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At least 19 recordsLinked to original sources
PubMed1977

Morphologic and immunologic studies in experimental autoimmune myasthenia gravis and myasthenia gravis.

An indirect immunoperoxidase technique was used to study by light microscopy the binding of serum from experimental autoimmune myasthenia gravis (EAMG) rabbits to junctionally and extrajunctionally located acetylcholine receptors (AChRs) in human and rat muscles. Binding was restricted to junctional AChR. Alpha bungarotoxin (a-BGT) partially blocked the binding of EAMG serum, while myasthenia gravis serum, carbamylcholine, decamethonium, and tubocurarine did not. A radioimmunoassay showed significant binding of antibodies in EAMG sera to 125l AChR. This binding was not inhibited by a-BGT, nor by carbamylcholine, decamethonium, or tubocurarine. Sera from 10 myasthenia gravis patients did not contain antibodies binding to the 125l AChR. We suggest that EAMG in rabbits induced by Torpedo AChR differs serologically from myasthenia gravis in patients, probably owing to antigenic differences between Torpedo and human AChR, and that antigenic differences also exist between junctional and extrajunctional receptors.

Acetylcholine↗
PubMed1979

The role of acetylcholine receptor antibodies in myasthenia gravis.

Myasthenia gravis is an autoimmune disease of man characterized by remitting and relapsing muscle fatigability. Although the etiology and pathogenesis are incompletely understood, the presence of circulating antibodies directed against the nicotinic acetylcholine (ACh) receptor in 80--90% of patients with myasthenia gravis and the identification of immune complexes at their neuromuscular junction have helped explain the altered neuromuscular transmission. The ACh receptor antibodies do not block access of ACh to the receptor, but do decrease the number of receptors by accelerating their degradation both in rat myotube cultures and in vivo models. In vitro these antibodies play a major role in myasthenia gravis. However, correlations of antibody titers with the clinical state following thymectomy or in neonatal myasthenia suggest that host factors may be equally important in determining whether the ACh receptor antibodies will result in clinical myasthenia.

Acetylcholine↗
PubMed1979

The otolaryngologic presentation of myasthenia gravis.

Myasthenia gravis is a neuromuscular disease of insidious onset, characterized by weakness and fatigability of voluntary muscles. Most patients present with symptoms relating to the head and neck and thus may be seen first by the otolaryngologist. Predominant symptoms may be ocular (ptosis or diplopia) or related to fatigue of the oropharyngeal or laryngeal musculature (dysarthria, dysphonia, or dysphagia). Alleviation of muscular weakness and fatigability after administration of anticholinesterase drugs is pathognomonic of myasthenia gravis.

Adolescent↗
PubMed1978

Essentials in the management of myasthenia gravis.

Myasthenia gravis is a disorder that most commonly affects young adults but occasionally appears in the elderly. Muscle weakness and easy fatigability, particularly of the ocular muscles, are characteristic. Diagnosis is confirmed by electromyography and the edrophonium (Tensilon) test. The pathology results from inability of acetylcholine to gain access to receptor sites at the neuromuscular junction, possibly because of a blocking antibody produced by the thymus. Initial treatment (in the absence of a thymoma) consists of administration of an anticholinesterase drug. If that is ineffective, thymectomy and/or corticosteroids may be useful.

Cholinesterase Inhibitors↗
PubMed1979

Humoral and cellular immunity to intrinsic factor in myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease often associated with other autoimmune disorders. A case history of MG with a coexisting atypical megaloblastic anaemia with vitamin B12 deficiency and anti Intrinsic Factor (IF) antibodies, led to a study of humoral and cellular immunity to IF in 81 MG patients. Within this series, 3 other patients had a disturbed humoral and cellular immunity to IF. These 3 patients presented no other features of pernicious anaemia. The possible origins and significance of the anti IF antibodies in MG patients are discussed.

