Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004364 (autoimmune disease)
 24,845 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The anti-CD4 mAb W3/25 inhibits experimental autoimmune encephalomyelitis (EAE) in Lewis rats by blocking Th cell responses to encephalitogenic determinants of myelin basic protein (MBP). However, it has yet to be resolved how W3/25 modulates CD4 to inhibit EAE-associated T cell responses. This study revealed that W3/25 profoundly inhibited MBP-stimulated proliferation by sensitized lymph node cells but only partially inhibited the respective response of uncloned and cloned lines of MBP-specific T cells. That is, low concentrations of W3/25 blocked 30 to 60% of MBP-stimulated proliferation, but 100-fold higher concentrations did not result in additional inhibition. W3/25 also inhibited MBP-induced acquisition of EAE transfer activity, but only in cultures of freshly isolated lymph node cells and not in cultures of continuously propagated T cells. Studies focusing on the GP2.E5 T cell line revealed that the lack of sensitivity to W3/25 in encephalitogenic and proliferative assays was nevertheless associated with an effective blockage of MBP-stimulated IL-2 production. Importantly, W3/25 specifically inhibited antigenic but not mitogenic stimulation of IL-2 production. Reverse transcriptase/polymerase chain reaction analyses revealed that MBP-activated GP2.E5 T cells produced mRNA for both IL-2 and IL-4, and that W3/25 selectively inhibited accumulation of IL-2 as compared to IL-4 mRNA. Thus, GP2.E5 T cells apparently express a IL-4-dependent pathway that confers resistance to the inhibitory activity of W3/25. Studies focusing on two CD4+ T cell hybridomas revealed that W3/25 profoundly inhibited MBP-stimulated IL-2 production but did not affect the alternative response of MBP-induced growth inhibition. Several other hybrids also mediated MBP-stimulated IL-2 production but did not express CD4 and were not affected by W3/25. These results indicate that: 1) interactions of W3/25 with CD4 do not necessarily block class II MHC-restricted recognition of MBP; and 2) expression of CD4 is not necessary for Ag recognition by several clonotypes of MBP-reactive T cells. Rather, the results of this study are consistent with the concept that W3/25 inhibits transduction of costimulatory signals that are required specifically for initiation of IL-2 production. These findings may have important implications for understanding the therapeutic potential of anti-CD4 mAb in autoimmune disease.
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PMID:Differentiation of encephalitogenic T cells confers resistance to an inhibitory anti-CD4 monoclonal antibody. 750 25

The cause of MS is uncertain, but an autoimmune disorder of the CNS is likely, and myelin basic protein (MBP) is a candidate antigen. MBP exists in different isoforms, generated by differential splicing of exons, and in charge isomers, generated by posttranslational modifications. Different isoforms and charge isomers presumably subserve different functions, and they vary in abundance in immature myelin found during myelinogenesis and remyelination compared with mature myelin. The 18.5-kd isomer is most abundant in normal human adults and consequently has been used almost exclusively for immunologic studies in MS. In the present study, we examined a different but abundant charge isomer of MBP, termed MBP-C8, to determine whether it could be recognized by MBP-specific cytotoxic and proliferative T-cell lines (TCL) and whether a T-cell response directed exclusively against citrulline-containing residues of MBP-C8 exists in MS patients and healthy controls. We showed that citrulline affects antigen recognition by some TCL that are specific for areas of MBP that contain the citrulline residues. Following stimulation with MBP-C8, MBP-C8-specific TCL could be generated from both MS patients and controls. T-cell responses against antigens that appear during myelinogenesis and during remyelination may be important in inducing and perpetuating an autoimmune response involved in the pathogenesis of MS.
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PMID:Citrulline-containing myelin basic protein is recognized by T-cell lines derived from multiple sclerosis patients and healthy individuals. 750 25

