TH17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1

Abstract

T-helper type 17 cells (T(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(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(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(H)17. These findings suggest that T(H)1 cells may mitigate uveitis by antagonizing the T(H)17 phenotype through the IFN-gamma-mediated induction of IL-27 in target tissue. The finding that IL-2 promotes T(H)17 expansion provides explanations for the efficacy of IL-2R antibody therapy in uveitis, and suggests that antagonism of T(H)17 by IFN-gamma and/or IL-27 could be used for the treatment of chronic inflammation.

Nanomicelle‐Assisted Targeted Ocular Delivery with Enhanced Antiinflammatory Efficacy In Vivo

“…In addition to PGE 2 , inflammation mediators can induce the release of other inflammatory cytokines such as IL‐6. Several previous studies demonstrated that IL‐6 plays an important role in ocular inflammation 31, 32, 33, 34. In this study, we found that production of IL‐6 increased 4.6 and 6.3 times in tears and aqueous humor, respectively, after ocular inflammation was induced.…”

Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA

“…Recently, a new insight with Th17 cells has emerged for the pathogenesis of EAU (Amadi-Obi et al 2007). In the present study, OPN-siRNA treatment suppressed not only Th1 cytokines but also IL-17 production, which could also account for the amelioration of EAU.…”

“…EAU induced with immunization of retinal Ag now represents not only Th1 but also Th17-cell-mediated ocular diseases. A massive inflammatory infiltration composed primarily of mononuclear cells causes a rapid and irreversible destruction of photoreceptor cells (Jiang et al 1999;Silver et al 1999;Caspi 2003;Amadi-Obi et al 2007;Luger et al 2008). It has been demonstrated that the augmentation of the Th2 response and T regulatory cytokine production and down-regulation of the Th1 response can mitigate inflammation and protect against the development of EAU (Saoudi et al 1993;Kezuka et al 1996;Caspi 2002).…”

Persistence of IL‐2 expressing Th17 cells in healthy humans and experimental autoimmune uveitis

“…Although these studies suggest the possible involvement of Th17 cells in clinical uveitis, more direct and compelling evidence has come from studies in experimental autoimmune uveitis (EAU) [13]. In this well-characterized mouse model of human uveitis [14], dynamic changes in the levels of IL-17-expressing cells occur during the course of uveitis [15]. Before the inception of EAU, only trace numbers of IL-17-expressing T cells are detectable in the PBMCs, LNs or retina but their numbers in these tissues increase with disease progression, with the highest levels detected in the retina at the peak of disease [15].…”

“…In this well-characterized mouse model of human uveitis [14], dynamic changes in the levels of IL-17-expressing cells occur during the course of uveitis [15]. Before the inception of EAU, only trace numbers of IL-17-expressing T cells are detectable in the PBMCs, LNs or retina but their numbers in these tissues increase with disease progression, with the highest levels detected in the retina at the peak of disease [15]. On the other hand, recovery from the disease coincides with rapid diminution in the IL-17-expressing T cells [15].…”