Myasthenia gravis: the future is here
Henry J. Kaminski, … , S. Isabel Coronel, Linda L. Kusner
Henry J. Kaminski, … , S. Isabel Coronel, Linda L. Kusner
Published June 17, 2024
Citation Information: J Clin Invest. 2024;134(12):e179742. https://doi.org/10.1172/JCI179742.
View: Text | PDF
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

×

Figure 4

Thymic pathology associated early-onset MG.

Options: View larger image (or click on image) Download as PowerPoint
Thymic pathology associated early-onset MG. The thymus is the organ of T...
The thymus is the organ of T cell maturation and establishment of central tolerance. Self-peptides are presented by medullary thymic epithelial cells (mTECs). Self-reactive T cells undergo apoptosis or are controlled by Tregs; however, suppressor functions of thymic Tregs are impaired in MG. Type I and II IFN induction in the thymus promotes expression of AChR, cytokines, and chemokines by thymic epithelial cells. Increased expression of IL-17 and IL-23 promotes expansion of Th1/Th17 cells. High endothelial venules (HEVs) and secretion of CCL21 and CXCL13 facilitate recruitment of B cells and ectopic germinal center formation associated with thymic hyperplasia. In the germinal center, B cells undergo somatic hypermutation, affinity maturation, and selection, processes that are implicated in development of AChR+ long-lived plasma cells. Anti-AChR–producing plasma cells exit the germinal center and migrate to the bone marrow. fDC, follicular DC.