Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.161003.
Abstract
Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory autoimmune disorders of the CNS. Immunoglobulin G autoantibodies targeting the aquaporin-4 water channel (AQP4-IgG) are the pathogenic effector of NMOSD. Dysregulated T follicular helper (Tfh) cells have been implicated in the loss of B-cell tolerance in autoimmune diseases. The contribution of Tfh cells to disease activity and the therapeutic potential of targeting these cells in NMOSD remain unclear. Here, we established an autoimmune model of NMOSD by immunizing mice against AQP4 via in vivo electroporation. After AQP4 immunization, mice displayed AQP4 autoantibodies in the blood circulation, blood-brain barrier disruption, and IgG infiltration in the spinal cord parenchyma. Moreover, AQP4 immunization induced motor impairments and NMOSD-like pathologies including astrocytopathy, demyelination, axonal loss, and microglia activation. These were associated with increased splenic Tfh, T helper 1 (Th1) and T helper 17 (Th17) cells, memory B cells and plasma cell. AQP4-deficient mice did not displayed motor impairments and NMOSD-like pathologies after AQP4 immunization. Importantly, abrogating inducible costimulator (ICOS)/inducible costimulator ligand (ICOS-L) signalling using anti-ICOS-L antibody depleted Tfh cells and suppressed the response of Th1 and Th17 cells, memory B cells, and plasma cells in AQP4-immunized mice. These findings were associated with ameliorated motor impairments and spinal cord pathologies. This study suggests a role of Tfh cells in the pathophysiology of NMOSD in a novel mouse model with AQP4 autoimmunity. It also provides an animal model for further investigating the immunological mechanisms underlying AQP4 autoimmunity, and for developing novel therapeutic interventions targeting the autoimmune reactions in NMOSD.
Authors
Leung-Wah Yick, Oscar Ka-Fai Ma, Ethel Yin-Ying Chan, Krystal Xiwing Yau, Jason Shing-Cheong Kwan, Koon-Ho Chan
