Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
J Autoimmun. 2020 Nov;114:102507. doi: 10.1016/j.jaut.2020.102507. Epub 2020 Jun 24.
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. IfngIl17a 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 IfngIl17a 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 IfngIl17a 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 各自均可引发眼自身免疫，而不依赖于另一种细胞因子。由于单独缺乏 IFN-γ 或 IL-17A 均未能消除实验性自身免疫性葡萄膜炎 (EAU) 的病变，我们研究了在缺乏这两种细胞因子的情况下 EAU 的发展情况。与 WT 小鼠中的单核细胞浸润相反，IfngIl17a 小鼠对 EAU 具有完全易感性，表现为嗜酸性粒细胞浸润的眼部病变。在缺乏 IFN-γ 和 IL-17A 的情况下，当嗜酸性粒细胞被基因缺失或其迁移被阻断时，双缺陷小鼠的视网膜病变得到改善，这支持嗜酸性粒细胞在 EAU 中的致病性作用。在受到 EAU 挑战的 IfngIl17a 小鼠中，眼内浸润物中含有更多产生 GM-CSF 的 CD4 T 细胞，并且视网膜抗原刺激的脾细胞上清液中含有更高水平的 GM-CSF，这些 GM-CSF 有助于嗜酸性粒细胞在体外的激活和迁移。GM-CSF 的全身性或局部阻断可改善 IfngIl17a 小鼠的 EAU，降低眼内和血清中的嗜酸性粒细胞过氧化物酶水平，并减少嗜酸性粒细胞向眼内的浸润。这些结果支持以下解释：在缺乏 IFN-γ 和 IL-17A 的情况下，GM-CSF 作为一种炎症效应细胞因子发挥主要作用，并驱动以嗜酸性粒细胞为主的病变。我们的研究结果可能会影响旨在针对自身免疫性葡萄膜炎的 IFN-γ 和 IL-17A 的治疗策略。
