Anti-MOG IgG in EAE models clinical aspects of pediatric MOGAD.

INTRODUCTION: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a severe, autoantibody-mediated neuroinflammatory syndrome that disproportionately impacts children. Detection of conformation-specific anti-MOG IgG1 in the serum is central to MOGAD diagnosis, yet the pathogenic role of these antibodies remains unclear. We sought to develop a clinically informed model of pediatric MOGAD to study the immunopathogenesis that recapitulates 1) early age of disease onset, 2) anti-MOG IgG1 in serum, and 3) widespread inflammation in the CNS. METHODS: We employed two approaches to model MOGAD using anti-MOG IgG in mice: 1) treating young C57BL/6 mice with the murine-derived monoclonal MOG antibody 8-18C5, and 2) using young IgHMOG transgenic (Tg) mice, engineered to express the immunoglobulin heavy chain of 8-18C5. These mice were induced with experimental autoimmune encephalomyelitis (EAE) by immunizing with MOG35-55 to elicit inflammatory demyelination. RESULTS: Both exogenous and endogenous anti-MOG IgG exacerbated EAE disease in young mice. Compared to wild-type littermates (+/+), young IgHMOG Tg mice (Tg/+) exhibited reduced peripheral immune cells and greater neutrophil-to-lymphocyte ratios. Tg/+ mice also had increased CNS leukocyte infiltration compared to wild-type littermates. Tg/+ mice developed monophasic circumferential longitudinal myelitis, bilateral optic neuritis, and multifocal brain inflammation. Innate immune cells in the CNS, including microglia, showed significant downregulation of surface FcγRII/III. This downregulation on microglia was accompanied by enhanced uptake of cells expressing MOG, suggesting Fc receptor-mediated internalization of MOG immune complexes. DISCUSSION: Introduction of anti-MOG IgG in EAE recapitulates key aspects of pediatric MOGAD and enables dissection of the mechanisms underlying anti-MOG antibody-mediated immunopathogenesis.

Duke Scholars

Author Mari L. Shinohara Integrative Immunobiology

Author Yike Jiang Pediatrics, Rheumatology

Author Heather Ann Van Mater Pediatrics, Rheumatology