Modulation of experimental myasthenia gravis by IVIg

Myasthenia Gravis (MG) is an autoimmune disease mediated by antibodies directed against the acetylcholine receptor (AChR). Treatment by IVIg is effective in acute forms of myasthenia gravis. In order to determine the in vivo effects of the various fractions of human immunoglobulins, we used an experimental model of myasthenia gravis in SCID mice. To this end, thymic cells from MG patients are transferred to these mice according to a well defined protocol. When establishing of the model, we noticed the appearance of anti-AChR antibodies and the loss of AChR expression at the muscle level. After treatment with IVIgG or IVIgM, the mice displayed a lower anti-AChR antibody titer compared to control mice (albumin treated) and the loss of the AChR number at the muscle was significantly reduced. These results obtained from one MG patient indicate that the human immunoglobulin preparations induce significant effects on pathogenic parameters in the SCID mouse model. Therefore this model is interesting to approach the mechanisms of action of human immunoglobulins and deserves further investigation.     

Myasthenia gravis

Myasthenia gravis is an autoimmune disease, which leads to load-dependent weakness of voluntary skeletal muscles with recovery of function after resting. The disease is caused by autoantibodies directed against the postsynaptic nicotinic acetylcholine receptors (AChR) leading to a reduction of neuromuscular transmission. Muscles and nerves are not affected. Disorders of the thymus play a role in the pathogenesis of AChR antibody-positive myasthenia. The clinical symptoms include exercise-induced fatigue either of the ocular muscles alone (ocular myasthenia) or striated skeletal muscle and the ocular, facial and bulbar musculature (generalized myasthenia). Treatment of myasthenia gravis involves administration of acetylcholine esterase inhibitors and immunosuppressive drugs. A myasthenic crisis is characterized by life-threatening complications with severe weakness, swallowing difficulties and respiratory failure, which requires intensive care treatment.     

Acetylcholine receptors and myasthenia gravis

Recent years have seen considerable progress in understanding the nature of the molecular events involved in neuromuscular transmission. The acetylcholine receptor (AChR) has been purified to homogeneity and acetylcholine-induced ion transport has been reconstituted by incorporation of pure AChR into artificial membranes. Immunization against purified AChR induces a condition, clinically and physiologically similar to the human disease myasthenia gravis, which is due to circulating anti-AChR antibodies. This model, experimental autoimmune myasthenia gravis, is proving useful for investigating the role of genetic factors in determining the immune response to AChRs and for testing various experimental approaches to specific treatment. Myasthenia gravis is an autoimmune disease in which there is loss of acetylcholine receptors at the neuromuscular junction. Anti-AChR antibodies can be detected in the majority of patients and they cause loss of AChR by a variety of mechanisms. Anti-AChR antibody is heterogeneous and not restricted in idiotype. The role of the thymus in MG is still uncertain, but recent experiments implicate the presence of a cell type in MG thymus which may be involved in autosensitization to AChR.     

重症肌无力全身表现及发病机制探讨

６４４例重症肌无力（ＭＧ）患者合并多种免疫有关性疾病，并且有多种自身抗体阳性，同时发现了一些骨骼肌以外受损害的表现，伴锥体束征者（ＰＳ）１１例，伴发癫痫４例，原因未明的周围神经病变３例，部分重症肌无力病人伴有血清ＡＬＴ增高，１４例ＭＧ患者的超声心动图，射血指数，２例心脏核素扫描，均未见明显异常。ＭＧ病人的骨骼肌以外损伤的表现，一般不需要特殊处理，随着重症肌无力的好转，绝大部分能够好转，其发病机制可能与乙酰胆碱受体抗体（ＡＣｈＲＡｂ）有关，或者是免疫泛化产生的其他免疫因素的作用，由此可见ＭＧ可能是一种主要累及神经肌肉接头处突触后膜上ＡＣｈＲ的全身性自身免疫性疾病。     

