Immunogenetics of spontaneous, drug-induced, and experimental myasthenia gravis.
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Animals↗
Biomedical subjects
M J Garlepp
Publications and source records attributed to M J Garlepp.
Penicillamine induced polymyositis and dermatomyositis.
Eight Australian cases of D-penicillamine induced polymyositis/dermatomyositis (PM/DM) are reported. In terms of clinical, pathological and electromyographic features, D-penicillamine PM/DM is similar to idiopathic PM/DM but is generally less severe. Recovery is usually rapid when D-penicillamine is withdrawn. Sera were available for study in 6 of the 8 reported cases. Two of the 6 had elevated titers of acetylcholine receptor autoantibodies. Neither of these patients had clinical signs of myasthenia gravis. In 3 of 6 patients typed for C2, no bands were detected suggesting homozygous C2 deficiency. D-penicillamine PM/DM is associated with HLA-B18, B35 and DR4 and is immunogenetically different from idiopathic PM/DM, rheumatoid arthritis and D-penicillamine myasthenia gravis.
Adult↗
Rearrangement of 21-hydroxylase genes in disease-associated MHC supratypes.
Human cDNA probes for 21-hydroxylase (21-OH) and for complement component C4 are used on restriction digests of the members of several families with interesting supratypes. The presence of two Taq I fragments of 3.7 kb and 3.2 kb in size with a 21-OH probe is confirmed in most individuals who show no evidence of C4 deletions or 21-OH deficiency. Most individuals also show a doublet of weakly hybridizing bands at approximately 2.5 kb, the smaller of which is part of the 21 A gene. The arrangement of the 21-OH genes on disease-associated supratypes was examined, and it is shown that copies of the same supratype from unrelated individuals are usually identical. Evidence is provided for deletions of 21A on the B8, C4AQ0, C4B1, BfS, DR3 and B18, C4A3, C4BQ0, BfF1, DR3 supratypes and a duplication of 21A on the B14, C4A2, C4B1/B2, BfS supratype. Gene rearrangements may be relevant to diseases such as juvenile onset diabetes mellitus.
Alleles↗
Susceptibility to murine experimental autoallergic myasthenia gravis: the role of antibody specificity.
To examine the differing susceptibility of C57BL/6J and C3H/HeJ mice to experimental autoallergic myasthenia gravis (EAMG), we have compared the pathogenicity of sera from the two strains. Mice were immunized with acetylcholine receptor from T. californica and muscle weakness assessed as the time mice were capable of running on an exercise drum following the administration of a sub-lethal dose of D-tubocurarine. 16 of 20 C57BL/6J and only 4 of 19 C3H/HeJ mice developed muscle weakness. However, anti-AChR antibody titres were similar in both strains. The effect of transfer of pooled immune sera from each strain to naive recipients was therefore compared. Transfer of pooled C57BL/6J sera to naive C3H/HeJ and C57BL/6J mice produced significant muscle weakness (P less than 0.001 & P less than 0.001 respectively). Transfer of pooled C3H/HeJ sera did not produce statistically significant muscle weakness in either strain. It is concluded that differences in disease susceptibility result from differences in antibody specificities of the major antibody populations, rather than differences in total antibody amounts or other factors.
Acetylcholine↗
The coexistence of IgA deficiency and 21-hydroxylase deficiency marked by specific MHC supratypes.
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Adrenal Hyperplasia, Congenital↗
Autoimmunity in spontaneous myasthenia gravis in dogs.
Spontaneous canine myasthenia gravis (MG) mimics the human disease in almost every respect. Both dogs reported here exhibited the autoantibodies characteristic of MG, i.e., anti-acetylcholine receptor (anti-AChR) and antistriational (AStr). Fluctuations in the anti-AChR titer during spontaneous remission and recurrence of MG in one dog provide support for the concept of a symptomatic threshold titer above which anti-AChR must rise before disease signs develop. The increase in the anti-AChR titer and recurrence of disease signs followed vaccination and an infection. Interestingly AStr also reappeared in this dog and serum IgG concentration increased. AStr in the second dog was associated with the presence of a thymoma and had a staining pattern characteristic of human MG.
Animals↗
Myasthenia gravis and HLA antigens in American blacks and other races.
The association of HLA B8 and DR3 with generalised adult onset myasthenia gravis (GMG) in European Caucasoids is now well established. Studies of the HLA association with myasthenia gravis (MG) in other races might help to determine the location of a critical disease locus. Some previous studies in Japanese, Thais, Asian Indians and Filipinos have been reported. In this study HLA A, B, C and DR typing on 28 American blacks with either GMG or ocular myasthenia gravis (OMG) is reported. A significant increase in both HLA A1 and B8 was detected but there was an increase in DR5 rather than DR3. A review of the HLA antigen frequencies in other races and in D-penicillamine (D-Pen) induced MG suggests that prior claims implicating immune response genes marked by DR3 require review. It seems unlikely that any particular HLA allele is involved directly. Other possibly relevant combinations of alleles or supratypes are suggested. These may provide the basis for future studies of the immunogenetic basis for MG.
Asian People↗
Inflammatory disorders of muscle. Immunological aspects.
