To systematically profile the biochemical and functional landscape of human Myelin oligodendrocyte glycoprotein (MOG)-antibodies (Abs) in pediatric and adult patients diagnosed with MOG-Ab-associated disease (MOGAD) using an unbiased, high-throughput systems serology platform and to identify humoral correlates for human MOG-Ab associated clinical disease features.

MOGAD is an inflammatory demyelinating disease of the central nervous system. Although MOG is encephalitogenic in different mammalian species, the mechanisms by which human MOG-specific Abs contribute to MOGAD are poorly understood.

A systems-level approach combined with high-dimensional characterization of Ab-associated immune features was employed to deeply profile humoral immune responses in 123 patients with MOGAD.

We show that age is a major determinant for MOG-antibody related immune signatures. Unsupervised clustering additionally identifies two dominant immunological endophenotypes of MOGAD. The pro-inflammatory endophenotype characterized by increased binding affinities for activating Fcγ receptors (FcγR), capacity to activate innate immune cells, and decreased frequencies of galactosylated and sialylated IgG glycovariants is associated with clinically active disease.

Our data support the concept that FcγR-mediated effector functions control the pathogenicity of MOG-specific IgG and suggests that FcγR-targeting therapies should be explored for their therapeutic potential in MOGAD.