Pathogenic autoantibody internalization in myositis.

Area of Science:

• Immunology
• Autoimmune diseases
• Muscle biology

Background:

• Myositis encompasses autoimmune muscle diseases where autoantibodies target intracellular proteins, leaving their pathogenic role unclear.
• Understanding how autoantibodies interact with intracellular targets is crucial for elucidating myositis pathogenesis.

Approach:

• Utilized confocal immunofluorescence microscopy to visualize antibody and autoantigen localization in myositis muscle biopsies.
• Performed bulk RNA sequencing on 668 patient samples (myositis, disease controls, healthy controls) and on patient-derived myoblasts electroporated with myositis autoantibodies.

Key Points:

• Myositis autoantibodies were found to accumulate within muscle fibers, colocalizing with their cognate autoantigens.
• Specific autoantibodies correlated with distinct functional disruptions: anti-Mi2 with gene derepression, anti-PM/Scl with RNA exosome complex dysfunction, and anti-HMGCR with lipid accumulation.
• Electroporation of patient antibodies into cultured myoblasts replicated disease-specific transcriptomic changes.

Conclusions:

• Demonstrated that autoantibodies are internalized into muscle fibers in myositis.
• Established that these internalized autoantibodies disrupt the biological function of their autoantigens.
• Concluded that autoantibody-mediated disruption of autoantigen function is a key mechanism in myositis pathophysiology.