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Benjamin C. Chaon, Reiko Horai, Jun Chen, Carlos Zárate-Bladés, Rafael Villasmil, Chi-Chao Chan, Rachel R. Caspi; The Role of Interleukin-17A in a Spontaneous Model of Autoimmune Uveitis Elicited by Retina-specific T Cells. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6307.
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Th17 cells and their cytokine product, IL-17A, have been implicated as major pathogenic mediators in autoimmune disease models induced by immunization with self-antigen, including uveitis. Recently, we generated transgenic (R161H) mice that express a T cell receptor (TCR) specific to the retinal protein IRBP and spontaneously develop uveitis by 2 months of age. This study aims to examine the importance of Th17 cells and IL-17A to the pathogenesis of uveitis in this spontaneous model.
R161H mice were crossed to IL-17A KO mice (R161H-17KO) or to IL-17A-GFP reporter mice (R161H-17Agfp) all on the B10.RIII background. IRBP-specific T cells were detected using an IRBP161-180/I-Ar/IgG1 dimer. Disease was monitored by weekly fundoscopy and confirmed by histology. Lymphocyte proliferation was measured by [3H]-Thymidine incorporation. Flow cytometry and ELISA were used to quantify cytokine production.
IL-17A-GFP+ cells were detected ex vivo in the uveitic eyes and lymph nodes of R161H-17Agfp mice. The majority of ocular infiltrating IL-17A-GFP+ cells were CD4+, exhibited a memory (CD62LlowCD44high) phenotype, and expressed the Th17-associated chemokine receptor, CCR6. Interestingly, CCR6+ IL-17A-GFP+ cells were also enriched in the intestinal lamina propria of R161H mice compared to normal wild-type littermates, and a proportion of these IL-17A GFP+ cells appeared to be IRBP-specific by dimer staining. Notably, R161H-17KO mice showed a slower disease development, but no apparent reduction in final scores compared to their R161H IL-17A sufficient littermates. Ex vivo analysis of eye-infiltrating and peripheral lymphocytes confirmed the absence of IL-17A producing cells in R161H-17KO mice. A compensatory increase in IRBP-induced IL-17F, but not IFN-γ production, was observed in R161H-17KO mice compared to IL-17A-sufficient controls.
IL-17A is produced by IRBP-specific T cells in spontaneous uveitis and may contribute to disease. Notably, IRBP-specific Th17 cells are present not only in the eye but also in the intestinal lamina propria, suggesting a crosstalk between the gut and the eye in pathogenesis of uveitis. Nevertheless, IL-17A appears to be dispensable in this spontaneous uveitis model as normal levels of IFN-γ and/or increased IL17F may be sufficient to drive disease in its absence.
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