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

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.