A Prospective Assessment of the Characteristics of Dysphagia in Myasthenia Gravis

Fatigable muscle weakness is the clinical hallmark of the human autoimmune disease myasthenia gravis (MG). Weakness of the oropharyngeal muscles produces dysphagia, which continues to be a major source of morbidity in MG. In this study we prospectively assessed 20 patients with myasthenia gravis who described difficulties with swallowing. Videofluoroscopic assessment showed disordered swallowing in all, with abnormalities in oral, pharyngeal, and, to a lesser extent, oral preparatory phases. Of the 20 studied, 7 aspirated, most of whom did so silently. Laryngeal penetration occurred in many more patients. The characteristics of dysphagia in MG are described and compared with other neurological disorders that can produce dysphagia.     

Newly diagnosed multiple sclerosis in a patient with ocular myasthenia gravis: A case report

Rationale:Patients with myasthenia gravis may also have comorbid autoimmune diseases. Since both myasthenia gravis and neuromyelitis optica spectrum disease are mediated by antibodies, they are likely to occur together. However, since multiple sclerosis is an autoimmune disease that is not mediated by a specific antibody, it has fewer immune mechanisms in common with myasthenia gravis than neuromyelitis optica spectrum disease. We encountered a case of newly developed multiple sclerosis in a patient with myasthenia gravis.Patient concerns:A 46-year-old man was diagnosed with ocular myasthenia gravis 6 years ago and had been taking pyridostigmine to control his symptoms.Diagnosis:The patient developed right optic neuritis, and multiple sclerosis was suspected based on the brain magnetic resonance imaging findings. However, the required diagnostic criteria were not met.Interventions:Disease-modifying therapy was not initiated, and clinical progression of the disease was monitored.Outcomes:One year after the onset of optic neuritis, the patient developed myelitis and was diagnosed with multiple sclerosis, prompting treatment with disease-modifying therapy.Lessons:When optic neuritis occurs in patients with myasthenia gravis, careful evaluation is necessary while considering the possibility that it may be the first symptom of a demyelinating central nervous system disease. Therefore, it is important to conduct shorter-interval monitoring and symptom screening for patients with neurological autoimmune diseases, such as myasthenia gravis, even if multiple sclerosis is not initially suspected, to achieve early detection of multiple sclerosis.     

自身免疫多内分泌腺病综合征Ⅲ型合并重症肌无力一例报道及人类白细胞抗原基因分析

1型糖尿病合并自身免疫性甲状腺疾病是自身免疫多内分泌腺病综合征(APS)Ⅲ型最常见的类型,但重症肌无力合并APS Ⅲ型罕见报道。本研究对1例先后出现眼肌型重症肌无力、1型糖尿病、桥本甲状腺炎的APS Ⅲ型合并重症肌无力的男性患者进行了人类白细胞抗原(HLA)基因分析及文献回顾11例APSⅢ合并重症肌无力,发现HLA-D...     

Association of HLA-DQA1*0101/2 and DQB1*0502 with Myasthenia Gravis in Southern Iranian Patients

Background: Myasthenia gravis is an autoimmune disorder of neuromuscular junction characterized by skeletal muscle weakness and fatigability. Different genes may control the induction and clinical presentation of this disease. Various HLA alleles are reported as predisposing or protective genetic elements in myasthenia gravis. Objective: The aim of this study was to investigate the probable association between HLA-DQ alleles and myasthenia gravis in southern Iranian patients. Methods: HLA-DQA1 and DQB1 alleles were determined in 104 sporadic patients with myasthenia gravis using polymerase chain reaction - restriction fragment length polymorphism method and the results were compared to 816 healthy controls. Results: HLA-DQA1*0101/2 (39.4%) and DQB1*0502 (21.6%) were the most frequent alleles in southern Iranian patients with myasthenia gravis. These alleles revealed positive associations with the disease with relative risks of 1.69 and 2.41, respectively. The most common haplotype was DQA1*0101/2-DQB1*0502 in these patients. Conclusion: According to the results of this study, DQA1*0101/2 and DQB1*0502 alleles might be considered as predisposing genetic factors to myasthenia gravis while DQA1*0501, DQB1*0301 and *0602/3 show protective roles against this disease.     

