Immuno-pathogenesis of neuromyelitis optica and emerging therapies

Neuromyelitis optica (NMO) is an inflammatory disease that resembles MS in the relapsing clinical course of optic neuritis and myelitis. Two decades of studies have revealed that autoantibodies, reactive to the water channel protein aquaporin 4 (AQP4) are detected in the core group of patients. These autoantibodies play a crucial role in the inflammatory pathology of NMO, involving proinflammatory cytokines, chemokines, and various inflammatory cells such as Th17 cells. Anti-AQP4 antibody–positive NMO differs fundamentally from MS, particularly in the responsiveness to therapies and the neuropathology accompanying destruction of astrocytes. Research into the immunological mechanism has led to the identification of possible targets of therapy, including complement pathway and interleukin-6 (IL-6) receptor signaling. Recent randomized controlled clinical trials have shown the remarkable efficacy of antibodies specific for complement C5, IL-6 receptor, and CD19+ B cells in prevention of NMO spectrum disorder relapses, although no such effects were found in anti-AQP4 antibody–negative patients. These results imply that anti-AQP4 antibody is a biomarker predicting the efficacy of therapies, and indicate the future direction towards “precision medicine.”