Yike Jiang1, Estefany Reyes2, Elliot Lin2, Emily Troutman2, Miranda Lumbreras2, Devon DiPalma2, Heather Van Mater1, Mari Shinohara2
1Pediatric, 2Integrative Immunobiology, Duke University
Objective:
The objective of this study was to establish a pediatric MOGAD model that reproduces key clinical features and enables investigation of anti-MOG IgG-mediated immunopathogenesis.
Background:
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a severe, autoantibody-mediated demyelinating syndrome that disproportionally 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 immunopathogenesis that recapitulated (1) early age of disease onset, (2) anti-MOG IgG1 in the serum, and (3) diffuse inflammatory demyelination in the CNS.
Design/Methods:
We employed two complementary approaches to model anti-MOG IgG1: (1) passive transfer of the murine-derived monoclonal antibody 8‑18C5 into young C57BL/6 mice and (2) young transgenic IgHMOG mice expressing the same clonotype endogenously. Experimental autoimmune encephalomyelitis (EAE) was induced by immunization with MOG35-55 to elicit inflammatory demyelination. Immunophenotyping and neuroinflammation were characterized by flow cytometry, confocal microscopy, magnetic resonance imaging (MRI), and in vitro phagocytosis assays.
Results:
Following MOG35-55 immunization, both exogenous and endogenous anti-MOG IgG1 exacerbated EAE disease in young mice. Young IgHMOG mice exhibited reduced peripheral immune cell counts and increased CNS immune infiltration compared to wild-type littermates. IgHMOG mice developed circumferential longitudinal myelitis, bilateral optic neuritis, and multifocal brain inflammation. CNS innate immune cells, including microglia, showed downregulation of surface CD16/CD32, which corresponded with enhanced microglial phagocytosis of MOG in vitro.
Conclusions:
Anti-MOG IgG in EAE recapitulates key aspects of pediatric MOGAD and enables dissection of the mechanisms underlying antibody-mediated immunopathogenesis. Using these models, we identified antibody-mediated microglial phagocytosis of MOG as a novel activity of anti-MOG IgG.
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