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Discovery of the immunoglobulin G autoantibody involved in neuromyelitis optica (NMO-IgG) introduced the first clinically validated disease-specific biomarker for an inflammatory autoimmune demyelinating disease of the central nervous system (CNS). The astrocytic water channel aquaporin-4 (AQP4) is the antigen. Some, but not all, evidence suggests that NMO-IgG is directly involved in the pathogenesis of NMO spectrum disorders. Investigation of NMO-IgG's effects on living cells that express surface-membrane AQP4 (J Exp Med 2008; 205:2473 and J Immunol 2008; 181:5730) has revealed that NMO-IgG binds to the extracellular domain of AQP4, producing multiple outcomes: (1) AQP4 endocytosis/degradation and coupled glutamate transporter loss; (2) co…