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_H17 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.