The precise mechanisms of failure of immunological tolerance to self proteins are not known. Major histocompatibility complex (MHC) susceptibility alleles, the target peptides, and T cells with anti-self reactivity must be present to cause autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a murine model of a human autoimmune disease, multiple sclerosis. In EAE, residues 1-11 of myelin basic protein (MBP) are the dominant disease-inducing determinants in PL/J and (PL/J x SJL/J)F1 mice. Here we report that a six-residue peptide (five of them native) of MBP can induce EAE. Using peptide analogues of the MBP-(1-11) peptide, we demonstrate that only four native MBP residues are required to stimulate MBP-specific T cells. Therefore, this study demonstrates lower minimum structural requirements for effective antigen presentation by MHC class II molecules. Many viral and bacterial proteins share short runs of amino acid similarity with host self proteins, a phenomenon known as molecular mimicry. Since a six-residue peptide can sensitize MBP-specific T cells to cause EAE, these results define a minimum sequence identity for molecular mimicry in autoimmunity.
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PMID:Minimum structural requirements for peptide presentation by major histocompatibility complex class II molecules: implications in induction of autoimmunity. 750 53

Activation pathways responsible for myelin basic protein (MBP)-stimulated proliferation of encephalitogenic T cells were studied by derivation of new monoclonal antibodies against rat T cell surface proteins. These monoclonal antibodies were derived by immunization of Balb/c mice with THYB-2 T cell hybrids or with the GP2.E5 line of encephalitogenic T-helper cells. The LRTC1 mAb inhibited MBP-stimulated IL-2 production by THYB-2 hybrids but not by THYB-1 hybrids and did not inhibit the alternative response of MBP-induced growth inhibition by either hybrid subset. Although LRTC1 labeled virtually all rat leukocytes, it selectively inhibited proliferative responses to T cell mitogens but not to B cell mitogens. LRTC1 inhibited MBP-stimulated IL-2 production by GP2.E5 T cells but did not effectively block MBP-stimulated proliferation. Rather, LRTC1 acted in synergy with a second mAb (LRTC2) to effectively inhibit MBP-stimulated proliferation by GP2.E5 T cells. The observation that LRTC1 did not exhibit synergy with a third biologically active mAb (LRTC3) supported the hypothesis that LRTC1 and LRTC2 represented a specific combination of synergistic mAb. In contrast to the inhibitory activity on GP2.E5 T cells, LRTC1 and LRTC2 synergistically stimulated antigen-independent IL-2 production by the THYB-1 hybrid LSS-A1. These results support the hypothesis that GP2.E5 T cells respond to parallel costimulatory pathways that are respectively inhibited by LRTC1 and LRTC2 mAb. Furthermore, these synergistic mAb exhibited inhibitory or stimulatory activities that may be diagnostic of distinct T-helper cell subsets. These novel mAb may thereby facilitate studies of costimulatory pathways and T-helper cell subsets in the pathogenesis of autoimmune disease.
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PMID:Parallel costimulatory pathways promote myelin basic protein-stimulated proliferation of encephalitogenic rat T cells. 750 24

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease mediated by myelin protein-specific CD4+ T lymphocytes of the T(h)1-like phenotype. In rats, the disease is characterized by a monophasic clinical manifestation, followed by a subsequent spontaneous remission and the establishment of life-long resistance to reinduction of disease. Recent data indicate that intracerebral cytokine production, in particular synthesis of interleukin(IL)-10, is selectively up-regulated during the recovery phase of disease. This led us to assess the effects of IL-10 on different rat lymphoid cell functions in vitro and to consider the possibility of an IL-10-mediated treatment to prevent the induction of central nervous system (CNS) autoimmune disease in vivo. Human recombinant IL-10 suppressed interferon-gamma induced major histocompatibility complex class II up-regulation in rat peritoneal macrophages, exhibited pleiotropic effects on thymocytes and totally abrogated tumor necrosis factor production of encephalitogenic T lymphocytes in vitro, without simultaneously affecting proliferative responses of the cells. Upon systemic administration during the initiation phase of disease, IL-10 was effective in markedly suppressing the subsequent induction of EAE in Lewis rats. This suppression of clinical disease coincided with a significant and specific elevation of myelin basic protein-specific autoantibody production, a sustained T cell proliferative response to myelin basic protein and a diminution of CNS infiltrations and thymic involutions in diseased animals. These data implicate IL-10 as a possible candidate for treatment of T(h)1-mediated CNS (auto-) immune diseases.
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PMID:Interleukin-10 prevents experimental allergic encephalomyelitis in rats. 751 15

