Myasthenia gravis: studies on HL-A antigens and lymphocyte subpopulations in patients with myasthenia gravis.

Thirth-three patient with a clinical diagnosis of myasthenia gravis were tissue-typed for HL-A antigens. In agreement with earlier reports a significant increase in antigens HL-A1 and HL-A8 were found in this material. Two of the patients were treated with chronic thoracic duct drainage. Proportions of T and B lymphocytes in lymph and peripheral blood were estimated in these patients. In the lymph an initial decrease in the proportion of T cells occurred, which was accompanied by a subsequent increase in the proportion of B cells. Towards the end of the chronic drainage period this effect was reversed. A slightly different picture occurred in blood lymphocytes. Initially, there was an increase in both T and B cells, followed by a decrease in T-cells numbers in one patient, whereas in the second patient the proportion of T cells decreased from the onset of drainage while the proportion of B cells steadily increased. These studies showed that available markers for determination of T ANd B cells were useful for studies of lymphocyte subpopulations in blood and lymph. Lmyphocytes from the thoracic duct were also tested for their reactivity to various mitogens specific for either T or B cells. The B-cell mitogens which were used were dextran sulphate, lipopolysaccharide, purified protein derivative, as well as rabbit anti-human beta2-microglobulin serum. The T-cell mitogens investigated were concanavalin A and phytohaemagglutinin. No significant differences in the responsiveness of thoracic duct lymphocytes compared to normal peripheral blood lymphocytes were found.     

Myasthenia gravis patients with thymus hyperplasia and myasthenia gravis patients with thymoma display different HLA associations

Thirty myasthenia gravis (MG) patients (9 with thymoma, 12 with thymus hyperplasia and 9 with thymic atrophy) and 181 Norwegian healthy controls were serologically typed for HLA-A, -B and -DR antigens and genomically typed for HLA-DQA1 and HLA-DQB1 alleles by probing in vitro amplified DNA with sequence-specific oligonucleotides. In patients with thymus hyperplasia the frequency of the DQB1*0201 allele was increased compared to controls (RR = 3.5, p less than 0.05), whereas among the patients with thymoma this allele was not observed (RR = 0.06, p less than 0.01). The frequencies of HLA-B8, -DR3 and -DQA1*0501, which are in strong linkage disequilibrium with DQB1*0201, were increased in patients with hyperplasia and reduced in patients with thymoma. The data suggest that different HLA genes predispose to two different forms of MG.     

Plasma-exchange in myasthenia gravis: a study in 20 patients

Twenty patients with myasthenia gravis (MG) of generalized 2A and 2B types according to the Ossermann classification were treated with a course of nine plasma exchanges (PE) every two days. Before starting of the course, at the fourth exchange, and at the end of the course, the muscle balance was assessed following a special protocol. Other functions, such as respiratory function, stapedial reflex, phonation, and electro-oculographic activity were assessed and a Desmedt test was done. Three patients showed complete remission of symptoms, 8 showed good improvement and 6 mild improvement. Three showed no improvement. In total 85% of patients gained from PE. The onset of improvement was rapid in all patients but in some it lasted only a short time while in others it persisted for several weeks and even months, without the need for immunosuppressive therapy.     

重症肌无力患者交感神经皮肤反应的研究

目的:探讨交感神经皮肤反应(SSR)对评价重症肌无力(MG)患者自主神经功能损害的价值.方法:对30例MG患者(病例组)和30位健康受试者(对照组)分别进行了SSR测定,并将结果加以比较.结果:MG组SSR测定异常率为37%(11/30),SSR波潜伏期明显延长,波幅降低,与对照组比较,差异有显著意义(P＜0.01).结论:MG患者存在一定的自主神经功能损害,SSR可作为判断MG患者自主神经功能损害的神经电生理指标.     

Poly-autoimmunity in patients with myasthenia gravis: A single-center experience

Abstract

We evaluated the co-occurrence of autoimmune diseases (ADs) in a large population of myasthenia gravis (MG) patients from a single center. Our survey included 984 patients, 904 with anti-acetylcholine receptor antibodies and 80 with anti-muscle specific kinase antibodies. The anti-acetylcholine receptor positive population included patients with early-onset (age at onset ≤50 years), late-onset and thymoma-associated disease. Follow-up ranged 2–40 years. Two-hundred and fourteen ADs were diagnosed in 185 patients; 26 of them had two or more ADs in association with MG. Thyroid disorders were the most common and, together with vitiligo and thrombocytopenia, occurred in all disease subsets. Otherwise, there was a broad variability with partial overlap among patient groups. The highest rate of ADs was observed in early-onset patients, while clusters, i.e. 2 or more ADs other than MG in the same individual, were more common among thymoma cases. Thirty-four diseases were diagnosed at the same time, 88 occurred before and 92 after the onset of MG. On multivariate analysis, immunosuppressive treatment was the only independent variable which negatively influenced the risk of developing other ADs in our cohort.     

