Penicillamine-induced myasthenia gravis associated with antibodies to acetylcholine receptor

A woman with rheumatoid arthritis was treated with penicillamine and developed myasthenia gravis. This drug-induced disease was associated with characteristic autoantibodies to acetycholine receptor. After discontinuing the drug, her symptoms improved and the antibody titers fell. Penicillamine is now being used much more frequently in the treatment of rheumatoid arthritis and it is likely that this complication will become more prevalent.     

Thymoma-associated myasthenia gravis without acetylcholine receptor antibodies

Patients with myasthenia gravis and thymoma usually present antibodies to the acetylcholine receptor (AchR-Ab). Only two cases of thymoma-associated myasthenia gravis without AchR-Ab have been previously reported. We describe a case of seronegative thymoma-associated myasthenia gravis as a further evidence of the variability of myasthenia gravis in terms of antibody profile and thymic pathological findings.     

Suppressor T cells in myasthenia gravis and antibodies to acetylcholine receptor

We cultured blood mononuclear cells of patients with myasthenia gravis both with and without removal of T8 suppressor cells. The levels of synthesized antibodies to acetylcholine receptor and IgG as well as the frequency of immunoglobulin-secreting cells were all higher in pokeweed mitogen-stimulated cultures depleted of T8+ cells. Thus, autologous suppressor cells within the T8+ population exert some regulatory control over antiacetylcholine receptor-producing cells in patients with myasthenia gravis.     

High serum adenosine deaminase activity and its correlation with lymphocyte subsets in myasthenia gravis

Serum adenosine deaminase (ADA) activity and peripheral lymphocyte subsets of patients with myasthenia gravis (MG) were simultaneously measured. The ADA activity in MG (n = 30) was significantly higher as compared with normal control (n = 150) and multiple sclerosis (n = 12) (P < 0.05). The ADA activity of generalized MG was higher than that of ocular MG, while a significant elevation of ADA activity was observed in grade IIB as compared with grade I of Osserman's classification (P < 0.05). A trend of high ADA activity was demonstrated in those whose disease had advanced to a severe degree associated with unstable clinical features (P < 0.05). In addition, there was a significant elevation of ADA activity in patients who disclosed positive anti-Ach-receptor-antibody as compared with negative one (P < 0.05). There was no specific trend among the proportions of the subsets of peripheral lymphocytes which could reflect the severity of MG, however, the proportion of OKIa1 +tended to be higher with advancing the grade of MG. Interestingly enough, a close correlation was found between the ADA activity and the proportion of OKIa1 +cells (P < 0.05). From the above results, it was concluded that high ADA may be responsible for the pathophysiology of MG through the alteration of peripheral lymphocyte function.     

Myasthenia gravis: Antibodies to acetylcholine receptor in ocular myasthenia gravis

Summary To improve the sensitivity of the radioimmunoassay method for anti-AChR-antibody, large amounts of sera from patients with myasthenia gravis, and higher concentrations of antigens and rabbit anti-human-IgG-antiserum, were used. These procedures enabled measurement of the titre value of over 0.04 pmol/ml serum and this value revealed a sensitivity about 10 times higher than that predicted using the previous model.Antibodies against AChR were found in 13 out of 17 ocular myasthenia patients (70%) and 35 of 37 with generalized myasthenia (90%). However, the average titre value of sera in those with ocular myasthenia was significantly lower than the value obtained in the generalized cases. Even in the patients with ptosis or ophthalmoparesis, in the early stage (less than one year) of ocular myasthenia, anti-AChR-antibodies were not detectable using this more sensitive assay method.

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Zusammenfassung Um die Empfindlichkeit der Radioimmunoassay-Methode für Anti-AChR-Antikörper zu verbessern, wurden eine große Menge des myasthenischen Serums, höhere Konzentration des Antigens und Kaninchen-Anti-Menschen-IgG-Antiserum gebraucht.Mit dieser Methode konnten wir den Wert über 0.04 pmol/ml Serum vermessen. Diese neue Methode zeigt etwa zehnfach höhere Empfindlichkeit als die vergangenen Methoden.Antikörper gegen AChR waren in 13 von 17 okulären Myastheniepatienten (70%) und in 35 von 37 generalisierten Myastheniepatienten (90%) gefunden worden. Aber der durchschnittliche Messungswert des Serums im Patienten der okulären Form war signifikant niedriger als der der generlisierten Form. Wenn der Patient auch Augenptose oder Augenparese hatte, waren die Anti-AChR-Antikörper mit unserer empfindlichen Methode im Frühstadium (innerhalb eines Jahres) nicht nachgewiesen worden.