Comparative Study of Clinical Effects Between Plasma Adsorption and Double Filtration Plasmapheresis in Patients with Myasthenia Gravis

Abstract: Plasma exchange (PE) has been one of the most powerful treatments for patients with myasthenia gravis (MG) since Pinching et al. reported its clinical usefulness in 1976, despite the need for supplemental human plasma. However, new apheresis techniques, e.g., plasma adsorption (PA) and double filtration plasmapheresis (DFPP), which do not need human plasma, were developed and have been introduced for clinical use in MG. We compared the effects of these plasma purification therapies in patients with MG and found that DFPP improved such subjective symptoms as chest compression and general fatigue better than PA while both of them could decrease the serum level of acetylcholine receptor (AChR) antibodies and relieve objective muscle weakness to a similar degree. It may be that DFPP can remove some circulating pathogenic factors other than AChR antibodies more efficiently than PA.—     

Prevention of experimental autoimmune myasthenia gravis by manipulation of the immune network with a complementary peptide for the acetylcholine receptor.

Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are caused, in part, by the production of autoantibodies against the main immunogenic region, amino acids 61-76, of the alpha chain of the acetylcholine receptor (AChR). Theoretically, induction of anti-idiotypic (Id) antibodies (Abs) should be a highly specific treatment for the disease by virtue of their potential ability to neutralize Abs to the AChR. We have tested this idea by attempting to evoke such anti-Id Abs by immunization with a peptide (termed RhCA 67-16) encoded by RNA complementary to the Torpedo AChR main immunogenic region and determining whether such treatment will prevent the development of EAMG. Immunization with RhCA 67-16, but not a control peptide termed PBM 9-1, was found to elicit the production of anti-Id Abs that blocked recognition of native Torpedo AChR by its Ab. This anti-Id Ab activity was ablated by incubation of the anti-RhCA 67-16 serum with RhCA 67-16, but PBM 9-1, prior to the assay for Ab binding to AChR. The anti-Id Ab-inducing activity of RhCA 67-16 was confirmed by the ability to produce a rat monoclonal Ab to RhCA 67-16 that showed anti-Id activity for polyclonal rat Ab reactive with AChR residues 67-76. Most importantly, RhCA 67-16 immunization also prevented the development of EAMG in Lewis rats challenged with Torpedo AChR (25% incidence versus 90% in the controls) and diminished the AChR Ab levels in animals injected with low doses of AChR. Our results suggest a therapy for MG and perhaps other autoimmune diseases through the induction of anti-Id Abs by peptide immunogens.     

Coexistence of Myasthenia Gravis and Hashimoto's Thyroiditis in a Chinese Woman

Summary: The coexistence of myasthenia gravis and Hashimoto's thyroiditis has rarely been described. A 64-year-old Chinese woman with myasthenia gravis and Hashimoto's thyroiditis is described. The literature on the occurrence of Hashimoto's thyroiditis and myasthenia gravis is briefly reviewed. The relationship between myasthenia gravis and thyroid dysfunction is outlined. It is suggested that the association of myasthenia gravis with Hashimoto's thyroiditis (a long-known autoimmune disease) provides further support to the hypothesis that myasthenia gravis may be an auto-immune disorder.     

Myasthenic Crisis with Delayed Recovery after Plasmapheresis

Abstract: We report on 2 elderly patients with myasthenia gravis in whom recovery from crisis was prolonged despite intensive plasmapheresis (PP). In both patients, the anti-acetylcholine (anti-AChR) titer failed to fall sufficiently after completing PP. These patients might have had antibodies that produced a more pronounced effect on the degradation of AChR, or the synthesis of AChR might have been reduced by aging. The anti-AChR titer did not correlate with a reduction of IgG after PP in 1 patient. Successful treatment was achieved by keeping the anti-AChR titer at a low level via the concomitant use of prednisolone with PP.     

