MuSK myasthenia gravis: from antigen-antibody to clinical translation.

Anti-MuSK antibody-positive myasthenia gravis (MuSK-MG) is characterized by severe and potentially life-threatening weakness. Anti-MuSK antibodies are key pathogenic drivers of this disorder. This review provides a comprehensive summary of the current state-of-the-art with respect to the understanding of MuSK and its role in MuSK-MG. MuSK, a receptor tyrosine kinase, is essential at the neuromuscular junction, where it forms an agrin-LRP4-MuSK tripartite functional complex that initiates and maintains agrin-induced acetylcholine receptor clustering at the postsynaptic membrane. Although anti-MuSK antibodies encompass all IgG subclasses (IgG1-4), IgG4 is the predominant pathogenic subclass. In vivo, IgG4 antibodies undergo Fab-arm exchange, acquiring functional monovalency; this monovalent IgG4 disrupts LRP4-MuSK interactions, thereby blocking downstream signaling and precipitating myasthenic symptoms. Emerging evidence indicates that IgG1-3 anti-MuSK antibodies are also pathogenic, although some clones exhibit agonistic effects on MuSK phosphorylation. Further, this review examines the various diagnostic methods for this condition and weighs the advantages and disadvantages. Both MuSK protein and its autoantibodies are pivotal for diagnosis and therapy. Radioimmunoprecipitation assays and enzyme-linked immunosorbent assays and their benefits ad limitations are discussed, and cell-based assays are noted for their high accuracy. Anti-MuSK antibody testing is the gold standard diagnostic biomarker. Finally, the review covers the various therapeutic strategies for MuSK-MG, including immunosuppressants, monoclonal antibodies, CAR-T cell therapy, and neonatal Fc receptor blockade. B-cell-targeted therapies (e.g., anti-CD20 monoclonal antibodies) and MuSK agonists represent promising future therapeutic strategies for MuSK-MG. Overall, this review provides a definitive summary of the present practices and future strategies for the diagnosis and treatment of MuSK-MG, laying out clear markers for further studies that have to be undertaken to enhance our understanding of this condition.