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Interleukin-10 (IL-10)-producing regulatory B ([B.sub.reg]) cells suppress autoimmune disease, and increased numbers of [B.sub.reg] cells prevent host defense to infection and promote tumor growth and metastasis by converting resting [CD4.sup.+] T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of [B.sub.reg] cells remain unclear. Here we show that IL-35 induces [B.sub.reg] cells and promotes their conversion to a [B.sub.reg] subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less [B.sub.reg] cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of [B.sub.reg] cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 ([T.sub.H]17) and [T.sub.H]1 cells while promoting [T.sub.reg] cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into [B.sub.reg] cells, these findings suggest that IL-35 may be used to induce autologous [B.sub.reg] and [IL-35.sup.+] [B.sub.reg] cells and treat autoimmune and inflammatory disease., B cell depletion is an effective therapy for a number of T cell-mediated autoimmune diseases, suggesting that B cells may contribute to autoimmunity (1-4). However, subsequent studies showed that the [...]

T-helper type 17 cells (T[sub.H]17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T[sub.H]17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-[gamma]. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-[alpha] in retinal cells, suggesting a mechanism by which T[sub.H]17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-[gamma] and inhibited proliferation of T[sub.H]17. These findings suggest that T[sub.H]1 cells may mitigate uveitis by antagonizing the T[sub.H]17 phenotype through the IFN-[gamma]-mediated induction of IL-27 in target tissue. The finding that IL-2 promotes T[sub.H]17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of T[sub.H]17 by IFN-[gamma] and/or IL-27 could be used for the treatment of chronic inflammation., Author(s): Ahjoku Amadi-Obi [1, 4]; Cheng-Rong Yu [1, 4]; Xuebin Liu [1]; Rashid M Mahdi [1]; Grace Levy Clarke [2]; Robert B Nussenblatt [2]; Igal Gery [3]; Yun Sang Lee [...]

Nat. Med.; doi:10.1038/nm.3554; corrected online 30 May 2014 In the version of this article initially published online, there were several errors in the text and figures. Two authors' names were [...]

T-helper type 17 cells (TH17) are implicated in rodent models of immune-mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. TH17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)-2 and inhibited by interferon (IFN)-γ. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)-α in retinal cells, suggesting a mechanism by which TH17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-γ and inhibited proliferation of TH17. These findings suggest that TH1 cells may mitigate uveitis by antagonizing the TH17 phenotype through the IFN-γ–mediated induction of IL-27 in target tissue. The finding that IL-2 promotes TH17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of TH17 by IFN-γ and/or IL-27 could be used for the treatment of chronic inflammation. [ABSTRACT FROM AUTHOR]