Heterogeneity in autoimmune myasthenia gravis: classifying disease variants by unique immune mechanisms to inform personalized therapeutic strategies

About This Grant

Project Summary. Myasthenia gravis (MG) is an autoimmune disorder that impairs neuromuscular transmission, leading to muscle weakness and fatigue. In about 80% of cases, the disease is driven by autoantibodies targeting the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction (NMJ). While MG is traditionally attributed to IgG autoantibodies that mediate pathology through complement activation, receptor blockade, and AChR internalization, this project focuses on the less-studied role of IgM autoantibodies in AChR-positive MG. Our work rests on our preliminary data that shows the existence of distinct MG subtypes characterized by pathogenic, AChR-specific IgM autoantibodies. We hypothesize that the unique features of IgM—such as its pentameric structure and high avidity—enable it to efficiently drive disease mechanisms. This may help explain why some patients do not respond to IgG-targeted therapies like neonatal Fc receptor (FcRn) inhibitors. By investigating IgM, the study aims to redefine MG subtypes and identify mechanisms relevant to treatment-resistant cases. The project has two main goals: The first, is the molecular characterization of AChR- specific IgM autoantibodies. This includes generating recombinant human monoclonal antibodies from patient B cell subsets to assess their binding specificity, epitope targets, and genetic features, as well as define the B cell phenotype where they are expressed. The second goal focuses on mechanistic investigation of IgM-driven pathology using cell-based assays to evaluate complement activation, AChR blockade, and receptor internalization. This investigation aims to establish IgM-associated MG as a distinct clinical and immunological subset, providing new diagnostic markers and therapeutic targets. By moving beyond the IgG-centric framework, this work is anticipated to lead to personalized, mechanism-based treatments for patients with MG.