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)

Myasthenia gravis (MG) is a T-cell regulated autoimmune disease. A peptide representing a sequence of the human acetylcholine receptor alpha-subunit (p195-212) was previously shown to stimulate proliferative responses of peripheral blood lymphocytes from MG patients and to be an immunodominant and myasthenogenic T-cell epitope in SJL mice. The authors generated a panel of analogues of p195-212 that contain single amino acid substitutions. Three of the analogues (203PHE, 204GLY and 207ALA) triggered low to no proliferative responses of a p195-212-specific T-cell line designated TCSJL195-212. Two of these analogues were able to stimulate the line to produce interleukin-2 (IL-2) and IL-4 (203PHE and 204GLY), whereas one analogue, 207ALA, did not stimulate the line to produce these cytokines. Binding assays revealed that the binding affinity of an altered peptide for a given major histocompatibility complex (MHC) molecule is not sufficient to determine whether it will be stimulatory or inhibitory to a native peptide-specific T-cell line. Two of the analogues, 204GLY and 207ALA, inhibited proliferative responses of cells of the TCSJL195-212 line when co-cultured with p195-212 and syngeneic antigen presenting cells (APC). The two inhibitory analogues were also able to inhibit proliferative responses of the TCSJL195-212 line when APC were pre-pulsed with p195-212, indicating that MHC blockade is not the only mechanism of action of these peptides. Moreover, both analogues inhibited the ability of p195-212 to prime lymph node cells for proliferative responses even when the analogues were administered in a soluble form. Thus the altered peptide ligands 207ALA and 204GLY can modulate T-cell responses both in vitro and in vivo and may have therapeutic potential for the treatment of MG.
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PMID:Altered peptide ligands of a myasthenogenic epitope as modulators of specific T-cell responses. 894 4

Clinical research has focused on autoimmune disease (AID) for a couple of decades. More sensitive and specific methods have been developed for neuroimmunological research. Gamma fraction bands (bands separated by electrophoresis and visualized by amino black staining) and IgG fraction bands (bands separated by iso-electric focusing and visualized by immunostaining) are used instead of oligoclonal bands. Myasthenia gravis (MG) mainly involves acetylcholine receptors of the postsynaptic membrane at the neuromuscular junction. Myasthenia gravis has been considered to be a generalized AID, because 7% of patients with myasthenia gravis associate with other AIDs and more than one autoimmune antibody is detected in 52.5% patients with myasthenia gravis. Pyramidal signs in myasthenia gravis patients are described; the possible mechanism may at least be partly due to the acetylcholine receptor antibody. P2 protein and its antibody are studied in patients with acute and chronic inflammatory demyelinating polyneuropathy.
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PMID:Clinical neuroimmunology. 896 24

We have shown in several distinct experimental systems that the immune system of intact Lewis rats contains T cells which, upon activation, are able to mediate autoimmune brain inflammation. These T cells seem to differentiate within the thymus although the autoantigens are produced (and presumably expressed in a recognizable fashion) within the thymic medulla. Furthermore, an intact fully MHC compatible thymic microenvironment seems to be required for the development of all features of the autoimmune TCR repertoire. Biased utilization of V beta 8.2 gene for the TCR, a hallmark of the Lewis rat T cell response to MBP, is only seen in T cells having matured in thymuses entirely composed of stroma elements of rat origin. It seems that the thymus contains a large spectrum of protein structures, which hitherto had been considered autoantigens specific for "peripheral" tissues, and, most surprisingly, components of the CNS, the classical "sequestered" organ. Deletion of autoreactive T cell clones by many local intrathymic autoantigens is leaky, at best. The reduced expression of CD4 on thymus-derived autoreactive T cells may be construed to reflect abortive efforts of negative selection. Alternatively, however, it may be worthwhile to consider a positive role for intrathymic autoantigens and their complementary T cells clones. It is possible that the requirement of an intact thymus milieu for the typical, V beta 8.2 dominated MBP specific T cell repertoire in the Lewis rat could reflect self peptide presentation by thymus epithelium cells in positive selection stages. In that case, the unusual diversity of thymic autoantigens could indeed have a role in shaping the immune system's TCR diversity, possible in the sense of an "immunological homunculus" as postulated by Cohen (Cohen 1992). Finally, there is a need to explain the mechanisms that in the healthy organism prevent the numerous, potentially autoaggressive T cell clones from attacking the body's own tissues. This is especially important, as T cells reactive against potentially pathogenic autoantigens, e.g. MBP (Ota et al. 1990, Pette et al. 1990b) and acetylcholine receptor (Salvetti et al. 1991, Sommer et al. 1991), are seen at especially high frequency in the human immune repertoire. Clearly, in all experimental paradigms investigated, activation of self-reactive T cells was the critical prerequisite for induction of autoimmune disease. Thus, in principle, prevention of such activation would be one way to maintain self tolerance. The mechanisms that achieve this goal in most individuals remain to be elucidated.
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PMID:The shaping of the brain-specific T lymphocyte repertoire in the thymus. 900 17

