Pivotal roles of EBI3 for the initiation and maintenance of experimental autoimmune uveitis

Abstract

Purpose: Epstein Barr induced gene 3 (EBI3), one of the components of IL-27, is a heterodimeric inflammatory cytokine. Recently, EBI3 also has been reported to be one of the components of IL-35 which mediates proliferation of CD4+CD25+ regulatory T cells (Tregs). We have reported that IL-27 Receptor plays important roles in Th1 induction in EAU. In this study, we investigated the role of EBI3 in experimental autoimmune uveitis (EAU).

Methods: Mice (either wild-type (WT) or EBI3-deficient (EBI3 KO)) were immunized with interphotoreceptor retinoid-binding protein (IRBP) peptide 1-20 previously described. Severity of EAU was evaluated clinically and histopathologically. The induction of IRBP-specific cytokines in the draining lymph node was assessed by ELISA and flow cytometry. The frequency of Tregs was examined by flow cytometry.

Results: The clinical score of EAU in EBI3 KO in the early phase was diminished as compared with that in WT. Consistently, histological analysis revealed that significant reduction of cellular infiltration into the retina was seen in EBI3 KO. The induction of IFN-γ by draining lymph node cells from EBI3 KO on day9 was less than that from WT, suggesting that EBI3 plays important roles in the induction of Th1. However, compared with WT mice, the score reached to the same level in EBI3 KO on day 22 and comparably diminished. The production of IL-17 by draining lymph node cells from EBI3 KO on day9 was the same as compared with that in WT, but IL-17 production in EBI3 KO on day16 was increased as compared with that in WT. There was no difference of IL-10 and Foxp3 expression, which is concerned with CD4+ Tregs, between WT and EBI3 KO.

Conclusions: These results indicate that EBI3 may affect Th1 response in the initiation phase and that EBI3 may suppress Th17 in the late phase independently of CD4+ Tregs.

Keywords: 746 uveitis-clinical/animal model • 557 inflammation • 555 immunomodulation/immunoregulation