Transplacental transmission of experimental autoimmune myasthenia gravis. A morphological study

Using neonates born from experimental autoimmune myasthenic rabbits, the authors demonstrated antibodies to acetylcholine receptor (AChR) in the newborn sera. By radioimmunoassay, antibody titers of 1-day-old neonates were roughly one seventh to one ninth of the mothers. At 8 weeks postpartum, the antibody was no longer detectable. Ultrastructural observations of the intercostal muscles of the neonates revealed two types of changes. The first type was degenerative alterations in the postsynaptic membrane. The second type of change, which was morphometrically analyzed, was immaturity of postsynaptic membrane structure with underdeveloped secondary synaptic clefts. After 28 days postpartum, these changes were not visible, thereby indicating that the process is reversible as the antibody titer decreases. These results suggested the possibility that the antibody to AChR, transferred transplacentally, arrested the development of postsynaptic structure, although reversible, by blocking of the receptor sites in the end-plate.     

Familial myasthenia gravis: nine patients in two generations.

In two generations of a family followed up for 15 years, nine patients suffering from myasthenia gravis were observed. The family, being of special genetic importance, is unique in the literature.     

Ocular myasthenia gravis.

Ocular dysfunction accounts for nearly 70% of the initial manifestations of myasthenia gravis. Since the prevalence rate of myasthenia gravis is two to 10 cases per 100,000 population, it is important for clinicians to be cognizant of this disorder and its varied ocular presentations. The clinical manifestations, diagnosis, treatment, and prognosis of ocular myasthenia gravis are reviewed.     

重症肌无力的重复神经刺激检查研究

目的：研究重复神经刺激（ＲＮＳ）检查对重症肌无力（ＭＧ）疾病的诊断价值。方法：对４４例ＭＧ患者进行重复神经刺激检查,共检查１３２条神经。结果：ＭＧ患者１３２条神经ＲＮＳ诱发的波幅衰减阳性率６５２％。受检的三组肌肉中三角肌阳性率最高（８４１％）,测量波面积对ＭＧ的诊断价值优于测量波幅,两种测量方法阳性率比较有显著性差异（Ｐ＜００５）。ＲＮＳ阳性的ＭＧ患者１００％的在低频刺激时即可获得阳性结果,波幅衰减最明显的刺激频率为５Ｈｚ。结论：ＲＮＳ检查在ＭＧ疾病诊断中具有重要价值     

Subpopulations of T lymphocytes in myasthenia gravis patients.

Subpopulations of human peripheral blood T lymphocytes were examined in twenty-three myasthenic patients. T lymphocytes bearing receptors for the Fc portion of IgG (T gamma) were significantly increased in a third of the patients examined. T lymphocytes bearing receptors for the Fc portion of IgM (Tmu) were within normal values in all but two patients. Possible implications of these cells in the pathogenesis of myasthenia gravis are discussed.     

A case of myasthenia gravis proven by ultrastructural study

Although light microscopic features of muscle are not pathognomonic in most cases of myasthenia gravis (MG), careful examination of neuromuscular junction by electron microscopy (EM) can reveal important clues for this disease. We report here a case of MG confirmed by EM study to emphasize that tissue diagnosis is still the best adjuvant to confirm the diagnosis. An 18-year-old female visited our hospital complaining of progressive muscle weakness for 3 years. She had difficulty in running, going upstairs and doing routine activities. Symptoms were aggravated with continuous work and resolved after rest. She had weakness of bilateral masseter and facial muscles and proximal portions of extremities without definite diurnal variation. Electromyography showed myopathic changes in proximal muscles of extremities. MG was considered but tensilon test was equivocal. Repetitive nerve stimulation tests revealed 20-30 percent decrease in responses to low and high rate stimulation. Muscle biopsy revealed selective type 2 atrophy. Ultrastructurally, abnormalities of neuromuscular junctions, i.e., wide primary synaptic cleft, and wide and shallow secondary synaptic clefts with mild myopathic features were present. These findings were pathognomonic for MG. Later, her symptoms were improved completely 3 months after thymectomy. The histologic finding of thymus was follicular hyperplasia.     

Autoimmunity in myasthenia gravis: a family study

The prevalence of autoantibodies to muscle, epithelial cells of calf thymus, thyroid, gastric parietal cells and antinuclear and rheumatoid factors has been studied in the sera of thirty-two patients with myasthenia gravis and their relatives.

Previous reports of an increased prevalence of autoantibodies in the sera of patients with myasthenia gravis have been confirmed and it has been shown that concurrent reactivity to muscle and thymus is closely correlated with the severity of the myasthenia and the presence of a thymoma, whereas no such correlation occurred with the other antibodies studied. None of the sera from relatives or spouses showed concurrent reactivity with thymus and muscle, and with the exception of one patient with pernicious anaemia, sera from patients with a variety of other diseases were also negative.

A slight increase in the prevalence of autoantibodies to thyroid and gastric components and antinuclear factor was found in first degree relatives of patients with myasthenia gravis; this could be accounted for by their aggregation in a few families.

