Blocking interleukin-23 ameliorates neuromuscular and thymic defects in myasthenia gravis
José Adolfo Villegas, Jérôme Van Wassenhove, Judith Merrheim, Karen Matta, Samy Hamadache, Clémence Flaugère, Pauline Pothin, Frédérique Truffault, Sébastien Hascoët, Nicola Santelmo, Marco Alifano, Sonia Berrih‐Aknin, Rozen Le Panse, Nadine Dragin
Abstract
Abstract Acetylcholine receptor (AChR) myasthenia gravis (MG) is a chronic autoimmune disease characterized by muscle weakness. The AChR + autoantibodies are produced by B-cells located in thymic ectopic germinal centers (eGC). No therapeutic approach is curative. The inflammatory IL-23/Th17 pathway is activated in the thymus as well as in the blood and the muscle, contributing to the MG pathogenic events. We aimed to study a potential new therapeutic approach that targets IL-23p19 (IL-23) in the two complementary preclinical MG models: the classical experimental MG mouse model (EAMG) based on active immunization and the humanized mouse model featuring human MG thymuses engrafted in NSG mice (NSG-MG). In both preclinical models, the anti-IL-23 treatment ameliorated MG clinical symptoms. In the EAMG, the treatment reduced IL-17 related inflammation, anti-AChR IgG2b antibody production, activated transduction pathway involved in muscle regeneration and ameliorated the signal transduction at the neuromuscular junction. In the NSG-MG model, the treatment reduced pathogenic Th17 cell population and expression of genes involved in eGC stabilization and B-cell development in human MG thymus biopsies. Altogether, these data suggest that a therapy targeting IL-23p19 may promote significant clinical ameliorations in AChR + MG disease due to concomitant beneficial effects on the thymus and skeletal muscle defects.