Abstract Autoimmune uveitis is a group of blinding diseases triggered by activated retina-specific T cells. Studies in uveitis patients and experiments in animal models of experimental autoimmune uveitis (EAU) support the notion that Th1 and Th17 cells are both pathogenic effectors and each can elicit ocular autoimmunity independently of the other. Since absence of IFN-γ or IL-17A individually failed to abolish pathology of EAU, we examined EAU development in the absence of both cytokines. Ifng−/−Il17a−/− mice were fully susceptible to EAU and displayed eosinophil-dominant ocular infiltrates, as opposed to mononuclear infiltrates in WT mice. EAU was ameliorated in double-deficient mice when eosinophils were genetically absent or their migration was blocked, supporting a pathogenic role of eosinophils in the absence of both IFN-γ and IL-17A. In Ifng−/−Il17a−/− mice immunized for EAU, ocular infiltrates contained increased GM-CSF-producing CD4 T cells, and supernatants of antigen-recalled splenocytes contained enhanced levels of GM-CSF that contributed to activation and migration of eosinophils in vitro. Systemic or local blockade of GM-CSF ameliorated EAU in Ifng−/−Il17a−/− mice. Neutralization of GM-CSF during the induction phase of EAU decreased eosinophil infiltration to the eye and eosinophil peroxidase levels in the eye and in the serum. These results support the interpretation that, in the concurrent absence of IFN-γ and IL-17A, GM-CSF takes on a major role as a pathogenic effector cytokine and induces an eosinophil-dominant pathology. This may impact therapeutic strategies aiming to target IFN-γ and IL-17A in autoimmune uveitis.
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