Abstract
Myasthenia gravis (MG) is a rare autoimmune disease mediated by pathogenic antibodies (Ab) directed against components of the neuromuscular junction (NMJ), mainly the acetylcholine receptor (AChR). The etiological mechanisms are not totally elucidated, but they include a combination of genetic predisposition, triggering event(s), and hormonal components. MG disease is associated with defective immune regulation, chronic cell activation, inflammation, and the thymus is frequently abnormal. MG is characterized by muscle fatigability that is very invalidating and can be life-threatening when respiratory muscles are affected. MG is not cured, and symptomatic treatments with acetylcholinesterase inhibitors and immunosuppressors are life-long medications associated with severe side effects (especially glucocorticoids). While the muscle is the ultimate target of the autoimmune attack, its place and role are not thoroughly described, and this mini-review will focus on the cascade of pathophysiologic mechanisms taking place at the NMJ and its consequences on the muscle biology, function, and regeneration in myasthenic patients, at the histological, cellular, and molecular levels. The fine structure of the synaptic cleft is damaged by the Ab binding that is coupled to focal complement-dependent lysis in the case of MG with anti-AChR antibodies. Cellular and molecular reactions taking place in the muscle involve several cell types as well as soluble factors. Finally, the regenerative capacities of the MG muscle tissue may be altered. Altogether, the studies reported in this review demonstrate that the muscle is not a passive target in MG, but interacts dynamically with its environment in several ways, activating mechanisms of compensation that limit the pathogenic mechanisms of the autoantibodies.
Highlights
Autoimmune Myasthenia Gravis (MG) is characterized by muscular weakness aggravated by exercise and improved by rest
The agrin receptor LRP4, which forms a complex with muscle-specific kinase (MuSK), has been recognized as a novel autoantigen in a small proportion of MG patients without anti-acetylcholine receptor (AChR) or -MuSK Ab [4]
The degradation of the postsynaptic membrane results in a decrease in the expression of the AChR and the VGSCs channels, both contributing to the significant reduction of the safety factor: 1) endplate potential (EPP) is lowered by the partial loss of functional AChRs and 2) the firing threshold is raised due to the reduction in the density of the sodium channels [30]
Summary
SBA,JTV wrote the manuscript with support from RLP. AB conceived and designed the figure. Word count: 249 Myasthenia gravis (MG) is a rare autoimmune disease mediated by pathogenic antibodies (Ab) directed against components of the neuromuscular junction (mainly the acetylcholine receptor). While the muscle is the ultimate target of the autoimmune attack, its place and role are not thoroughly described, and this mini-review will focus on the cascade of pathophysiologic mechanisms taking place at the neuromuscular junction (NMJ) and its consequences on the muscle biology, function, and regeneration in myasthenic patients, at the histological, cellular, and molecular levels. In review Sorbonne Université, Inserm UMRS 974, Association Institut de Myologie, Centre de Recherche en Myologie, Groupe hospitalier Pitié-Salpêtrière, 105 Bd de l’hôpital, 75013 Paris, France Keywords: myasthenia, muscle, neuromuscular junction, acetylcholine receptor, autoimmunity, cytokines, transcriptome Running title: The muscle in Myasthenia Gravis
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