AChR Autoantibody Pathogenic Properties Are Heterogeneously Distributed and Undergo Temporal Changes Among Patients...

Area of Science:

• Immunology
• Neurology
• Autoimmune Diseases

Background:

• Acetylcholine receptor (AChR) autoantibodies drive myasthenia gravis (MG) pathogenesis via complement activation, receptor internalization, and ACh binding site blockade.
• Current therapies target these autoantibodies by inhibiting complement or blocking the neonatal Fc receptor (FcRn), but have limitations in addressing all pathogenic mechanisms or antibody types.

Purpose of the Study:

• To investigate the heterogeneity of AChR autoantibody pathogenic mechanisms, isotypes, and IgG subclasses in generalized MG patients.
• To understand how these autoantibody characteristics vary longitudinally and potentially correlate with disease severity.

Main Methods:

• Utilized advanced live cell-based assays to analyze serum samples from 50 generalized MG patients over two years.
• Assessed complement activation, AChR internalization, ACh binding site blockade, and the presence of IgA, IgM, and IgG subclasses (IgG1, IgG2, IgG3).

Main Results:

• A significant portion of patients exhibited co-occurring IgA and IgM autoantibodies alongside IgG.
• Complement activation and AChR internalization were the most prevalent pathogenic mechanisms, often co-occurring.
• Autoantibody binding capacity correlated with complement activation and AChR internalization; temporal fluctuations were observed.

Conclusions:

• Identified distinct patient subsets with MG characterized by specific autoantibody profiles and pathogenic mechanisms that may not be fully addressed by current therapies.
• Recommended comprehensive autoantibody profiling in clinical trials to explore associations with treatment responses in MG.