Involvement of human muscle acetylcholine receptor alpha-subunit gene (CHRNA) in susceptibility to myasthenia gravis.

The muscle acetylcholine receptor is the major target of the autoimmune response in generalized myasthenia gravis. To investigate the role of the gene encoding the alpha subunit of the receptor (CHRNA), two stable polymorphic d[(GT).(CA)]dinucleotide repeats, designated HB and BB, were characterized within the first intron of CHRNA. The HB*14 allele conferred a relative risk for myasthenia gravis of 2.5 in 81 unrelated patients compared with 100 control subjects. Very significantly, family analysis based on haplotype segregation data indicated that parental haplotypes associated with HB*14 always segregated to the child with myasthenia gravis (P < 0.0002 for the comparison with the transmission of haplotypes not bearing HB*14), whereas their transmission to unaffected siblings was equilibrated. Myasthenia gravis patients also showed a high frequency of microsatellite variants unseen in controls. These findings implicate the CHRNA in susceptibility to myasthenia gravis.     

Therapeutic vaccines in autoimmunity

Similarly to prophylactic vaccines whose purpose is to prevent infectious diseases, therapeutic vaccines against autoimmune diseases are based on their similarity to the putative causes of the disease. We shall describe here two such examples: a copolymer of amino acids related to myelin basic protein, in the case of multiple sclerosis, and a peptide derived from the nicotinic acetylcholine receptor (AChR), in the case of myasthenia gravis (MG). Copolymer 1 (Cop 1, glatiramer acetate, Copaxone) is a synthetic amino acid random copolymer, immunologically cross-reactive with myelin basic protein and suppresses experimental allergic encephalomyelitis in several animal species. Cop 1 slows the progression of disability and reduces relapse rate in exacerbating-remitting multiple sclerosis patients. It was approved by the Food and Drug Administration in 1996, and today is used by tens of thousands of patients. Cop 1 is a potent inducer of T helper 2 (Th2) regulatory cells in mice and humans, and Th2 cells are found both in the brains and spinal cords of Cop 1-treated mice. MG and experimental autoimmune MG are T cell-regulated, antibody-mediated autoimmune diseases. Two peptides, representing sequences of the human AChR alpha-subunit, p195-212 and p259-271, are immunodominant T cell epitopes in MG patients and in two strains of mice. Altered peptide ligand, composed of the tandemly arranged two single amino acid analogs, inhibits in vitro and in vivo MG-associated autoimmune responses. The active suppression is mediated by the CD4(+)CD25(+) immunoregulatory cells and is associated with the down-regulation of Th1-type cytokines and the up-regulation of the secretion of IL-10 and the immunosuppressive cytokine, transforming growth factor beta.     

Acute presentation of autoimmune hepatitis in a patient with myasthenia gravis, thymoma, Hashimoto thyroiditis and connective tissue disorder

Myasthenia gravis is an antibody-mediated autoimmune disease at the neuromuscular junctions. It can be associated with many other autoimmune diseases. We report a case of acute presentation of autoimmune hepatitis with myasthenia gravis, thymoma, Hashimoto thyroiditis and connective tissue disorder.     