     

重症肌无力血清乙酰胆碱受体抗体的阳性率及其影响因素

采用ABC-ELISA法检测162例重症肌无力患者的224份血清标本,100例正常人和78例其他疾病病人的血清中AchRab。重症肌无力病人的抗体阳性率为80.2％,其中单纯眼肌型63.1％,脊髓肌型90.0％,延髓肌型93.8％和全身肌型91.5％。合并胸腺瘤的阳性率为83.3％,与全组阳性率无显著性差异。激素和血浆交换治疗均未影响抗体阳性结果。随访观察表明,重症肌无力病人的AchRab阳性率与疾病严重程度不成线性相关。我们认为,AchRab滴度虽然与临床状况不相关,但在重症肌无力的诊断和自身免疫病因的研究中,仍是一项重要参数。     

Two cases of thymoma-associated myasthenia gravis without antibodies to the acetylcholine receptor

Thymoma-associated myasthenia gravis is considered a more severe disease compared with non-thymomatous myasthenia gravis and is generally associated with antibodies to the acetylcholine receptor (AChR-Ab). Even though a single case of thymoma-associated myasthenia gravis with anti-muscle specific kinase (MuSK) antibodies has been reported, to our knowledge, seronegative thymoma-associated myasthenia gravis has not been described. We report on two cases of this disease without antibodies to AChR or MuSK as a further evidence of the variability of myasthenia gravis in terms of antibody profile and thymic pathological findings.     

Anti-MuSK antibodies: correlation with myasthenia gravis severity

The authors measured anti-muscle-specific tyrosine kinase (anti-MuSK) antibodies (Abs) in 83 serum samples from 40 patients and evaluated their correlation with myasthenia gravis severity and treatment response. Ab concentrations were often reduced by immunosuppression but not after thymectomy. Both in individual cases and in the whole population, a correlation between Ab levels and disease severity was found.     

重症肌无力病人乙酰胆碱受体抗体的测定及临床意义

用ＥＬＩＳＡ（固相酶联免疫吸附）法测定１７２例ＭＧ病人血清乙酰胆碱受体抗体（ＡｃｈＲａｂ），结果显著高于健康献血员组和非ＭＧ病人组。不同性别、病程及临床类型与ＡｃｈＲａｂ无相关性，但４１～５０岁组的显著高于其他年龄组。６７例类固醇激素治疗组、２２例大剂量两种球蛋白治疗组、１２例胸腺切除术组及３例ＭＧ危象病人２４次血浆交换疗法（ＰＥ）组，治疗后伴随肌无力症状的好转，ＡｃｈＲａｂ均显著低于治疗前。结果表明：ＡｃｈＲａｂ测定为ＭＧ诊断提供了可靠的实验依据，为类固醇激素、大剂量丙种球蛋白、胸腺切除术和ＰＥ等治疗ＭＧ提供理论依据和疗效评定的实验指标，进一步证实了ＭＧ免疫学发病机理。     

Autoantibodies to acetylcholine receptor in myasthenia gravis: light chains

We studied the light chain type of autoantibodies to acetylcholine receptor (AChR) by affinity chromatography with monoclonal anti-kappa and anti-lambda antibodies. The autoantibodies in four of eight myasthenic patients were of a single light chain type; the others comprised both types. In Graves' disease and cold-reactive hemolytic anemia, the pathogenic autoantibodies are confined to a single light chain type in individual patients, and in other diseases, doubtfully pathogenic autoantibodies are invariably mixtures of both light chain types. AChR antibodies may comprise both pathogenic and nonpathogenic types of autoantibody.     