Myasthenia gravis (MG) is the classical organ specific, autoantibody mediated and T cell dependent human autoimmune disease. It is almost invariably associated with pathological alterations of the thymus. These are described here with reference to distinct models of autoimmunization against the acetylcholine receptor (AChR). In MG with thymitis B cells are increased in the medulla forming germinal centers or diffuse B cell infiltrates. Intrathymic production of AChR-specific autoantibodies is the result of a classical antigen-driven immune reaction that occurs completely inside the thymus and involves AChR on myoid cells as the triggering (myasthenogenic) antigen. In thymomas no intratumorous immune reaction occurs and the AChR is not the myasthenogenic antigen. Instead, an abnormal neurofilament that shares epitopes with the AChR is expressed in thymomas and may trigger AChR-specific, non-tolerogenic T cell selection by molecular mimicry. These data support the hypothesis that initial steps in the pathogenesis of MG take place within abnormal thymic microenvironments, be they inflammatory or neoplastic. The etiology of MG remains enigmatic.
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PMID:Myasthenia gravis. 902 May 69

Activation of inflammatory and cytotoxic complement effectors that include the C5b-9 complex plays an important pathogenic role in myasthenia gravis, an inflammatory autoimmune disease of the muscle. Altered muscle-specific gene expression has been observed in experimental myasthenic rats. In this study, we have examined the effect of sublytic C5b-9 on myotubes differentiated from C2C12 myoblasts, by generating C5b-9 with C7-deficient serum with or without C7. Within 2 h, C7-deficient serum plus C7, compared with C7-deficient serum alone, induced markedly decreased levels of mRNAs encoding alpha-actin, troponin I slow twitch isoform, acetylcholine receptor alpha, and muscle aldolase A, whereas the heat shock protein 83 mRNA level remained constant, by northern analysis. Because the half-life of the acetylcholine receptor alpha was estimated to be > 8 h, the C5b-9 effect was, in part, due to enhanced mRNA decay. Because C5b-9 also induced c-jun mRNA and reduced the myoD mRNA level, a possible inhibition of muscle gene transcription by C5b-9 was examined in myotubes transfected with troponin promoter-luciferase gene constructs. Luciferase activity was reduced to 50% in response to C5b-9 at 2 h. Thus, C5b-9 appears to inhibit the muscle-specific gene expression by stimulating mRNA decay and by decreasing the transcription process. The data also indicate a possible pathogenic role of C5b-9 in immune-mediated inflammatory muscle disorders in which complement activation has been implicated.
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PMID:Sublytic terminal complement attack on myotubes decreases the expression of mRNAs encoding muscle-specific proteins. 908 29

Myasthenia gravis (MG) is a T cell-regulated, antibody-mediated autoimmune disease. Two peptides representing sequences of the human acetylcholine receptor alpha-subunit, p195-212 and p259-271, were previously shown to stimulate peripheral blood lymphocytes of patients with MG and were found to be immunodominant T cell epitopes in SJL and BALB/c mice, respectively. Single amino acid substituted analogs of p195-212 (analog Ala-207) and p259-271 (analog Lys-262) were synthesized. We showed that analogs Ala-207 and Lys-262 inhibited, in vitro and in vivo, the proliferative responses of T cell lines specific to the relevant peptide and lymph node cells of mice immunized to p195-212 and p259-271, respectively. To inhibit T cell responses to both peptides (p195-212 and p259-271), we synthesized dual analogs composed of the tandemly arranged two single (Ala-207 and Lys-262) analogs (dual analog) either sequentially (Ala-207-Lys-262) or reciprocally (Lys-262-Ala-207). In the present study, we report that both dual analogs could bind to major histocompatibility complex class II molecules on antigen-presenting cells of SJL and BALB/c mice. Analog Lys-262-Ala-207, which bound more efficiently to major histocompatibility complex class II molecules, was found to inhibit the proliferative responses of both p195-212- and p259-271-specific T cell lines. Furthermore, the analog inhibited the in vivo priming of lymph node cells of both SJL and BALB/c mice when administered i.v., i.p., or per os. The dual analog Lys-262-Ala-207 could also immunomodulate myasthenogenic manifestations in mice with experimental autoimmune MG induced by inoculation of a pathogenic T cell line. Thus, a single peptide that is composed of analogs to two epitope specificities can be used to regulate T cell responses and disease associated with each epitope.
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PMID:A peptide composed of tandem analogs of two myasthenogenic T cell epitopes interferes with specific autoimmune responses. 909 70

