論文 - 詳細
| RRC ID | 88542 |
|---|---|
| 著者 | Arellano G, Loda E, Chen Y, Neef T, Cogswell AC, Primer G, Joy G, Kaschke K, Wills S, Podojil JR, Popko B, Balabanov R, Miller SD. |
| タイトル | Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder. |
| ジャーナル | Brain |
| 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. |
| 巻・号 | 147(4) |
| ページ | 1344-1361 |
| 公開日 | 2024-4-4 |
| DOI | 10.1093/brain/awad373 |
| PII | 7335883 |
| PMID | 37931066 |
| PMC | PMC10994540 |
| MeSH | Animals Aquaporin 4 Autoantibodies / metabolism B-Lymphocytes Humans Interferon-gamma / metabolism Mice Mice, Inbred C57BL Neuromyelitis Optica* / pathology |
| IF | 11.337 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 5 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC10053 |