W111 - Individual Myasthenia Gravis Autoantibodies Can Mediate Three Distinct Mechanisms of Pathology

Gianvito Masi, MD – Neurology and Immunobiology – Yale University; Abeer Obaid, BS – Neurology and Immunobiology – Yale University; Rosa Patzina – Neurology and Immunobiology – Yale University; Seneca Oxendine, BS – Neurology and Immunobiology – Yale University; Sangwook Oh, PhD – Dermatology – University of Pennsylvania; Aimee Payne, MD, PhD – Dermatology – University of Pennsylvania; Richard Nowak, MD – Neurology – Yale University; Kevin O'Connor – Neurology and Immunobiology – Yale University

Abstract Text: Serum autoantibodies targeting the acetylcholine receptor (AChR) in autoimmune myasthenia gravis (MG) can mediate pathology via three distinct mechanisms: complement activation, receptor blockade, and antigenic modulation. However, it is unclear whether multi-pathogenicity is mediated by individual or multiple autoantibody clones. Using an unbiased B cell screening approach, we generated a library of 11 human-derived AChR-specific monoclonal autoantibodies (mAb) and assessed their pathogenic profiles. Five mAbs activated complement, 3 blocked the receptor, and 7 induced modulation. Furthermore, 2 mAbs were each highly efficient at all three mechanisms, demonstrating that pathogenic mechanisms are not mutually exclusive. Using novel cell lines individually expressing each AChR subunit (α2βδε), triple-pathogenic mAbs were determined to exclusively bind the α subunit, demonstrating a link between mAb specificity and pathogenic mechanism. These findings provide new insight into the immunopathology of MG, demonstrating that single autoreactive clones can efficiently mediate three modes of pathology. Therapeutic approaches targeting only one autoantibody-mediated mechanism may be evaded by mAbs with multifaceted pathogenicity.