Seronegative Myasthenia Gravis: Evidence for Plasma Factor(s) Interfering with Acetylcholine Receptor Functiona

Vincent, Angela; Li, Z.; Hart, Adam; Barrett‐Jolley, Richard; Yamamoto, Takeshi; Burges, Judith; Wray, Dennis; Byrne, Nick; Molenaar, P.; Newsom‐Davis, John

doi:10.1111/j.1749-6632.1993.tb22936.x

Cited by 65 publications

(29 citation statements)

References 14 publications

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“…Three pieces of evidence demonstrate that seronegative MG patients probably have antibodies that bind to another distinct muscle membrane target, closely associated with the AChRs at the neuromuscular junction. First, their sera inhibit AChR function in an acute, but transient, manner [52] and this inhibition is very similar to that found with addition of calcitonin gene related peptide and adrenergic agonists that act through G protein-coupled receptors [52,53] and lead to AChR desensitization [54]. This indicates that the antibodies can activate second messengers leading to AChR phosphorylation; phosphorylation of AChRs has been demonstrated in preliminary studies (P. Plested, T. Tang & A. Vincent, unpublished results).…”

Section: Seronegative Mgsupporting

confidence: 57%

Molecular targets for autoimmune and genetic disorders of neuromuscular transmission

2000

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The neuromuscular junction is the target of a variety of autoimmune, neurotoxic and genetic disorders, most of which result in muscle weakness. Most of the diseases, and many neurotoxins, target the ion channels that are essential for neuromuscular transmission. Myasthenia gravis is an acquired autoimmune disease caused in the majority of patients by antibodies to the acetylcholine receptor, a ligand-gated ion channel. The antibodies lead to loss of acetylcholine receptor, reduced efficiency of neuromuscular transmission and muscle weakness and fatigue. Placental transfer of these antibodies in women with myasthenia can cause fetal or neonatal weakness and occasionally severe deformities. Lambert Eaton myasthenic syndrome and acquired neuromyotonia are caused by antibodies to voltage-gated calcium or potassium channels, respectively. In the rare acquired neuromyotonia, reduced repolarization of the nerve terminal leads to spontaneous and repetitive muscle activity. In each of these disorders, the antibodies are detected by immunoprecipitation of the relevant ion channel labelled with radioactive neurotoxins. Genetic disorders of neuromuscular transmission are due mainly to mutations in the genes for the acetylcholine receptor. These conditions show recessive or dominant inheritance and result in either loss of receptors or altered kinetics of acetylcholine receptor channel properties. Study of these conditions has greatly increased our understanding of synaptic function and of disease aetiology.

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Section: Seronegative Mgsupporting

confidence: 57%

Molecular targets for autoimmune and genetic disorders of neuromuscular transmission

2000

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“…Hence, although the well-known defect in neuromuscular transmission is the main cause of weakness and enhanced fatigue of muscles in MG patients, defects in E-C coupling and contractility may also play an important part in enhancing the fatigue. Furthermore, our studies indicate that such extrajunctional defects may play a significant role in the weakness and enhanced fatigue in patients with seronegative MG. 39,52 …”

Section: Dlscusslonmentioning

confidence: 98%

Mechanisms of fatigue in normal intercostal muscle and muscle from patients with myasthenia gravis

et al. 1993

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Fatigue mechanisms in normal intercostal muscle and muscle from patients with myasthenia gravis (MG) were evaluated by monitoring the compound muscle action potential (CMAP) and tetanic tension responses to repetitive nerve or muscle stimulation in vitro. When fatigue was induced by nerve stimulation at 30 Hz for 0.5 s every 2.5 s, about half of the original tension decreased after 30 min in normal muscle and 5 min in MG muscle. Analysis of the changes in area of CMAPs and tension indicated that impairment of neuromuscular transmission, muscle membrane excitation, and excitation-contraction (E-C) coupling and contractility accounted for 40%, 29%, and 31% of fatigue in normal muscle, and 83%, 0%, and 17% of fatigue in MG muscle. When fatigue was induced by muscle stimulation at 30 Hz, tension declined by a quarter after 30 min in normal muscle, but by a half after 17 min in MG muscle. Impairment of muscle membrane excitation and E-C coupling and contractility accounted for 58% and 42% of fatigue in normal muscle, and 22% and 78% of fatigue in MG muscle. Thus, fatigue of normal muscle is caused by impairment of at least four processes, and enhanced fatigue of MG muscle is caused by greater impairment of neuromuscular transmission, E-C coupling, and contractility.

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“…However, these patients, too, respond to plasma exchange and immunosuppressive therapy,2g and diaphragm muscles from mice injected with Ig from SMG patients show increased sensitivity of neuromuscular transmission to ~-t u b o c u r a r i n e .~~ Drachman and coworkers found that there was some reduction in muscle AChRs in SMG muscle, 8 as we have also found in several cases. 36 Drachman et al also showed that both mepp amplitudes and Seronegative Myasthenia Gravis "'I-cL-BuTx were reduced in mice injected with Ig from 3 SMG patients. * In contrast, diaphragm muscles from mice injected with Ig from 10 SMG patients showed increased sensitivity of neuromuscular transmission to D-tubocurarine without any substantial change in '251-a-BuTx binding.,' Collectively, these findings point to an autoantibodymediated disorder of neuromuscular transmission in SMG patients, but do not clearly indicate the site of action.…”

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confidence: 97%

Passive transfer of seronegative myasthenia gravis to mice

et al. 1994

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Muscle weakness in myasthenia gravis is due to autoantibody-induced loss of functional acetylcholine receptors (AChR). About 15% of myasthenia gravis patients, however, do not have detectable anti-AChR antibodies. To investigate the effect of their plasma immunoglobulins on neuromuscular transmission, mice were injected with plasma (and in some cases purified immunoglobulin G (IgG)) from 7 "seronegative" myasthenia gravis (SMG) patients, and neuromuscular transmission parameters were examined. When injected for 15 days, all patients' plasma caused reductions in miniature endplate potential amplitudes, while endplate potential quantal content was significantly reduced by plasma from 4 of the 7 patients. There were no changes in ACh-induced depolarization or single channel properties, and 125I-alpha-bungarotoxin binding studies showed no effect on AChR number, except in 1 case. Purified IgG injected for 3 days had similar effects to plasma injected for 15 days. Our findings confirm that SMG is autoantibody mediated and that there are pathogenic IgG antibodies. SMG appears to be a heterogeneous disorder and the target(s) for the antibodies may be diverse.

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Seronegative Myasthenia Gravis: Evidence for Plasma Factor(s) Interfering with Acetylcholine Receptor Functiona

Abstract: CLINICAL OBSERVATIONSSNMG must first be distinguished from congenital myasthenic syndromes. The latter usually present at birth or within the first two years, do not respond to a J. Burges and R. Barrett-Jolley were supported by Action Research for the Crippled

Cited by 65 publications

References 14 publications

Molecular targets for autoimmune and genetic disorders of neuromuscular transmission

Molecular targets for autoimmune and genetic disorders of neuromuscular transmission

Mechanisms of fatigue in normal intercostal muscle and muscle from patients with myasthenia gravis

Passive transfer of seronegative myasthenia gravis to mice

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