Year: 2023
Type: article
Abstract: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an inflammatory demyelinating CNS condition characterized by the presence of MOG autoantibodies. We sought to investigate whether human MOG autoantibodies are capable of mediating damage to MOG-expressing cells through multiple mechanisms. We developed high-throughput assays to measure complement activity (CA), complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cellular cytotoxicity (ADCC) of live MOG-expressing cells. MOGAD patient sera effectively mediate all of these effector functions. Our collective analyses reveal that (a) cytotoxicity is not incumbent on MOG autoantibody quantity alone; (b) engagement of effector functions by MOGAD patient serum is bimodal, with some sera exhibiting cytotoxic capacity while others did not; (c) the magnitude of CDC and ADCP is elevated closer to relapse, while MOG-IgG binding is not; and (d) all IgG subclasses can damage MOG-expressing cells. Histopathology from a representative MOGAD case revealed congruence between lesion histology and serum CDC and ADCP, and we identified NK cells, mediators of ADCC, in the cerebrospinal fluid of relapsing patients with MOGAD. Thus, MOGAD-derived autoantibodies are cytotoxic to MOG-expressing cells through multiple mechanisms, and assays quantifying CDC and ADCP may prove to be effective tools for predicting risk of future relapses.
Source: JCI Insight
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: National Multiple Sclerosis Society, Bristol-Myers Squibb, AstraZeneca, Yale University, Biogen, Alexion Pharmaceuticals, Guthy-Jackson Charitable Foundation, CSL Behring, TG Therapeutics, Georgia Clinical and Translational Science Alliance, Argenx, NGM Biopharmaceuticals, Horizon Therapeutics, Multiple Sclerosis Society, Narodowym Centrum Nauki, Narodowa Agencja Wymiany Akademickiej, Grifols, National Institutes of Health, Genentech, EMD Serono, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences
Awards: G1044130170, G161547206, G3234714797, G3426671974, G3615449143, G431889876, G649594342, Defining the autoimmune mechanisms driving human MOG antibody disease pathology, G6887224063, Molecular determinants driving diverse mechanisms of antibody-mediated pathology, G846228670, The Radiologically Isolated Syndrome in Children, G9000041528, G9000193685, G9000203077, Rare Disease Network for Myasthenia Gravis, Yale Clinical and Translational Science Award, Mechanisms of autoimmunity in myasthenia gravis
OpenAlex ID: W4366983161