Humoral signatures of MOG-antibody-associated disease track with age and disease activity
Marianna Spatola, Omar Chuquisana, Wonyeong Jung, Joseph A. Lopez, Eva‐Maria Wendel, Sudarshini Ramanathan, Christian W. Keller, Tim Hahn, Edgar Meinl, Markus Reindl, Russell C. Dale, Heinz Wiendl, Douglas A. Lauffenburger, Kevin Rostásy, Fabienne Brilot, Galit Alter, Jan D. Lünemann
Abstract
Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is an inflammatory demyelinating disease of the CNS. Although MOG is encephalitogenic in different mammalian species, the mechanisms by which human MOG-specific Abs contribute to MOGAD are poorly understood. Here, we use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features 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 (FcγRs), capacity to activate innate immune cells, and decreased frequencies of galactosylated and sialylated immunoglobulin G (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 suggest that FcγR-targeting therapies should be explored for their therapeutic potential in MOGAD.