| RRC ID |
88542
|
| Author |
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.
|
| Title |
Interferon-γ controls aquaporin 4-specific Th17 and B cells in neuromyelitis optica spectrum disorder.
|
| Journal |
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.
|
| Volume |
147(4)
|
| Pages |
1344-1361
|
| Published |
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
|
| Resource |
| Mice |
RBRC10053 |
