Distribution and Temporal Changes of Autoantibody-Mediated Pathogenic Mechanisms Among Acetylcholine Receptor-Positive Myasthenia Gravis Patients

Objective: Given that acetylcholine receptor-positive (AChR+) myasthenia gravis (MG) is mediated by AChR-specific autoantibodies, the emergence of new therapeutics underscores the importance of investigating AChR-specific autoantibody repertoire. This study aimed to assess the distribution of AChR-specific autoantibody isotypes, IgG subclasses, and the pathogenic mechanisms they mediate in AChR+ MG patients. Furthermore, we investigated longitudinal changes in autoantibody repertoire and the associated pathogenic mechanisms. Methods: Serum samples (N=210) from 50 AChR+ generalized MG patients collected longitudinally over two years as part of the B-Cell Targeted Treatment in MG (BeatMG) study were evaluated using a set of cell-based assays. Results: In cross-sectional samples, IgA and IgM AChR-specific autoantibodies were observed in the co-occurrence of IgG in 10% and 12% of patients, respectively. Among them, 4% had all three isotypes. AChR-IgG1 was found in 67.4%, followed by IgG3 (21.7%) and IgG2 (17.4%). Complement was active in 84.8%, followed by AChR internalization (63%) and blocking (30.4%). Complement and AChR internalization were simultaneously active in 45.6%, complement and blocking were active in 10.8%, and all three pathomechanisms were active in 17.4%. Blocking alone was active in only 2.1%; AChR internalization alone was not found. Temporal fluctuations of autoantibody isotypes/ IgG subclasses and the associated pathogenic mechanisms were observed. Interpretation: These results demonstrate that a subset of patients have autoantibodies that can mediate pathogenic mechanisms and include isotypes/IgG subclasses that current therapeutics may not effectively target. Accordingly, defining individual patient AChR-specific autoantibody profiles may afford more accurate application of therapeutics designed to target specific autoantibody-mediated mechanisms.