视神经脊髓炎
免疫学
发病机制
医学
免疫系统
多发性硬化
自身免疫性疾病
炎症
光谱紊乱
水通道蛋白4
疾病
白细胞介素17
抗体
病理
精神科
作者
Gabriel Arellano,Eileah Loda,Yanan Chen,Tobias Neef,Andrew C. Cogswell,Grant Primer,Godwin Joy,Kevin Kaschke,Samantha M. Wills,Joseph R. Podojil,Brian Popko,Roumen Balabanov,Stephen D. Miller
出处
期刊:Brain
[Oxford University Press]
日期:2023-11-01
卷期号:147 (4): 1344-1361
被引量:4
标识
DOI:10.1093/brain/awad373
摘要
Abstract 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.
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