NMOSD: Innate Immunology Revisited

ABSTRACT Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune/inflammatory disease of the central nervous system (CNS) that causes severe neurological deficits, including optic neuritis and longitudinally extensive myelitis. The autoantigen of NMOSD is the water channel “aquaporin‐4 (AQP4),” which is highly expressed in the endfeet of astrocytes, the ependymal cell lining of the ventricles, and Müller cells in the retina throughout the CNS. AQP4‐IgG autoantibodies produced by peripheral plasmablasts/plasma cells can cross the blood–brain barrier and primarily damage astrocytes, leading to secondary demyelination and axonal injury. The mechanism of AQP4 antibody‐guided CNS injury ‘AQP4‐opathy’ in NMOSD is mainly complement‐dependent cytotoxicity, but it can also be attributed to antibody‐dependent cellular cytotoxicity or AQP4 internalization. Moreover, recent research has demonstrated that stage‐dependent immune dynamics orchestrate AQP4 antibody‐guided lesions as follows: adaptive immune elements, including AQP4 autoantibodies with activated T H 17 cells, could form AQP4‐opathy specific to NMOSD, synchronizing with the activation of innate immune dynamics, including complements, granulocytes, and microglia/macrophages in active phases. In particular, activated neutrophils with extracellular traps and tissue‐resident memory T cells expressing granzyme B infiltrate during the initial and early active phases of NMOSD. These immune cells may be involved in lesion expansion and trigger relapses in cooperation with active AQP4 antibody‐guided NMOSD pathology. These newly identified insights will lead to a better understanding of innate immunology and novel therapeutic strategies for NMOSD.