Adult-onset myasthenia gravis is an acquired autoimmune disorder of neuromuscular transmission in which acetylcholine receptor antibodies attack the postsynaptic membrane of the neuromuscular junction. Although the cause of this disease is unknown, the role of immune responses in its pathogenesis is well established. Circulating acetylcholine receptor antibodies are present in 80% to 90% of patients with the generalized form of myasthenia gravis. Most patients have ptosis, diplopia, dysarthria and dysphagia. The weakness and fatigue worsen on exertion and improve with rest. Respiratory muscle and limb weakness are rare at the onset of the disease. For the past two decades, there has been considerable progress in understanding the diagnosis and management of myasthenia gravis. The diagnosis is based on clinical presentation, neurologic examination, and confirmation by means of electrophysiologic testing and immunologic studies. Myasthenia gravis mimics many neuromuscular diseases and even illnesses such as depression and chronic fatigue syndrome. One should always exclude drug-induced myasthenia gravis for all patients. With the introduction of new modalities of treatment, particularly immunosuppressive or immunomodulating drugs, plasma exchange and thymectomy, the morbidity and mortality of myasthenia gravis have decreased dramatically to the point that myasthenia gravis should not be considered as serious a disease as it once was. Although the several therapeutic options are usually effective and have meant independence in daily life to many patients with myasthenia gravis, well-designed, controlled, prospective studies are still lacking.
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PMID:Myasthenia gravis. 911 87

Myasthenia gravis (MG) is a human autoimmune disease mediated by anti-acetylcholine receptor (AChR) antibodies. The thymus is probably the site where the autoimmune response is triggered and maintained. Recent reports have linked various autoimmune disease with defective Fas expression. We thus analyzed Fas expression in thymocytes and peripheral blood lymphocytes (PBL) from MG patients. The proportion of a thymocyte subpopulation with strong Fas expression (Fas(hi)) was markedly enhanced in MG patients with anti-AChR antibodies (P < .0003, compared with controls). In this group of patients, the proportion of CD4+ Fas(hi) and CD4+ CD8+ Fas(hi) thymocytes were significantly increased (P < .002 for both subsets). Fas(hi) thymocytes were enriched in activated cells and showed intermediate CD3 expression. They were preferentially Vbeta5.1-expressing cells, previously shown to be enriched in potentially autoreactive cells. The proliferative response of thymocytes from MG patients to peptides from the AChR was abolished after depletion of Fas(hi) cells. Fas(hi) thymocytes were sensitive to an agonistic anti-Fas antibody. In peripheral blood, Fas(hi) lymphocytes proportion was not significantly modified in MG patients whatever their anti-AChR antibody titer, compared with controls. Altogether, these results indicate that Fas(hi) thymocytes, which accumulate in MG patients with anti-AChR antibodies, could be involved in the autoimmune response that targets the AChR.
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PMID:Thymocyte Fas expression is dysregulated in myasthenia gravis patients with anti-acetylcholine receptor antibody. 912 34

Various studies over the last 25 years in Man and animal models have revealed many steps in the pathogenesis of myasthenia gravis (MG) which is now considered the classical organ specific, autoantibody mediated and T cell dependent human autoimmune disease. Though not a disease entity, MG is associated with pathological alterations of the thymus in about 80% of cases. These are described here with reference to distinct models of autoimmunization against the acetylcholine receptor (AChR). In MG with thymitis, intrathymic production of AChR-specific autoantibodies is the result of a classical antigen-driven immune reaction that occurs completely inside the thymus and probably involves AChR on myoid cells as the triggering (myasthenogenic) antigen. Genetic factors contribute essentially to the pathogenesis of this form of MG. In thymoma-associated MG genetic factors are probably of marginal significance. Neither intratumour autoantibody production nor T cell activation seem to occur and the AChR is not the myasthenogenic antigen. Instead, abnormal neurofilaments that share epitopes with the AChR and other auto-antigen targets in paraneoplastic MG are expressed in thymomas and may trigger autoantigen-specific, non-tolerogenic T cell selection by molecular mimicry. These data support the hypothesis that initial steps in the pathogenesis of most MG cases take place within abnormal thymic microenvironments, be they inflammatory or neoplastic. Where these initial steps occur in MG cases without thymic pathology is not known. Likewise, the factors involved in the initial triggering of MG remain enigmatic in all MG subtypes.
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PMID:Pathogenesis of myasthenia gravis. 917 25

Seronegative (SN) patients with myasthenia gravis (MG) have clinical and electrophysiologic features similar to those of seropositive (SP) patients, and they respond to the same therapeutic measures. However, because SN patients lack detectable (by standard radioimmunoassays) serum antibodies to acetylcholine receptor (AChR), which are considered to have a crucial role in MG, the pathophysiologic basis for the disease is not clear. We therefore compared the ability of peripheral blood lymphocytes (PBL) of SN patients (11) and SP patients (39) to respond to myasthenogenic T cell epitopes of human AChR. We tested two aspects that relate to T-cell immunity: 1) T cell responses to myasthenogenic peptides by proliferation and IL-2 production, and 2) the ability of antigen-presenting cells to bind these T-cell epitopes. T cells of SN patients did not differ from those of SP patients in their ability to respond and to bind the two human AChR-derived myasthenogenic peptides. This supports the belief that most SN patients indeed suffer from an autoimmune disease directed against the AChR. The presence of T-cell immunity in the absence of antibodies may emphasize the importance of AChR-specific T cells in MG.
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PMID:Reactivity of T cells from seronegative patients with myasthenia gravis to T cell epitopes of the human acetylcholine receptor. 919 80


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