Adolescent↗
PubMed1979

A modified assay for antibody against the nicotinic acetylcholine receptor in myasthenia gravis.

Myasthenia gravis is an autoimmune disease which may be detected by the presence of serum antibodies against the nicotinic acetylcholine receptor at the neuromuscular junction. Immunoprecipitation assays have been developed to measure these immunoglobulins and calculate titres. These assays require the labelling of the receptor with 125I-alpha-bungarotoxin which binds irreversibly. However, the standard immunoprecipitation assay may significantly underestimate the titres of some myasthenic patients. We have discovered patients with antibodies specific for the alpha-bungarotoxin binding site of purified rat muscle receptor. If labelled toxin is already present on the receptor, these antibodies are unable to bind to the protein. This phenomenon may lead to underestimates of the actual antibody titre. To circumvent this problem, we have designed a modified immunoprecipitation assay to evaluate titres.

Acetylcholine↗
PubMed1976

Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies.

Passive transfer of experimental autoimmune myasthenia gravis (EAMG) was achieved using the gamma globulin fraction and purified IgG from sera of rats immunized with Electrophus electricus (eel) acetylcholine receptor (AChR). This demonstrates the critical role of anti-AChR antibodies in impairing neuromuscular transmission in EAMG. Passive transfer of anti-AChR antibodies from rats with chronic EAMG induced signs of the acute phase of EAMG in normal recipient rats, including invasion of the motor end-plate region by mononuclear inflammatory cells. Clinical, eletrophysiological, histological, and biochemical signs of acute EAMG were observed by 24 h after antibody transfer. Recipient rats developed profound weakness and fatigability, and the posture characteristic of EAMG. Striking weight loss was attributable to dehydration. Recipient rats showed large decreases in amplitude of muscle responses to motor nerve stimulation, and repetitive nerve stimulation induced characteristic decrementing responses. End-plate potentials were not detectable in many muscle fibers, and the amplitudes of miniature end-plate potentials were reduced in the others. Passively transferred EAMG more severely affected the forearm muscles than diaphragm muscles, though neuromuscular transmission was impaired and curare sensitivity was increased in both muscles. Some AChR extracted from the muscles of rats with passively transferred EAMG was found to be complexed with antibody, and the total yield of AChR per rat was decreased. The quantitative decrease in AChR approximately paralleled in time the course of clinical and electrophysiological signs. The amount of AChR increased to normal levels and beyond at the time neuromuscular transmission was improving. The excess of AChR extractable from muscle as the serum antibody level decreased probably represented extrajunctional receptors formed in response to functional denervation caused by phagocytosis of the postsynaptic membrane by macrophages. The amount of antibody required to passively transfer EAMG was less than required to bind all AChR molecules in a rat's musculature. The effectiveness of samll amounts of antibody was probably amplified by the activation of complement and by the destruction of large areas of postsynaptic membrane by phagocytic cells. A self-sustaining autoimmune response to AChR was not provoked in animals with passively transferred EAMG.

Animals↗
PubMed1977

Myasthenia gravis: steroid-induced effects on lymphocyte subpopulations in myasthenia gravis.

Lymphocyte subpopulations from patients with myasthenia gravis were evaluated during chronic steroid therapy. A marked lymphocytopenia (10-70%) was initially (day 3-21) noticed as well as a preferential depletion of thymus-derived cells which paralleled the clinical deterioration. Thus there was a relative increase in B cells, although their absolute number remained rather constant. These changes were reverted within 2-4 weeks in spite of continuous treatment. These findings are compatible with a release of myasthenic factors (anti-acetylcholine receptor antibodies?) during the initial steroid-induced cell damage, the long-term beneficial effects being due to loss or suppression of autoreactive helper t cells.

Adolescent↗
PubMed1978

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.

Animals↗
PubMed2026

Proteomic and machine learning analysis predicts treatment response signatures in Myasthenia Gravis.