Multiple sclerosis (MS) may be an autoimmune disease, partially caused by autoreactivity to myelin basic protein (MBP) and other central nervous system proteins. Acute optic neuritis (ON) is a frequent first symptom of MS. The role of the HLA system in anti-MBP antibody production in ON was investigated employing a restriction fragment length polymorphism system for genomic HLA-DQ and -DR typing and an immunospot assay for the detection of individual cells secreting antibodies to three different synthetic MBP peptides. Thirty-two out of 40 patients (80%) with ON had cells in cerebrospinal fluid secreting anti-MBP peptide antibodies while this occurred in 10/19 patients with other neurological diseases (53%; mainly in patients with inflammatory diseases in the central nervous system). This difference was statistically significant (P = 0.03). None of the three examined peptides were immunodominant in any patient group. It was found, however, that presence of HLA DR15, which is associated with MS, may be associated further with predominant production of antibodies to the MBP amino acids 63-88 in patients with ON (P = 0.002, corrected for multiple comparisons).
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PMID:Peptide specificity of anti-myelin basic protein antibodies in patients with acute optic neuritis and the HLA system. 751 73

Different models of experimental autoimmune encephalomyelitis (EAE) have been successfully applied to investigate and manifold aspects of the autoimmune pathogenesis of multiple sclerosis. Studies using myelin-specific T-cell lines that transfer EAE to naive recipient animals established that only activated lymphocytes are able to cross the endothelial blood-brain barrier and cause autoimmune disease within the local parenchyma. All encephalitogenic T cells are CD4+ Th1-type lymphocytes that recognize autoantigenic peptides in the context of MHC class II molecules. In the case of myelin basic protein (MBP) specific EAE in the Lewis rat, the T-cell response is directed against one strongly dominant peptide epitope. The encephalitogenic T cells preferentially use one particular set of T-cell receptor genes. Although MBP is a strong encephalitogen in many species, a number of other brain protein are now known to induce EAE. These include mainly myelin components (PLP, MAG, and MOG), but also, the astroglial S-100 beta protein. Encephalitogenic T cells produce only inflammatory changes in the central nervous system, without extensive primary demyelination. Destruction of myelin and oligodendrocytes in these models requires additional effector mechanisms such as auto-antibodies binding to myelin surface antigens such as the myelin-oligodendrocyte glycoprotein.
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PMID:Animal models. 751 26

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

Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease that serves as an animal model for multiple sclerosis. Oral administration of myelin basic protein (MBP) suppresses EAE by inducing peripheral tolerance. T cell clones were isolated from the mesenteric lymph nodes of SJL mice that had been orally tolerized to MBP. These clones were CD4+ and were structurally identical to T helper cell type 1 (TH1) encephalitogenic CD4+ clones in T cell receptor usage, major histocompatibility complex restriction, and epitope recognition. However, they produced transforming growth factor-beta with various amounts of interleukin-4 and interleukin-10 and suppressed EAE induced with either MBP or proteolipid protein. Thus, mucosally derived TH2-like clones induced by oral antigen can actively regulate immune responses in vivo and may represent a different subset of T cells.
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PMID:Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. 752 Jun 5

A T cell response against myelin basic protein (MBP) is thought to contribute to the central nervous system (CNS) inflammation that occurs in the human demyelinating disease multiple sclerosis. To test whether MBP-reactive T cells that are normally retrieved from the circulation are capable of inducing CNS disease, MBP-reactive T cell clones were isolated from the peripheral blood of healthy, unimmunized Callithrix jacchus (C. jacchus) marmosets. This primate species is characterized by a natural chimerism of bone marrow elements between siblings that should make possible adoptive transfer of MBP-reactive T cells. We report that MBP-reactive T cell clones efficiently and reproducibly transfer CNS inflammatory disease between members of C. jacchus chimeric sets. The demyelination that is characteristic of experimental allergic encephalomyelitis induced in C. jacchus by immunization against human white matter did not occur after adoptive transfer of the MBP-reactive clones. It was noteworthy that encephalitogenic T cell clones were diverse in terms of their recognition of different epitopes of MBP, distinguishing the response in C. jacchus from that in some inbred rodents in which restricted recognition of MBP occurs. These findings are the first direct evidence that natural populations of circulating T cells directed against a CNS antigen can mediate an inflammatory autoimmune disease.
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PMID:In healthy primates, circulating autoreactive T cells mediate autoimmune disease. 808 76


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