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)

Human autoreactive helper T lymphocytes with specificity for acetylcholine receptor (AChR) were isolated from three HLA-DR3-positive patients who had myasthenia gravis (MG), an autoimmune disease known to be associated with HLA-DR3 in the North European population. The antigen-specific T cells were evaluated for genetic restriction. Antigen presentation studies were performed with mitomycin C-treated accessory cells from a panel of HLA-typed unrelated donors. AChR-induced proliferation of the autoreactive T cells was maximal in the presence of autologous or HLA-DR-compatible antigen-presenting cells. In two DR-heterozygous patients both parental DR specificities served as restriction elements of the polyclonal AChR-reactive T cell populations. Preferential restriction to HLA-DR3 was observed in one patient, but this was also seen with PPD-specific T cells from the same donor. A series of monoclonal antibodies against HLA class II molecules was used for inhibition experiments. The inhibitory effects of the antibodies were not due to unspecific toxicity and could be observed after separate treatment of the antigen-presenting cells but not of the responding T cells. Several monoclonal antibodies against monomorphic HLA-DR determinants (DA 231, MAS 53, MAS 54, L243, OKIa1) had pronounced inhibitory effects. Anti-HLA-DQ(DC) monoclonal antibodies (Leu-10; TU 22) had only mild or no inhibitory effects in two patients but significantly inhibited AChR-specific T cells in one patient. A monoclonal antibody against HLA-DR3 (antibody 16.23) was not or was only weakly inhibitory in the DR3-positive patients, although it bound to autologous T line cells and B cells by indirect immunofluorescence. In one patient it was possible to compare the inhibition patterns of AChR-specific and PPD-specific T cells. Most of the monoclonal antibodies affected AChR- and PPD-specific T cells to a similar extent, but three antibodies (TU 22, 36, 39) inhibited PPD-specific T cells more than AChR-specific T cells, indicating the possibility of differential restriction of antigen- and autoantigen-specific T cells. It is suggested that the in vitro system described here may be helpful for the evaluation of anti-HLA class II antibodies as potential immunotherapeutic reagents.
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PMID:Genetic restriction of autoreactive acetylcholine receptor-specific T lymphocytes in myasthenia gravis. 241 94

The binding domains of 28 monoclonal antibodies (mAbs) against the alpha, beta, and delta subunits of the Torpedo acetylcholine receptor were mapped on the primary sequences of these subunits. Small peptide fragments (2000-20,000 daltons) of the purified subunits were obtained by digestion with staphylococcal V8 protease and papain, separated on a discontinuous polyacrylamide gel electrophoretic system, and electroblotted onto diaminophenyl thioether paper. The blots were probed with the various monoclonal antibodies and also with antibodies against carboxy-terminal decapeptides of the alpha, beta, and delta subunits to identify the carboxy-terminal fragments. From inspection of the binding patterns of the various antibodies to the subunits fragments and the molecular weights of these fragments, and by using the carboxy termini of the subunits as reference points, it was possible to deduce the regions on the primary sequence of each subunit in which the antibodies bound and in some cases to order the binding sites within these sequences. mAb 148, which inhibits receptor function by cross-linking receptor molecules on the cytoplasmic side, was mapped to the sequence beta 368-406. The main immunogenic region of the native receptor, which is of pathological importance in the autoimmune disease myasthenia gravis, was mapped by using mAb 210 to within 80 amino acid residues (alpha 46-127). The overall antigenic structure of alpha subunits was examined. Synthetic peptides have been used to locate determinants responsible for 83% of the antibodies in antisera to denatured alpha subunits and 46% of the antibodies to denatured alpha subunits in antisera to intact receptor. Theoretical models of the transmembrane orientation of the subunit polypeptide chains were tested by determining whether mapped monoclonal antibodies bound to the extracellular or intracellular surface of receptor-rich membranes. Our results confirm previous reports that the carboxy termini of the subunits are exposed on the intracellular surface, as is part of the region between a putative channel-forming domain (M5) and a putative membrane-spanning region (M3). However, contrary to current theoretical models, the region between M5 and the putative membrane-spanning sequence M4 also appears to be on the intracellular surface, implying that M4 and M5 are not membrane-spanning domains.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Location of antigenic determinants on primary sequences of subunits of nicotinic acetylcholine receptor by peptide mapping. 242 98

Myasthenia gravis (MG) is an autoimmune disease in which anti-acetylcholine receptor antibodies (anti-AChR) cause loss of functional endplate AChR by increasing AChR degradation, and by complement-mediated destruction. MG anti-AChR binds to regions on the human AChR which can be defined by monoclonal antibodies (mabs). Several congenital forms of myasthenia have been described, three of which may directly involve abnormalities of the AChR, including one in which the open-time of the ion channel is prolonged.
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PMID:Disorders affecting the acetylcholine receptor: myasthenia gravis and congenital myasthenia. 244 86