Adult celiac disease with acetylcholine receptor antibody positive myasthenia gravis

Celiac disease has been associated with some autoimmune disorders. A 40-year-old competitive strongman with celiac disease responded to a glutenfree diet, but developed profound and generalized motor weakness with acetylcholine receptor antibody positive myasthenia gravis, a disorder reported to occur in about 1 in 5000. This possible relationship between myasthenia gravis and celiac disease was further explored in serological studies. Frozen stored serum samples from 23 acetylcholine receptor antibody positive myasthenia gravis patients with no intestinal symptoms were used to screen for celiac disease. Both endomysial and tissue transglutaminase antibodies were examined. One of 23 （or, about 4.3%） was positive for both IgA-endomysial and IgA tissue transglutaminase antibodies. Endoscopic studies subsequently showed duodenal mucosal scalloping and biopsies confirmed the histopathological changes of celiac disease. Celiac disease and myasthenia gravis may occur together more often than is currently appreciated. The presence of motor weakness in celiac disease may be a clue to occult myasthenia gravis, even in the absence of intestinal symptoms.     

La myasthénie du côté de l’interniste

Myasthenia gravis is an autoimmune disease due to specific antibodies inducing a neuromuscular transmission defect causing muscle fatigability. If onset of the disease may be at any age, myasthenia gravis concerns mostly young adults, in majority females. The disease characteristic features are the following: ocular symptoms (ptosis or diplopia) as main initial manifestation, extension to other muscles in 80 % of the cases, variability of the deficit, effort induced worsening, successive periods of exacerbation during the disease course, severity depending on respiratory and swallowing impairment (if rapid worsening, a myasthenic crisis is to be suspected), association with thymoma in 20 % of patients and with other various autoimmune diseases, most commonly hyperthyroidism and Hashimoto's disease. Diagnosis relies on the clinical features, improvement with cholinesterase inhibitors, detection of specific autoantibodies (anti-AChR or anti-MuSK), and significant decrement evidenced by electrophysiological tests. The points concerning specifically the internist have been highlighted in this article: diagnostic traps, associated autoimmune diseases, including inflammatory myopathies that may mimic myasthenia gravis, adverse effects of medications commonly used in internal medicine, some of them inducing myasthenic syndromes. The treatment is well codified: the treatment is well codified: (1) respect of adverse drugs contra-indications, systematically use of cholinesterase inhibitors, (2) thymectomy if thymoma completed with radiotherapy if malignant, (3) corticosteroids or immunosuppressive agent in severe or disabling form, (4) intensive care unit monitoring, plasmapheresis or intravenous immunoglobulins for patients with myasthenic crisis.     

In vivo therapy with monoclonal anti-I-A antibody suppresses immune responses to acetylcholine receptor

A monoclonal antibody to I-A gene products of the immune response gene complex attenuates both humoral and cellular responses to acetylcholine receptor and appears to suppress clinical manifestations of experimental autoimmune myasthenia gravis. This demonstrates that use of antibodies against immune response gene products that are associated with susceptibility to disease may be feasible for therapy in autoimmune conditions such as myasthenia gravis.     

Myasthenia gravis and hyperthyroidism: two cases

It is well known that hyperthyroidism occurs in approximately 2 to 17.5% of patients with myasthenia gravis. Hyperthyroidism may influence the clinical course of myasthenia gravis. We report the cases of two patients, a 53-year-old man and an 18-year-old woman, who had both severe myasthenia gravis and hyperthyroidism due to Graves' disease. Myasthenia gravis affected in particular facio-ocular areas with diffuse myopathy and signs of neuromuscular block on the electromyogram. In one patient, the diagnosis of thyroid disease was made three months before the diagnosis of myasthenia gravis while in the other, thyroid disease was recognized four months after myasthenia gravis. Myasthenia gravis worsened after the development of hyperthyroidism in the second patient. Both patients were given anti-cholinesterase drugs. One underwent thymectomy. Radioiodine used for the treatment of hyperthyroidism improved the symptoms of myasthenia gravis in the first patient. The association of myasthenia gravis and hyperthyroidism is more than a coincidence; our cases illustrate the difficult diagnosis and management of these diseases. Clinicians should look for myasthenia gravis in hyperthyroid patients and vice versa, especially when symptoms of myasthenia gravis or hyperthyroidism worsen.