IFN-γ and IL-17A can each elicit ocular autoimmunity independently of the other. Since absence of IFN-γ or IL-17A individually failed to abolish pathology of experimental autoimmune uveitis (EAU), we examined EAU development in the absence of both these cytokines. Ifng^−/−Il17a^−/− mice were fully susceptible to EAU with a characteristic eosinophilic ocular infiltrate, as opposed to a mononuclear infiltrate in WT mice. Retinal pathology in double-deficient mice was ameliorated when eosinophils were genetically absent or their migration was blocked, supporting a pathogenic role for eosinophils in EAU in the concurrent absence of IFN-γ and IL-17A. In EAU-challenged Ifng^−/−Il17a^−/− mice, ocular infiltrates contained increased GM-CSF-producing CD4⁺ T cells, and supernatants of retinal antigen-stimulated 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, reduced eosinophil peroxidase levels in the eye and in the serum and decreased eosinophil infiltration to the eye. These results support the interpretation that, in the concurrent absence of IFN-γ and IL-17A, GM-CSF takes on a major role as an inflammatory effector cytokine and drives an eosinophil-dominant pathology. Our findings may impact therapeutic strategies aiming to target IFN-γ and IL-17A in autoimmune uveitis.

IFN-γ 和 IL-17A 可以各自独立地引发眼部自身免疫。由于单独缺乏 IFN-γ 或 IL-17A 未能消除实验性自身免疫性葡萄膜炎 (EAU) 的病理学，我们在缺乏这两种细胞因子的情况下检查了 EAU 的发展。Ifng ^-/- Il17a ^{- /-}小鼠对 EAU 完全敏感，具有特征性的嗜酸性眼浸润，与 WT 小鼠的单核浸润相反。当嗜酸性粒细胞在遗传上不存在或它们的迁移被阻断时，双缺陷小鼠的视网膜病理得到改善，支持在同时缺乏 IFN-γ 和 IL-17A 的情况下，嗜酸性粒细胞在 EAU 中的致病作用。在 EAU 挑战的Ifng ^-/- Il17a ^-/-对于小鼠，眼部浸润物含有增加的产生 GM-CSF 的 CD4 ⁺ T 细胞，并且视网膜抗原刺激的脾细胞上清液含有增加的 GM-CSF 水平，这有助于体外嗜酸性粒细胞的激活和迁移。GM-CSF 的全身或局部阻断改善了Ifng ^-/- Il17a ^{-/- 中的}EAU小鼠，眼睛和血清中的嗜酸性粒细胞过氧化物酶水平降低，嗜酸性粒细胞向眼睛的浸润减少。这些结果支持这样的解释，即在 IFN-γ 和 IL-17A 不存在的情况下，GM-CSF 作为炎症效应细胞因子发挥主要作用，并驱动嗜酸性粒细胞占主导地位的病理。我们的发现可能会影响针对自身免疫性葡萄膜炎中 IFN-γ 和 IL-17A 的治疗策略。