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

• Published in: Brain (London, England : 1878) Vol. 147; no. 4; pp. 1344 - 1361
• Main Authors: Arellano, Gabriel, Loda, Eileah, Chen, Yanan, Neef, Tobias, Cogswell, Andrew C, Primer, Grant, Joy, Godwin, Kaschke, Kevin, Wills, Samantha, Podojil, Joseph R, Popko, Brian, Balabanov, Roumen, Miller, Stephen D
• Format: Journal Article
• Language: English
• Published: England 04.04.2024
• Subjects: Animals; Aquaporin 4; Autoantibodies - metabolism; B-Lymphocytes; Humans; Interferon-gamma - metabolism; Mice; Mice, Inbred C57BL; Neuromyelitis Optica - pathology; immune tolerance; interferon-γ; animal model; neuromyelitis optica spectrum disorder; aquaporin 4
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awad373

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 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 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.