Aquaporin-4 in Neuromyelitis Optica Spectrum Disorders: A Target of Autoimmunity in the Central Nervous System

Since the discovery of a specific autoantibody in patients with neuromyelitis optica spectrum disorder (NMOSD) in 2004, the water channel aquaporin-4 (AQP4) has attracted attention as a target of autoimmune diseases of the central nervous system. In NMOSD, the autoantibody (NMO-IgG) binds to the extracellular loops of AQP4 as expressed in perivascular astrocytic end-feet and disrupts astrocytes in a complement-dependent manner. NMO-IgG is an excellent marker for distinguishing the disease from other inflammatory demyelinating diseases, such as multiple sclerosis. The unique higher-order structure of AQP4-called orthogonal arrays of particles (OAPs)-as well as its subcellular localization may play a crucial role in the pathogenesis of the disease. Recent studies have also demonstrated complement-independent cytotoxic effects of NMO-IgG. Antibody-induced endocytosis of AQP4 has been suggested to be involved in this mechanism. This review focuses on the binding properties of antibodies that recognize the extracellular region of AQP4 and the characteristics of AQP4 that are implicated in the pathogenesis of NMOSD.

Automated summary

The discovery of NMO-IgG in patients with neuromyelitis optica spectrum disorder (NMOSD) has highlighted the importance of the water channel aquaporin-4 (AQP4) in autoimmune diseases of the central nervous system. The unique structure of AQP4 and its subcellular localization may play a crucial role in the pathogenesis of NMOSD, in addition to the complement-dependent cytotoxic effects of NMO-IgG. Studies have also shown complement-independent cytotoxic effects of NMO-IgG, potentially involving antibody-induced endocytosis of AQP4.