T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis.
T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis.
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T细胞的自我反应性形成了引起自身免疫性关节炎的IL-17+ TH细胞自发发育的细胞因子环境。
DOI：
10.1084/jem.20062259
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发表时间：
2007-01-22
影响因子：
15.3
通讯作者：
Sakaguchi, Shimon
中科院分区：
文献类型：
--
作者：
Hirota, Keiji;Hashimoto, Motomu;Yoshitomi, Hiroyuki;Tanaka, Satoshi;Nomura, Takashi;Yamaguchi, Tomoyuki;Iwakura, Yoichiro;Sakaguchi, Noriko;Sakaguchi, Shimon
该报告显示，由于遗传改变的胸腺T细胞选择而在小鼠中产生的高度自身反应性T细胞自发分化为分泌白细胞介素（IL）-17的CD 4+辅助T（Th）细胞（Th 17细胞），其介导临床和免疫学上类似于类风湿性关节炎（RA）的自身免疫性关节炎。胸腺产生的自身反应性T细胞通过识别主要组织相容性复合物/自身肽复合物在外周中被激活，刺激抗原呈递细胞（APC）分泌IL-6。APC衍生的IL-6与T细胞衍生的IL-6一起驱动幼稚自身反应性T细胞分化成致关节炎性Th 17细胞。IL-17或IL-6缺乏可完全抑制关节炎的发生，而IFN-γ缺乏则可加重关节炎的发生。然而，致关节炎Th 17细胞本身的产生、分化和持续存在不足以产生明显的自身免疫性关节炎。然而，通过自身免疫性Th 17细胞的进一步扩增和活化（例如，通过IFN-γ缺乏、稳态增殖或微生物产物刺激先天免疫）来促成明显的疾病。因此，遗传决定的T细胞自身反应性形成促进自身反应性T细胞优先分化为Th 17细胞的细胞因子环境。外在或内在的刺激进一步扩大这些细胞，从而引发自身免疫性疾病。在细胞和分子水平上干预这些事件有助于治疗和预防自身免疫性疾病，特别是RA。
This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17–secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell–derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells. Deficiency of either IL-17 or IL-6 completely inhibits arthritis development, whereas interferon (IFN)-γ deficiency exacerbates it. The generation, differentiation, and persistence of arthritogenic Th17 cells per se are, however, insufficient for producing overt autoimmune arthritis. Yet overt disease is precipitated by further expansion and activation of autoimmune Th17 cells, for example, via IFN-γ deficiency, homeostatic proliferation, or stimulation of innate immunity by microbial products. Thus, a genetically determined T cell self-reactivity forms a cytokine milieu that facilitates preferential differentiation of self-reactive T cells into Th17 cells. Extrinsic or intrinsic stimuli further expand these cells, thereby triggering autoimmune disease. Intervention in these events at cellular and molecular levels is useful to treat and prevent autoimmune disease, in particular RA.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
64.8
作者：
Sakaguchi, N;Takahashi, T;Sakaguchi, S
通讯作者：
Sakaguchi, S
影响因子：
30.8
作者：
Vang, T;Congia, M;Bottini, N
通讯作者：
Bottini, N
影响因子：
32.4
作者：
Veldhoen, M;Hocking, RJ;Stockinger, B
通讯作者：
Stockinger, B
DOI：
10.1084/jem.20041758
发表时间：
2005-03-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Yoshitomi H;Sakaguchi N;Kobayashi K;Brown GD;Tagami T;Sakihama T;Hirota K;Tanaka S;Nomura T;Miki I;Gordon S;Akira S;Nakamura T;Sakaguchi S
通讯作者：
Sakaguchi S