Nonredundant role for GM-CSF in autoimmune pathology of the neureretina in the absence of IFN-γ and IL-17A

Abstract

Abstract Autoimmune uveitis is a complex group of sight-threatening CNS diseases caused by activated retina-specific Th1 or Th17 cells that acquired the ability to cross the blood-retinal barrier, but their respective contribution to disease is not fully understood. In this study, we used mice deficient in IL-17A, IFN-γ (GKO), or both (DKO) to dissect the role of Th1 and Th17 lineage-specific cytokines in pathogenesis of uveitis. Experimental autoimmune uveitis (EAU) was induced by active immunization with the retinal autoantigen IRBP in CFA. IL-17A−/− mice were protected from EAU, whereas GKO mice had exacerbated disease. Surprisingly, DKO mice were fully susceptible to EAU with scores similar to WT controls. The frequency of macrophages and production of proinflammatory cytokines (GM-CSF, IL-6, and TNF-α) was increased in the spleen and eyes of DKO mice. To test whether other T cell lineage-related cytokines contribute to pathology in the absence of IL-17A and IFN-γ, EAU-challenged DKO mice were treated with blocking Abs to IL-17F, IL-22, TNF-α, or GM-CSF. Blockade of IL-17F, IL-22, or TNF-α in DKO mice did not affect the severity of EAU. By contrast, treatment of DKO mice with an anti-GM-CSF Ab during the expression stage of disease significantly suppressed disease severity in DKO, but not in WT mice. These results suggest that IL-17F, IL-22 or TNF-α individually are dispensable, but GM-CSF appears to play a major and nonredundant role as a pathogenic cytokine in EAU when IFN-γ and IL-17A are both absent. Our results highlight that ‘classical’ Th1 and Th17 cells are not the only pathogenic effectors, and that other inflammatory cytokine(s), such as GM-CSF, can also drive uveitis.