biostudies-literatureArellano GAmy and David Fulton FoundationThomas and Deige McLaughlin FoundationRottering Family FoundationNIAID NIH HHSNINDS NIH HHSNational Institutes of HealthJohnnie Walkers MS FoundationNIH HHSCrammer Family Foundation1344-1361https://www.ebi.ac.uk/biostudies/studies/S-EPMC10994540biostudies-literatureUnknown147(4)Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (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 signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of Brain : a journal of neurologyInterferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.PMC10994540R21AI151438R21 AI151438R01 NS034939R01 NS099334Kaschke KPodojil JRMiller SDPopko BBalabanov RNeef TArellano GCogswell ACChen YPrimer GWills SJoy GLoda EfalseInterferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.Neuromyelitis optica spectrum disorder (NMOSD) is a CNS autoimmune inflammatory disease mediated by T helper 17 (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 signalling and that IFN-γ depletion in AQP4201-220-immunized C57BL/6 mice results in severe clinical disease resembling human NMOSD. Pathologically, the disease causes autoimmune astrocytic and CNS injury secondary to cellular and humoral inflammation. Immunologically, the absence of IFN-γ allows for increased expression of 2024-01-01T00:00:00Z2024 Apr2026-06-01T03:15:52.671Z2025-04-19T09:58:17.834ZS-EPMC109945403793106610.1093/brain/awad373