CD4+ T Cells In Vogt-koyanagi-harada Disease Show A Decreased Stimulation Of IL-27 Expression By Dendritic Cells

Abstract

Purpose: : VKH disease is a systemic autoimmune disease. IL-27 has emerged as an important regulator of proinflammatory T cell responses. This study was designed to investigate the pathophysiological role of IL-27 in VKH disease.

Methods: : Blood samples were taken from 67 patients with VKH disease and 67 healthy controls. PBMCs were subjected to analysis of IL-27 mRNA expression using RT-PCR. The levels of IL-10, IL-17, IL-22 and IFN-γin the CD4⁺ T cells culture supernatants and the concentration of IL-27 in the serum and supernatants of PBMCs, DCs, DC-T cocultures, or Transwell cultures were assayed by ELISA. CD4⁺ T cells were cultured with recombinant IL-27 to evaluate its influence of IL-17 expression by these cells. The in vivo and in vitro influence of corticosteroids and Cyclosporin on IL-27 was evaluated in VKH patients. rAAV2.CMV.mIL-27 was subretinally injected into the mice to evaluate its influence on EAU induced by IRBP_161-180 clinically and histologically.

Results: : The patients with active VKH disease showed a decreased IL-27 mRNA expression and protein expression in association with an increased IL-10, IL-21, IL-17, IFN-γand IL-22 expression. Upregulation of IL-10 and IL-21 by CD4⁺ T cells, but not cell contact, contributed to the downregulation of IL-27 by DCs in this disease. Recombinant IL-27 significantly inhibited the production of IL-17 by CD4⁺ T cells. Treatment with corticosteroids and Cyclosporin resolved the intraocular inflammation in association with an upregulation of IL-27 and a downregulation of IL-17. In vitro experiments showed that corticosteroids, but not Cyclosporin, significantly upregulated the expression of IL-27. Subretinal injection of rAAV2.CMV.mIL-27 into the mice significantly ameliorated EAU activity.

Conclusions: : CD4⁺ T cells in VKH disease have a lower stimulatory capacity to induce IL-27 expression by DCs, which in turn leads to an impaired regulation of Th17 response. These results suggests that IL-27 may be potentially used for the treatment of the diseases mediated by upregulated IL-17 response coupled with a downregulated IL-27 expression.

Keywords: autoimmune disease • uvea • inflammation