/-) develop spontaneous autoimmune pathology characterized by multi-organ lymphocytic infiltrates. Here, we asked whether impaired TSAs gene expression in the absence of Aire promoted spontaneous MS- or RA-like autoimmune pathology in the context of human HLA alleles in HLA-DR2b or HLA-DR4 transgenic (tg) mice. The results show that reduced TSAs gene expression in the thymus of Aire-deficient HLA-DR2b or HLA-DR4 tg mice corresponded to mild spontaneous inflammatory infiltrates in salivary glands, liver, and pancreas. Moreover, Aire-deficiency modestly enhanced experimental autoimmune encephalomyelitis (EAE) in HLA-DR tg mice, but the animals did not show signs of spontaneous neuroinflammation or arthritis. No significant changes were observed in CD4+ T cell numbers, T cell receptor (TCR) distribution, regulatory T cells (Treg), or antigen-induced cytokine production. Abrogating Treg function by treatment with anti-CTLA-4 or anti-CD25 mAb in Aire-deficient HLA-DR tg mice did not trigger EAE or other autoimmune pathology. Our results suggest a redundant role for Aire in maintaining immune tolerance in the context of autoimmune disease-associated human HLA alleles.
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PMID:Aire is not essential for regulating neuroinflammatory disease in mice transgenic for human autoimmune-diseases associated MHC class II genes HLA-DR2b and HLA-DR4. 2978 21