Myasthenia gravis (MG) is an autoimmune disease of man caused by antibodies directed against the acetylcholine receptor (AChR). In the experimental model of MG in mice, murine experimental autoimmune myasthenia gravis (EAMG), an anti-AChR immune response is induced by immunization with Torpedo AChR, and anti-AChR antibodies. AChR-sensitized T cells, and neuromuscular dysfunction result. The production of antibodies to AChR is thymus-dependent. In order to define the epitopes of the AChR identified by AChR-specific T cells, we generated T cell populations and T cell hybridoma clones and tested their reactivity to synthetic uniform-sized overlapping peptides representing the entire extracellular portion of the alpha-chain of the AChR. The predominant reactivity of the T cell clones and the parent lines was to a peptide corresponding to residues 146-162 of Torpedo AChR. This data is consistent with a highly limited recognition of AChR determinants in murine EAMG by AChR-specific T cells.
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PMID:An immunodominant site of acetylcholine receptor in experimental myasthenia mapped with T lymphocyte clones and synthetic peptides. 246 49

Cyclosporine A, an immunosuppressor and immunomodulator, has been proposed as an alternative in patients with autoimmune disease not responding to the usual immunosuppressants. We treated with cyclosporine 19 patients with severe myasthenia gravis in a 12-month open uncontrolled trial. There were 14 women and 5 men aged 51.5 +/- 18.5 years (range 20 to 81 years) who had had the disease for 50.8 +/- 43.6 months. Myasthenia gravis was generalized in 18 and ocular in 1. Previously, 4 patients had been unsuccessfully treated with azathioprine, 1 with cyclophosphamide, 12 with steroids; 5 had undergone thymomectomy and 5 thymectomy. Anti-acetylcholine receptor antibodies (AChR-ab) were detected in the sera of 15. The severity of the disease was assessed by a myasthenic muscle score (MMS) ranging from 0 to 100 and a 5-grade functional scale (FS) from 1 = severe disability to 5 = complete remission. Depending on changes in MMS and FS, the effectiveness of cyclosporine was deemed very good, good or nil. Cyclosporine was administered orally 3 times daily in doses of 5.6 +/- 1.6 mg/kg/day over 11.6 +/- 1.6 months. The final dosage was targeted to achieve a peak serum level and a trough level respectively below 200 and 100 mg/ml, and was adapted if side effects occurred. No other cytotoxic drug was allowed. Seventeen patients completed the treatment (M12); 1 died of uterine cancer at M6 and 1 was lost to follow-up at M5. At M12 clinical results were considered very good in 6 patients, good in 8, nil in 3. The MMS increased significantly from 56.1 +/- 17.2 (n = 19) at D0 to 83 +/- 15 (n = 17) (P less than 0.0005), as did the FS, from 2 +/- 1 to 3.7 +/- 0.85 (P less than 0.0005). Subsequently, cyclosporine was discontinued in 7 of the 14 patients who responded well and maintained in 7 at a reduced dosage (3.4 +/- 0.8 mg/kg/day). In the former group 3 patients relapsed 1, 1 and 5 months respectively after the drug was withdrawn; the remainder had, at the last follow-up (29.6 +/- 8.5 months from D0), MMS 62.9 +/- 34.1 and FS 3 +/- 2. In the latter group, at the last follow-up (17.6 +/- 3.6 months), MMS was 86.7 +/- 16.6 and FS 4.2 +/- 0.8, differing significantly from D0 values. AChR-ab titers and CD4/CD8 were unaltered at M12.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Treatment of severe myasthenia gravis with cyclosporin. A 12-month open trial]. 252 27

The large majority of patients with the autoimmune disease myasthenia gravis characteristically have detectable antibodies against the acetylcholine receptor (AChR). We used synthetic peptides to identify antibodies in sera of myasthenia gravis patients reactive with the human acetylcholine receptor (HuAChR) alpha-subunit, residues 160-167. Affinity purification of these antibodies, using the HuAChR alpha-subunit 157-170 peptide immobilized on thiopropyl-Sepharose, yielded IgG antibodies that bound to the native AChR and inhibited the binding of alpha-bungarotoxin to the receptor. The HuAChR alpha-subunit 160-167 peptide demonstrated specific immunological cross-reactivity with a shared homologous domain on herpes simplex virus glycoprotein D, residues 286-293, by both binding and inhibition studies. Thus, HuAChR alpha-subunit, residues 160-167, elicits antibodies in myasthenic patients that binds to the native AChR protein and is capable of eliciting a biologic effect. Immunologic cross-reactivity of this "self" epitope with herpes simplex virus suggest that this virus may be associated with the initiation of some cases of myasthenia.
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PMID:Molecular mimicry and myasthenia gravis. An autoantigenic site of the acetylcholine receptor alpha-subunit that has biologic activity and reacts immunochemically with herpes simplex virus. 255 24

