Abstract
Purpose: :
Experimental autoimmune uveitis (EAU) induced by immunization with the uveitogenic retinal antigen IRBP is a mouse model for autoimmune uveitis in humans. Recently, we showed that EAU can be driven either by Th1 or by Th17 as standalone effector responses. In keeping with this, knockout (KO) mice lacking either IFN-γ or IL-17 are susceptible to EAU, confirming that EAU can develop in the absence of either one of these cytokines. We posed the question what would happen if both of these cytokines were absent.
Methods: :
We generated IL-17/IFN-γ double knockout (DKO) mice that lack a normal Th17 as well as a normal Th1 effector response. After immunizing these mice with IRBP, we assessed the development of EAU by histology and fundoscopy, and examined the cytokines in extracts of inflamed eyes. Adaptive immune responses were measured as delayed-type hypersensitivity (DTH), and as ex-vivo proliferation and cytokine production of spleen and draining lymph node cells to IRBP. IL-6, TNF-, IL-5 and IL-13 production were measured by ELISA; IL-22 and IL-21 responses were examined by PCR.
Results: :
Strikingly, the DKO mice developed full-blown EAU and exhibited DTH and proliferative responses of similar magnitude to wild type controls. Additionally, upon ex-vivo stimulation with IRBP, splenocytes from diseased DKO mice produced robust amounts of IL-6, TNF-, IL-5 and IL-13. Furthermore, examination of inflamed eye tissues from these mice revealed the presence of IL-6 and Eotaxin, as well as, IL-22 and IL-21. Finally, histological analysis of diseased eyes uncovered a granulocytic/eosinophilic infiltrate in the DKO (and in IFN-γ KO) mice that is in contrast to the lymphocytic/monocytic infiltrate typically seen in diseased wild type (and IL-17 KO) mice.
Conclusions: :
Taken together, these findings suggest the presence of a pathogenic autoimmune response capable of driving EAU that develops in the concurrent absence of IFN-γ and IL-17 responses. Further studies using neutralizing Abs to the expressed cytokines or their receptors will address their role in pathogenesis.
Keywords: autoimmune disease • uveitis-clinical/animal model • inflammation