The emerging role of B cells in immune-mediated demyelinating diseases: mechanisms and therapeutic implications

Abstract

Immune-mediated demyelinating diseases of the central nervous system, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), are unified by inflammatory injury to myelin and axons but differ fundamentally in their immunopathological mechanisms. Adaptive immune cells, particularly B cells and T cells, are central drivers of disease, contributing through both antibody-dependent and antibody-independent mechanisms. In MS, B cells exacerbate pathology via antigen presentation, cytokine secretion, and organization of ectopic lymphoid structures, consistent with the efficacy of anti-CD20 therapies despite largely preserved circulating immunoglobulin levels. In NMOSD, B cells and plasma cell progeny play a direct pathogenic role through aquaporin-4–specific (AQP-4) antibodies, establishing a model of antibody-mediated astrocytopathy. MOGAD occupies an intermediate immunopathological niche, with pathogenic antibodies targeting myelin oligodendrocyte glycoprotein (MOG) coexisting with additional, incompletely defined immune mechanisms. Recent advances from single-cell profiling, high-resolution imaging, and experimental models suggest substantial heterogeneity in B-cell developmental states, tolerance checkpoints, and tissue residency, challenging uniform approaches to B-cell–directed therapy. This review synthesizes current understanding of B-cell biology across demyelinating diseases, highlighting mechanisms of pathogenicity, immune regulation, and tolerance failure, and discusses implications for precision immunomodulatory strategies.