The Balance Between Immune Activation and Tolerance in AQP4 Antibody‐Positive Neuromyelitis Optica Spectrum Disorders and MOG Antibody‐Associated Disease

ABSTRACT Aquaporin‐4 (AQP4) antibody‐positive neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) are distinct autoimmune inflammatory conditions of the central nervous system. Defined autoantigens characterize NMOSD and MOGAD; however, the mechanisms driving immune activation, tissue injury, and breakdown of immune tolerance differ substantially between these conditions. Both conditions reflect a breakdown of immune tolerance mechanisms, permitting the persistence and activation of autoreactive T and B cells. However, NMOSD is characterized by a more clearly defined antibody and complement‐mediated astrocytopathy, whereas MOGAD appears to require synergy with T‐cell‐driven inflammation, with a more variable contribution from complement‐mediated and innate effector pathways. This review summarizes the current understanding of innate and adaptive immune activation and mechanisms of immune tolerance failure in NMOSD and MOGAD and highlights how these features may inform emerging therapeutic strategies.