NMOSD: Adaptive Immunity Revisited

ABSTRACT Accumulating evidence underscores the pivotal role of adaptive immunity in the pathogenesis of AQP4‐IgG‐positive neuromyelitis optica spectrum disorder (NMOSD). Autoreactive B cells produce pathogenic antibodies against aquaporin‐4 (AQP4), and their dysregulation is evident in both peripheral blood and cerebrospinal fluid. These abnormalities include an increased frequency of plasmablasts and the expansion of atypical B‐cell subsets enriched for autoreactivity. Their activation and survival are supported by inflammatory cytokines such as interleukin‐6 (IL‐6), a key target of current immunotherapies. T‐cell subsets, including follicular helper T (Tfh) cells and Th17 cells, play essential roles by promoting B‐cell differentiation and amplifying inflammation. The interplay between B and T cells, together with cytokine dysregulation, constitutes a central immunopathogenic axis in NMOSD. Notably, some disease‐modifying therapies for multiple sclerosis have been shown to worsen NMOSD, suggesting fundamental differences in the underlying immune dynamics between the two diseases. This contrast highlights the need for disease‐specific therapeutic approaches and a deeper understanding of adaptive immune processes unique to NMOSD. Here, we revisit the immunopathogenesis of AQP4‐IgG‐positive NMOSD with a focus on adaptive immune mechanisms. We discuss current evidence on B‐ and T‐cell abnormalities, intrathecal immune responses, and how these insights have informed the development of targeted therapies.