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Reiko Horai, So Jin Bing, Phyllis B Silver, Yingyos Jittayasothorn, Jun Chen, Rachel R Caspi; Dependence of pathogenic cytokines differs between spontaneous and induced models of autoimmune uveitis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2542.
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© ARVO (1962-2015); The Authors (2016-present)
Autoimmune uveitis is a group of blinding diseases thought to be driven by activated retina-specific T cells. Studies in uveitis patients and experiments in animal models support the notion that both Th1 and Th17 cells are pathogenic effectors, although some cytokines produced by these subsets can also be protective. To better understand how the pathogenic Th1 or Th17 effectors and their respective signature cytokines, IFN-γ or IL-17A, contribute to pathogenesis of uveitis, we in parallel analyzed an immunization induced model of experimental autoimmune uveitis (EAU) and the IRBP-specific TCR transgenic spontaneous uveitis model (R161H).
EAU was induced by immunization with IRBP protein and/or peptides. Mice deficient in IL-17A (17AKO), or IFN-γ (GKO), or both (DKO) on the C57BL/6 background were backcrossed onto the B10.RIII background before the introgression of IRBP-specific R161H TCR. Cytokine deficient or sufficient R161H T cells were activated with IRBP peptide before adoptive transfer into naïve recipient mice. Uveitis was examined by fundoscopy and histology. Ocular infiltrates were characterized by flow cytometry. Differential gene expression in CD4 T cells was assessed by Nanostring and real-time PCR.
Adoptive transfer of in vitro polarized R161H T cells showed that IL-17A-deficient Th17 cells maintained pathogenicity, but IFN-γ-deficient Th1 cells were less pathogenic. Spontaneous uveitis was attenuated by lack of these cytokines in all three mutant strains, with similar onset in R161H-17AKO mice to control R161H mice, and with delayed onset in R161H-GKO or R161H-DKO mice. By contrast, in the immunization-induced EAU model, only IL-17AKO mice exhibited dampening of disease. In both models, DKO CD4 T cells produced more GM-CSF and more IL-24 in vitro upon activation, or in vivo upon immunization. These cytokines may have regulatory and/or pathogenic roles in the absence of both IFN-γ or IL-17A.
Our results indicate that IFN-γ is a dominant pathogenic cytokine in the spontaneous R161H model, whereas IL-17A is dominant in the induced EAU model, leading to the conclusion that Th1 and Th17 cytokines may play differential roles in models with different clinical course.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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