Interferon-γ controls aquaporin-4-specific Th17 and B cells in neuromyelitis optica spectrum disorder

Abstract Neuromyelitis Optica Spectrum Disorder (NMOSD) is a central nervous system (CNS) autoimmune inflammatory disease mediated by Th17 and antibody responses to the water channel protein, aquaporin-4 (AQP4), and associated with astrocytopathy, demyelination, and axonal loss. Knowledge about disease pathogenesis is limited and the search for new therapies impeded by the absence of a reliable animal model. In our work, we determined that NMOSD is characterized by decreased IFN-γ receptor signaling and that IFN-γ depletion in AQP4201-220 immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease demonstrates autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, absence of IFN-γ allows for an increased expression of IL-6 in B cells and activation of Th17 cells, and generation of a robust autoimmune inflammatory response. Consistent with NMOSD, the experimental disease is exacerbated by administration of IFN-β, whereas repletion of IFN-γ, as well as therapeutic targeting of IL-17A, IL-6R and B cells ameliorates it. We also demonstrate that immune tolerization with AQP4201-220 -coupled PLGA-nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for development of immune tolerance-based therapies avoiding the limitations of the current immunosuppressive therapies.