Anti-idiotypic antibodies, acetylcholine receptor antibodies and disturbed neuromuscular function in healthy relatives to patients with myasthenia gravis

Fifty-eight first-degree relatives to 40 patients with myasthenia gravis were investigated regarding presence of acetylcholine receptor antibodies, anti-idiotypic antibodies against the receptor antibodies and clinical and electrophysiological signs of disturbed neuromuscular function. No relative had clinical signs of muscle weakness. The prevalence of low concentrations of receptor antibodies was 54%, of anti-idiotypic antibodies 37% and of pathological and borderline single fibre EMG 45%. No sibling, only 2/11 children and 3/14 parents were normal in all three tests. A combination of receptor antibodies and anti-idiotypic antibodies was the most common finding and was especially frequent in children. In female siblings and children there was a positive correlation between the presence of HLA-antigen A1 and/or B8 and that of receptor antibodies and anti-idiotypic antibodies. Male siblings and children showed no such correlation but had a higher frequency of pathological single fibre EMG than females.     

Mechanisms of acetylcholine receptor loss in myasthenia gravis.

The fundamental abnormality affecting the neuromuscular junctions of myasthenic patients is a reduction of available AChRs, due to an autoimmune attack directed against the receptors. Antibodies to AChR are present in most patients, and there is evidence that they have a predominant pathogenic role in the disease, aided by complement. The mechanism of antibody action involves acceleration of the rate of degradation of AChRs, attributable to cross-linking of the receptors. In addition, antibodies may block AChRs, and may participate in producing destructive changes, perhaps in conjunction with complement. The possibility that cell-mediated mechanisms may play a role in the autoimmune responses of some myasthenic patients remains to be explored. Although the target of the autoimmune attack in myasthenic patients is probably always the acetylcholine receptors, it is not yet clear which of these immune mechanisms are most important. It is likely that the relative role of each mechanism varies from patient to patient. One of the goals of future research will be to identify the relative importance of each of these mechanisms in the individual patient, and to tailor specific immunotherapeutic measures to the abnormalities found.     

Cellular response to human acetylcholine receptor in patients with myasthenia gravis

A preparation of human skeletal muscle acetylcholine receptor (AchR) was used in vitro as an antigen to stimulate lymphocytes from patients with myasthenia gravis (MG). Clinical data obtained from the patients included duration and severity of disease; history of steroid treatment or prior thymectomy; and the presence of thymoma. Lymphocytes from patients with MG showed a significantly higher response to human AchR antigen than did lymphocytes from control subjects. Previous studies of cellular response to AchR have used receptor prepared from eel or ray electric organs. By stimulating lymphocytes from MG patients with a preparation of human AchR, we have come one step closer to documenting a possible contribution of a cellular immune response to the pathogenesis of MG.     

Cellular and humoral immunity to acetylcholine receptor in myasthenia gravis

At the same time in 21 myasthenic patients we measured a. the cellular immune response against acetylcholine receptor (AChR) of peripheral lymphocytes, T lymphocytes and non rosette forming lymphocytes (50% B lymphocytes); b. the antibodies to AChR and c. the antigenic modulation activity of their sera on rat myotube AChR. At least one of these parameters was positive in each patient and this further supports the relevance of the immune response to acetylcholine receptor in myasthenia gravis. Strict correlations between the response of lymphocytes, antigenic modulation, antibody titer and disease severity were not evident.     

Central acetylcholine receptor function in patients with myasthenia gravis

There are some reports on central nervous system involvements in patients with myasthenia gravis, such as abnormal EEG, and memory disturbance. Myasthenia gravis is considered to be an autoimmune disease with antibodies against the skeletal nicotinic acetylcholine receptor (n-AChR). ACh is a neurotransmitter in osmoregulation. Neuronal n-AChR plays an important role in this regulation. In order to investigate the function of neuronal n-AChR in patients with myasthenia gravis, we performed a 5% hypertonic saline infusion test on 9 patients and 9 healthy volunteers. We also carried out an orthostatic stress test (50 degree passive head-up tilt) on 6 patients with myasthenia gravis and 5 healthy controls to evaluate arginine-vasopressin (AVP) release via baroreceptors. Three of the 9 MG patients showed exaggerated plasma AVP secretion, and one revealed a blunt response to hypertonic stimulation. Both patients and controls did not differ significantly in terms of plasma AVP response to orthostatic stress. To conclude, we suggest the possibility that function of neuronal n-AChR in the central nervous system is impaired in patients with myasthenia gravis.