Immunological abnormalities associated with inflammatory disorders of muscle have the potential for diagnostic utility but current data suggest that there is considerable heterogeneity with overlap between many of the conditions considered in the differential diagnosis. Immunogenetic factors may influence the expression of disease. For example, D-penicillamine may induce myasthenia gravis and/or polymyositis, depending on the HLA antigens of the recipient.
Antibodies↗
HLA antigens and acetylcholine receptor antibodies in penicillamine induced myasthenia gravis.
Antibodies to the acetylcholine receptor and HLA antigens have been studied in patients with myasthenia gravis occurring in association with penicillamine treatment. The properties of the antiacetylcholine receptor in these patients differed from those in patients with idiopathic myasthenia gravis in terms of specificity and affinity. These patients had an increased prevalence of HLA Bw35 and DR1 compared to controls and a decreased frequency of B8 and DR3 compared to patients with idiopathic myasthenia gravis. Likewise, they had a decreased frequency of DR4 compared to patients with rheumatoid arthritis. These data provide supportive evidence for a role for penicillamine in the induction of myasthenia gravis in genetically predisposed individuals.
Adult↗
The diagnostic significance of autoantibodies to the acetylcholine receptor.
The predictive value of the assay for antibodies to the acetylcholine receptor (anti-AChR) is dependent upon the reference range used and the question being asked by the clinician. A reference range has been established after assaying sera from 200 healthy individuals, 314 patients with diseases often considered in the differential diagnosis of myasthenia gravis (MG) or found in association with MG, and 72 patients with active adult onset MG. If the assay is to be used to screen an unselected population for MG a conservative cut off point (2 units) should be used. After establishment of a differential diagnosis more significant may be attributed to a lower result (1 unit or greater). A negative result does not exclude MG. In patients with Systemic Lupus Erythematosus. Graves' disease or thymoma anti-AChR has been demonstrated in the absence of signs of MG. Such patients may have latent or subclinical MG. Two such patients subsequently developed clinically evident MG concomitant with a rise in anti AChR titre above their particular 'biological threshold'.
Autoantibodies↗
Autoimmunity in ocular and generalised myasthenia gravis.
Restricted ocular myasthenia gravis (OMG) and generalised myasthenia gravis (GMG) have been shown to differ in a number of respects. In OMG, antiacetylcholine receptor, antistriational and antinuclear antibodies were rare relative to their frequency in GMG. In contrast, antithyroid antibodies and a history of thyroid disease were much more prevalent in OMG than in GMG, OMG was not associated with the female predominance seen in GMG and appeared to be relatively common in some races rather than others. It is suggested that different pathogenetic mechanisms are responsible for these two forms of MG.
Age Factors↗
Autoantibodies and HLA antigens in ocular, generalized and penicillamine-induced myasthenia gravis.
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Adult↗
Cross-reactivity of anti-acetylcholine receptor autoantibodies.
The heterogeneity of the specificities of anti-acetylcholine receptor (anti-AChR) antibodies of myasthenia gravis (MG) patients has been demonstrated by comparing reactions against a panel of xenogeneic AChR. For each patient there was a more or less unique cross-reactivity profile. Such heterogeneity emphasizes the need to use human AChR for the routine detection of anti-AChR. In vitro cross-reactivity was important in predicting the effect of anti-AChR after passive transfer to rats. Specificity may influence the outcome in human neonates receiving maternal anti-AChR via the placenta. In contrast to the extreme heterogeneity seen in spontaneous MG, the antibodies associated with D-penicillamine-induced MG were more homogeneous.
Animals↗
Heterogeneity of steroid 21-hydroxylase genes in classical congenital adrenal hyperplasia.
Careful genotyping of three families, each having a member with classical salt-losing steroid 21-hydroxylase deficiency, has allowed identification of carrier haplotypes. Digestion with TaqI or EcoRI and probing with a cDNA probe for the 21-hydroxylase genes (pC21/3c) revealed that all six affected haplotypes are abnormal with at least EcoRI. The data suggest that there is extreme polymorphism of the 21-hydroxylase genes and that dysfunction may result from several different abnormalities.
Adrenal Hyperplasia, Congenital↗
Immunobiology of D-penicillamine.
D-penicillamine holds the key to a better understanding of autoimmunization and the pathogenesis of autoimmune disease. Analysis of its mode of action is complicated by its multiplicity of effects. In respect to anti-acetylcholine receptors and myasthenia gravis, the major effect may be at the level of immunoregulation and/or immunogenicity. Anti-striated muscle antibody is much more common and is influenced by the HLA antigen of the patient. Thus, HLA-linked immune response genes may be involved.
Animals↗
Myasthenia gravis and D-penicillamine.
There has been some uncertainty as to whether the apparent association between myasthenia gravis (MG) and D-penicillamine (D-P)-treated rheumatoid arthritis (RA) could be due to chance or whether the drug is responsible. In the absence of D-P, RA is found in association with MG, but this may simply reflect the high prevalence of RA. Although MG may be more common than expected after D-P treatment of RA, it probably occurs in only approximately 1% of such patients. In these circumstances, it is difficult to prove that D-P can induce MG, but compelling evidence in support for this possibility comes from the finding of differences between autoantibodies when spontaneous and D-P-associated MG are compared. These serologic differences could be explained in terms of an effect of D-P on antigen presentation and/or immunoregulation.
Adult↗