Amadi-Obi Ahjoku, Yu Cheng-Rong, Liu Xuebin, Mahdi Rashid M, Clarke Grace Levy, Nussenblatt Robert B, Gery Igal, Lee Yun Sang, Egwuagu Charles E
Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Med. 2007 Jun;13(6):711-8. doi: 10.1038/nm1585. Epub 2007 May 13.
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.
17型辅助性T细胞（T(H)17）在免疫介导疾病的啮齿动物模型中发挥作用。在此，我们报告它们在人类葡萄膜炎和巩膜炎中的作用，并在葡萄膜炎模型——实验性自身免疫性葡萄膜视网膜炎（EAU）中验证了我们的发现。T(H)17细胞存在于人类外周血单个核细胞（PBMC）中，可被白细胞介素（IL）-2扩增，并被干扰素（IFN）-γ抑制。在活动性葡萄膜炎和巩膜炎期间它们的数量增加，治疗后减少。EAU中IL-17升高，并上调视网膜细胞中的肿瘤坏死因子（TNF）-α，提示T(H)17可能导致眼部病理改变的一种机制。此外，IL-27在视网膜神经节细胞和光感受器细胞中组成性表达，被IFN-γ上调，并抑制T(H)17的增殖。这些发现表明，T(H)1细胞可能通过在靶组织中通过IFN-γ介导诱导IL-27来拮抗T(H)17表型，从而减轻葡萄膜炎。IL-2促进T(H)17扩增这一发现解释了IL-2R抗体疗法在葡萄膜炎中的疗效，并提示IFN-γ和/或IL-27对T(H)17的拮抗作用可用于治疗慢性炎症。