     

The immunopathology of myasthenia gravis.

Experimental autoimmune myasthenia gravis, induced by immunization with solubilized acetylcholine receptors, has proven an excellent animal model for the study of myasthenia gravis. The role of the thymus in myasthenia gravis is not yet known. Its content of skeletal muscle elements and acetylcholine receptors and the presence of germinal centers in myasthenia gravis suggest that the thymus could be a site of autoimmunization. An effector role has not been demonstrated for T cells in the pathogenesis of experimental autoimmune or clinical myasthenia gravis, but helper T cells participate in the rat's autoantibody response to acetylcholine receptors. Antibodies and lymphocytes reactive with acetylcholine receptors are demonstrable in the peripheral blood of patients with myasthenia gravis and appear to be specific for this disease. Parallel studies of both experimental autoimmune and clinical myasthenia gravis have provided evidence for an autoimmune basis for the pathophysiology in myasthenia gravis. Antiacetylcholine receptor antibodies appear to play a central role in impairing neuromuscular transmission. Numerous antibody specificities have been described, but none seems to be directed at the acetylcholine binding site of the receptor. Addition of antiacetylcholine receptor antibodies to cultured muscle cells, in the absence of complement, causes redistribution of the receptors on the membranes of myotubes, accelerated receptor degradation, apparent impairment of ionophore function, and loss of sensitivity to acetylcholine. In vivo complement appears to be an important mediator of antiacetylcholine receptor antibody pathogenicity. Its presence is essential for the passive transfer of experimental autoimmune myasthenia gravis with antibodies. In muscle biopsy specimens from patients with myasthenia gravis, IgG and C3 have been demonstrated on the postsynaptic membrane and on degenerated fragments of membrane in the synaptic cleft. This suggests that complement activation in vivo is associated with focal lysis of the postsynaptic membrane. A causal relationship appears to exist between the binding of antibody to acetylcholine receptors, the reduction in muscle acetylcholine receptors, and impairment of neuromuscular transmission.     

Antibodies to polyadenylic acid in patients with myasthenia gravis.

Sera from 100 patients with myasthenia gravis and 45 patients with non-myasthenia gravis neuromuscular diseases were studied for antibodies to poly rA, poly rA-rU, native and denatured DNA. All patients with myasthenia gravis had significant anti-acetylcholine receptor antibodies with a mean titre of 1.2 X 10(-7)M. Forty-eight per cent of the myasthenia gravis patients had anti-poly rA antibody levels which were greater than 3 standard deviations from the mean of 65 control patients by Millipore filter radioimmunoassay. The antibody was specific for poly rA and present in a much higher frequency than antibodies to the other nucleic acids tested. Sucrose-gradient ultracentrifugation demonstrated that the antibody was limited to the IgM class alone. Mechanisms relating these findings to a more generalized immunological dysfunction are discussed.     

Lymphocyte subpopulations in non-neoplastic thymus from myasthenia gravis patients.

Lymphocyte populations in non-neoplastic thymuses from fifteen patients with myasthenia gravis (MG) were examined. As in normal subjects, the great majority of thymic lymphocytes of MG patients are T cells. When MG thymuses were compared to normal glands, lower percentages of lymphocytes able to form E rosettes resistant to incubation at 37 degrees C (stable E rosettes) were found in MG thymuses. A negligible B cell content was detected in eight normal and in eight MG thymuses with absent or rare lymph follicles; but there was a substantial B cell presence in the thymuses of seven MG cases with thymic hyperplasia containing many germinal centres. Normal and MG thymuses contain the same percentage of lymphocytes bearing receptors for the Fc portion of IgM (TM). Moreover, the IgM Fc receptor was found mostly on cells which did not form stable E rosettes and did not bear surface immunoglobulin. The possible significance of these findings is discussed.     

TAP polymorphisms in Swedish myasthenia gravis patients

The association between myasthenia gravis (MG) and TAP polymorphisms was studied in 79 Swedish patients and 155 unrelated controls. TAP typing was performed by ARMS-PCR technique and stratification analysis was used to determine if the TAP associations were independent or secondary to linkage disequilibrium with DQ2 and DR3. TAP1 and TAP2 alleles did not confer independent risk for MG. TAP2*0101 was, however, positively associated with MG in patients with an early onset of disease compared to patients with a late onset of disease. TAP1 and TAP2 alleles did not confer risk in MG patients negative for DQ2. In conclusion, susceptibility to MG is not primarily conferred by TAP alleles in the extended DR3 haplotype.     

Myasthenia gravis and the thymus gland. A historical review

The first report of an association between myasthenia gravis (MG) and the thymus gland was in 1901. Although the underlying mechanisms are uncertain, thymic abnormalities are clearly associated with MG. This review article summarises, from a historical point of view, our knowledge of these associations, and the surgical and medical treatment of MG, including symptom management, immunosuppression, intravenous immunoglobulin and plasmapheresis.