Myasthenia gravis: the future is here
Henry J. Kaminski, Patricia Sikorski, S. Isabel Coronel, Linda L. Kusner
Henry J. Kaminski, Patricia Sikorski, S. Isabel Coronel, Linda L. Kusner
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Review

Myasthenia gravis: the future is here

Abstract

Myasthenia gravis (MG) stands as a prototypical antibody-mediated autoimmune disease: it is dependent on T cells and characterized by the presence of autoantibodies targeting proteins located on the postsynaptic surface of skeletal muscle, known as the neuromuscular junction. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. Recent decades have witnessed substantial progress in understanding the underlying pathophysiology, leading to the delineation of distinct subcategories within MG, including MG linked to AChR or MuSK antibodies as well as age-based distinction, thymoma-associated, and immune checkpoint inhibitor–induced MG. This heightened understanding has paved the way for the development of more precise and targeted therapeutic interventions. Notably, the FDA has recently approved therapeutic inhibitors of complement and the IgG receptor FcRn, a testament to our improved comprehension of autoantibody effector mechanisms in MG. In this Review, we delve into the various subgroups of MG, stratified by age, autoantibody type, and histology of the thymus with neoplasms. Furthermore, we explore both current and potential emerging therapeutic strategies, shedding light on the evolving landscape of MG treatment.

Authors

Henry J. Kaminski, Patricia Sikorski, S. Isabel Coronel, Linda L. Kusner

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Figure 2

Effector mechanisms of AChR antibodies.

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Effector mechanisms of AChR antibodies. (A) Antibody binding to the AChR...
(A) Antibody binding to the AChR activates the complement cascade, resulting in the formation of membrane attack complex (MAC) and localized destruction of the postsynaptic NMJ membrane. This ultimately leads to a simplified, altered morphology of the postsynaptic membrane of the NMJ of patients with MG and EAMG animals. (B) Antibodies cross-link AChR molecules on the NMJ postsynaptic membrane, causing endocytosis of the cross-linked AChR molecules and their degradation (antigenic modulation). It is likely that antibodies attaching to different epitopes are required to produce modulation and complement activation. This ultimately leads to a reduced number of AChR molecules on the postsynaptic membrane. (C) Antibody binding of the ACh-binding sites of the AChR causes functional block of the AChR by interfering with binding of ACh released at the NMJ. It is important to appreciate that there may be overlap in the pathogenic mechanisms of individual AChR antibodies and these mechanisms may cooperate to induce disease.