Background/Purpose: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a devastating demyelinating disease that disproportionally affects children. Discovered in 2018, MOGAD is now internationally recognized as distinct from other autoimmune demyelinating conditions like multiple sclerosis and neuromyelitis optica. The clinical presentation of MOGAD is highly variable, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis (ADEM), cerebral cortical encephalitis, and FLAIR-hyperintense lesions in anti-MOG-associated encephalitis with seizures (FLAMES). The diagnosis of MOGAD requires detecting serum IgG1 to MOG in its conformational form using cell-based assays. However, the pathologic role of anti-MOG IgG1 is unclear, and there is a critical need for models of pediatric MOGAD to study immunopathogenesis. Our objective is to establish animal models of pediatric MOGAD. We sought to recapitulate three core aspects of pediatric MOGAD in our model system: 1) inflammatory demyelination in the CNS, 2) anti-MOG IgG1 in the serum, and 3) early age of onset.

Methods: We used two animal models using 4-5 week-old mice: The first model is to immunize C57BL/6 (B6) mice with MOG_35-55 peptide along with IV injection of anti-MOG IgG1 (8-18C5), and the second model is to immunize IgH^MOG mice, MOG-specific Ig heavy-chain knock-in mice, with MOG_35-55 peptide. We established a flow cytometric cell-based assay to measure conformation-specific anti-MOG, paralleling the clinical test. We performed immunofluorescent microscopy to measure demyelination and flow cytometry to measure CNS immune infiltration.

Results: For the first B6 model, a single injection of anti-MOG IgG1 exacerbates EAE score with worse demyelination in the spinal cord and optic nerves. Because MOG immunization did not enhance anti-MOG IgG1 generation, the phenotype was attributed to the injection of anti-MOG IgG1. For the second IgH^MOG mice model, IgH^MOG mice showed an earlier disease onset and a greater degree of demyelination in the spinal cord, compared to wild-type mice. IgH^MOG also has greater retinal swelling, as analyzed by optical coherence tomography (OCT), recapitulating a human MOGAD clinical finding. At the peak of EAE score, IgH^MOG mice have increased infiltration of CD4⁺ and CD8⁺ T lymphocytes and NK cells in the brain and optic nerves.    

Conclusion: Exacerbated EAE scores and optic nerve inflammation in mice with enhanced anti-MOG IgG1 in two animal models recapitulated core aspects of pediatric MOGAD. Using these models, we will further analyze MOGAD phenotypes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/animal-models-of-pediatric-mogad/