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Reiko Horai, So Jin Bing, Phyllis B Silver, Yingyos Jittayasothorn, Chi-Chao Chan, Rachel Caspi; GM-CSF mediates development of eosinophil-dominant autoimmune uveitis in the absence of both IFN-γ and IL-17A. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4298.
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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, we examined EAU development in the absence of both cytokines.
EAU was induced by immunization with IRBP and/or its peptides. Mice deficient in both IFN-γ and IL-17A (Ifng-/-Il17a-/-) on the C57BL/6 background or on B10.RIII background were used. EAU was examined by fundoscopy and histology. In some experiments, mice received injections of antibodies or antagonist, or a single intravitreal injection of an anti-GM-CSF antibody. Ocular infiltrates were characterized by flow cytometry. GM-CSF or eosinophil peroxidase (EPO) levels in supernatants and serum were measured by ELISA or a bead-based immunoassay.
Ifng-/-Il17a-/- mice were fully susceptible to EAU and displayed eosinophil-dominant ocular infiltrates, as opposed to mononuclear infiltrates in WT mice. These eosinophils appeared to play a pathogenic role, as EAU was ameliorated in Ifng-/-Il17a-/- mice when eosinophils were genetically absent (crossed to ΔdblGATA mice) or their migration was blocked by a CCR3 antagonist. Ocular infiltrates of EAU-induced Ifng-/-Il17a-/- mice contained increased GM-CSF-producing CD4 T cells. Supernatants from antigen-recalled splenocytes of Ifng-/-Il17a-/- mice contained more GM-CSF, whose presence promoted 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 EPO 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.
This is a 2020 ARVO Annual Meeting abstract.
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