BACKGROUND: Myasthenia gravis (MG) is a prototypical antibody-mediated autoimmune disease with variable treatment responses with a need for biomarkers to guide therapeutic decision making. Proteomic profiling, coupled with machine learning, offers a hypothesis-free approach to identify multi-protein signatures associated with treatment response. METHODS: We analyzed sera collected at entry (baseline) from participants in a phase 3 trial randomized trial comparing thymectomy plus prednisone versus prednisone alone, along with matched controls using liquid chromatography-mass spectrometry. We derived disease-specific proteomic signatures and evaluated associations between baseline proteins and 6-month clinical outcomes using multiple machine-learning approaches with internal validation. RESULTS: Baseline serum proteomes distinguished MG from controls, with pathway enrichment implicating complement activation, immunoglobulin production, and T-cell receptor signaling. Distinct protein panels predicted 6-month clinical improvement within each treatment arm. In the thymectomy-plus-prednisone group, models captured non-linear relationships of predictive proteins in contrast with the predominant additive patterns observed in the prednisone-alone group. Predictive proteins were enriched for T-cell signaling and leukocyte trafficking functions, providing insight into treatment-specific biology. CONCLUSIONS: Baseline serum proteomics captures core disease characteristics of MG and predicts short-term clinical response in a treatment-specific manner. While our results require validation in independent cohorts, these findings could enable biomarker-guided selection of thymectomy, refine risk stratification, and furnish mechanistic readouts for future MG trials and clinical care. We aim to conduct future studies using -omic approaches to validate these baseline predictive biomarkers and pathways of treatment response in patients with MG.

Adult↗
PubMed1976

Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis.

Immunization of Lewis rats with acetylcholine receptor (AChR) purified from either Electrophorus electricus electric organ or syngeneic rat muscle induced experimental autoimmune myasthenia gravis (EAMG). This was demonstrated by clinical signs of weakness and by electromyographic evidence of imparied neuromuscular transmission. The amount of rat AChR required to induce an autoimmune response was comparable to the amount of eel AChR required. In vitro complexing of rat AChrR with antibody reduced its immunogenicity. Autoantibody to muscle AChR was present in serum and complexed with AChR in muscle. Antibody was not bound to the ACh binding site of AChR, since antibody-AChR complexes extracted from muscle could still bind 125I-alpha-bungarotoxin. The amount of AChR extracted from muscle of rats with EAMG was diminished. The amount of AChR and antibody-AChR complexes in muscle was measured at intervals after immunization with eel AChR. The amount of AChR decreased in rats with acute EAMG, then transiently increased to more than normal amounts during remission, and finally decreased to only about 20% of normal in rats with chronic EAMG. At least half of the AChR remaining in animals with chronic EAMG was complexed with antibody. Thus, both a decrease in amount of AChR and the formation of antibody-AChR complexes contribute to impairment of neuromuscular transmission in rats with EAMG. The possible mechanisms involved in the changes in AChR content are discussed.

Animals↗
PubMed1976

Electrocardiographic findings in 24 patients with myasthenia gravis.

Twenty four myasthenia gravis patients, 14 females and 10 males, aged between 5 and 65 years (average 29) were studied electrocardiographically. The abnormalities found in the ECG were: prolonged "Q-T" intervals (10 cases, 44.1%), sinus tachycardias (5 cases, 20.8%), sinus arrhythmias (5 cases, 20.8%), right bundle branch block (4 cases, 16.6%), and non-specific "T" wave changes (2 cases, 8.3%). Among our 24 patients with myasthenia gravis, in contrast to previous reports, only two had non-specific "T" wave abnormalities. But prolonged "Q-T" intervals, right bundle branch block, sinus tachycardias and sinus arrhythmias, when compared to normal population incidence, were found to be quite significant. In pathogenesis, primary myocardial histo-pathological abnormalities, and the role of extracardiac factors in producing the changes were discussed.

Adolescent↗