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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-\u03b3 receptor signalling and that IFN-\u03b3 depletion in AQP4201\u2013220-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-\u03b3 allows for 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-\u03b2, whereas repletion of IFN-\u03b3, as well as therapeutic targeting of IL-17A, IL-6R and B cells, ameliorates it. We also demonstrate that immune tolerization with AQP4201\u2013220-coupled poly(lactic-co-glycolic acid) nanoparticles could both prevent and effectively treat the disease. Our findings enhance the understanding of NMOSD pathogenesis and provide a platform for the development of immune tolerance-based therapies, avoiding the limitations of the current immunosuppressive therapies.<\/jats:p>","DOI":"10.1093\/brain\/awad373","type":"journal-article","created":{"date-parts":[[2023,11,6]],"date-time":"2023-11-06T19:51:46Z","timestamp":1699300306000},"page":"1344-1361","source":"Crossref","is-referenced-by-count":29,"title":["Interferon-\u03b3 controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder"],"prefix":"10.1093","volume":"147","author":[{"given":"Gabriel","family":"Arellano","sequence":"first","affiliation":[{"name":"Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eileah","family":"Loda","sequence":"additional","affiliation":[{"name":"Department of Neurology, Feinberg School of Medicine, 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