Although increased platelet destruction and elevated platelet-associated IgG have been shown in patients with lymphomas and various autoimmune diseases, such as systemic lupus erythematosus (SLE), there have been few studies evaluating autoantibodies against platelet-specific antigens. We evaluated 24 patients retrospectively with disease-related thrombocytopenia (12 with lymphoproliferative diseases and 12 with various autoimmune disorders) using a recently reported antigen-specific assay. Autoantibodies against platelet GPIIb/IIIa or GPIb/IX were noted in 15 of the 24 patients (10 of 12 with autoimmune disease and five of 12 with lymphoproliferative disorders). Platelet-associated autoantibodies were present in 60% and plasma autoantibodies in 33%. Anti-GPIIb/IIIa autoantibodies were much more common than those against GPIb/IX. In one patient each with thrombocytopenia and either SLE or myasthenia gravis, absorption of plasma with platelets completely removed the anti-GPIIb/IIIa autoantibodies, but did not affect the level of anti-cochlear autoantibody involved with immune-mediated hearing loss in the SLE patient or the anti-acetylcholine receptor autoantibody in the myasthenic patient. These findings show that, in some cases of disease-related immune thrombocytopenia, autoantibodies against GPIIb/IIIa or GPIb/IX can be detected similar to those seen in chronic ITP. As shown in two patients with multiple autoimmune manifestations, the various autoantibodies have diverse specificities and do not crossreact.
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PMID:Autoantibodies to platelet glycoproteins in patients with disease-related immune thrombocytopenia. 260 22

Thalidomide is reported to have immunosuppressive and anti-inflammatory effects which have led to its use in the treatment of a number of immune-mediated disorders including leprosy, prurigo, discoid lupus, and Behcet's disease. In addition, thalidomide has recently been used to prevent immunological rejection phenomena following skin and bone-marrow grafts. The immune responses in these conditions are thought to be cell-mediated. However, little is known about the effectiveness of thalidomide in suppressing antibody-mediated immune responses. In the present study, we have examined the effect of thalidomide in a model antibody-mediated autoimmune disorder--experimental autoimmune myasthenia gravis (EAMG). To induce EAMG, Lewis rats were immunized with acetylcholine receptor (AChR) purified from the electric organ of Torpedo californicus. Groups of rats were treated daily, either with thalidomide in excess of doses reported to prevent graft-versus-host (GVH) disease in bone-marrow-transplanted rats, or with control treatments. Our results show that thalidomide failed to inhibit AChR antibody production despite good absorption and high blood levels of the drug. This suggests that thalidomide is not likely to be generally useful in the treatment of antibody-mediated autoimmune conditions. However the selective effect of thalidomide in suppressing certain presumably cellular immune responses, while sparing antibody production, is inherently interesting, and merits further study.
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PMID:The effect of thalidomide on experimental autoimmune myasthenia gravis. 278 25

Myasthenia Gravis (MG) is an autoimmune disorder of neuromuscular transmission associated with antibodies (Ab) against acetylcholine receptor (AChR). Autoantibody production is a T-cell-dependent phenomenon perhaps caused by aberrant immunoregulation. So far, a possible role for immunoregulatory molecules has not been investigated in the pathogenesis of MG. Since interleukin-2 (IL-2) is able to induce peripheral blood mononuclear cell (PBMC) proliferation without a previous activating signal and to upregulate IL-2-receptor expression, we have evaluated the activation state of PBMC in patients with MG, by cytofluorographic analysis of CD25 expression and by testing their sensitivity to recombinant IL-2 (rIL-2) without any known previous stimulation. We found no significant difference in CD25 expression in a large group of patients compared to controls. However, proliferative responses to rIL-2 were significantly higher in MG patients than in controls. In MG, as in controls, this response was time- and dose-dependent, was inhibited by an anti-IL-2 receptor Ab and correlated with an increased percentage of CD25+ T cells after rIL-2 exposure. The response was greater in patients with a high anti-AChR Ab titer and a severe form of the disease, and in patients tested before thymectomy. Thus blood T cells in MG showed functional signs of preactivation (high sensitivity to rIL-2 alone) without detectable CD25 expression on fresh cells, raising the possibility of aberrant IL-2 receptor regulation and/or expression in MG T cells. Decreased sensitivity to rIL-2 after thymectomy, associated with general clinical improvement, suggests a role for activated cells originating from the thymus in the pathogenesis of MG, and is of clinical relevance in patient follow-up. Our findings also provide a new approach in the study of MG pathogenesis: the search for aberrant immunoregulation mechanisms linked to defects in lymphokine circuits.
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PMID:High recombinant interleukin-2 sensitivity of peripheral blood lymphocytes from patients with myasthenia gravis: correlations with clinical parameters. 278 27

Myasthenia gravis (MG) is an acquired autoimmune disorder of neuromuscular transmission associated with a deficiency of acetylcholine receptor at the neuromuscular junction. Current therapeutic strategies are aimed at increasing the amount of acetylcholine at the neuromuscular junction or at addressing the abnormal immune response. Therapies influencing the immune response include thymectomy, corticosteroids, nonsteroidal immunosuppression, and plasmapheresis. Unfortunately, whether used alone or in combination the toxicities of these agents can be quite significant; thus, an agent with a distinct and more favorable side effect profile might be useful in MG. Intravenous immunoglobulin has such potential.
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PMID:Experience with intravenous immunoglobulin in myasthenia gravis. 279 45


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