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Study on the mechanism for establishment of the Thl-type immune response in rheumatoid arthritis

类风湿关节炎Thl型免疫应答建立机制的研究

基本信息

批准号：
12670426
负责人：
YAMAMURA Masahiro
金额：
$ 2.05万
依托单位：
OKAYAMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670426/
关键词：
CD4+T cells interferon-γ interleukin-12 interleukin-12 receptor interleukin-18 interleukin-18 receptor rheumatoid arthritis Th1 response Th1型:免疫反応 CXCR3 IP-10 Mig I-TAC Th1型免疫反応

项目摘要

Interleukin-12 (IL-12) was able to induce interferon-γ (IFN-γ) production by synovial tissue T cells of rheumatoid arthritis (RA). IL-18 had no direct IFN-γ-inducing activity, but IL-12-induced IFN-γ production was enhanced by IL-18, and was significantly diminished in the presence of anti-IL-18 antibody (Ab). Therefore, an abundance of IL-18 in RA joints appears to increase the responsiveness of Th1 cells to IL-12, thereby inducing the local IFN-γ synthesis in the paucity of IL-12.Cell surface expression of IL-12 receptor (IL-12R) β1/2 chains was undetectable on peripheral blood CD4+ T cells, but it was induced after anti-CD3 Ab stimulation. The induction of IL-12R was stronger in RA patients than in normal subjects. In the synovial tissue, both IL-12Rβ1/2 chains were expressed in a proportion of CD4+ T cells, and mRNA transcripts of the inducible β2 chain were detected. IL-12R expression on synovial tissue CD4+ T cells was enhanced by costimulation with anti-CD3 Ab and IL-18. On the … More other hand, DL-1 8Rα/β chains were constitutively expressed in peripheral blood CD4+ T cells, and the level of expression was greater in RA patients than in normal subjects and was further increased in RA synovial tissues. IL-12βl/2 chains were induced mainly in IL-18Rα-expressing CD4+ T cells, and synovial tissue CD4+ T cells are able to mostly express IL-18Rα and to predominantly produce IFN-γ when activated. IL-12 and IL-18 induced the activation of transcription factors STAT4 and NF-kB in T cells, respectively. These findings indicate that IL-18R+ CD4+ T cells are accumulated in the synovial tissue, where the functional IL-12R may be induced in a proportion of these cells by stimuli such as CD 3 activation and IL-18. Coexpression of IL-12R and IL-18R may be required for IFN-γ-production by Th1 cells in RA.Furthermore, we found the increased expression of CXCR3 chemokine receptor by RA synovial T cells., and that the ability of CD4+ T cells to express the Th2-related surface molecule CD30 was diminished in RA and CD30+ CD4+T cells of RA could be removed when activated through apoptosis. Less

白介素 12 (IL-12) 能够诱导类风湿性关节炎 (RA) 滑膜组织 T 细胞产生干扰素 - γ (IFN-γ)。 IL-18 没有直接的 IFN-γ 诱导活性，但 IL-18 增强了 IL-12 诱导的 IFN-γ 产生，并且在抗 IL-18 抗体 (Ab) 存在的情况下显着减弱。因此，RA关节中丰富的IL-18似乎增加了Th1细胞对IL-12的反应性，从而在IL-12缺乏的情况下诱导局部IFN-γ合成。IL-12受体（IL-12R）β1/2链的细胞表面表达在外周血CD4+T细胞上检测不到，但在抗CD3抗体刺激后被诱导。 RA 患者中 IL-12R 的诱导作用强于正常受试者。在滑膜组织中，部分 CD4+ T 细胞中表达两条 IL-12Rβ1/2 链，并检测到诱导型 β2 链的 mRNA 转录本。抗 CD3 Ab 和 IL-18 共刺激可增强滑膜组织 CD4+ T 细胞上的 IL-12R 表达。另一方面，DL-1 8Rα/β链在外周血CD4+T细胞中组成型表达，并且在RA患者中的表达水平高于正常人，并且在RA滑膜组织中进一步增加。 IL-12β1/2链主要在表达IL-18Rα的CD4+T细胞中诱导，并且滑膜组织CD4+T细胞能够大部分表达IL-18Rα并且在激活时主要产生IFN-γ。 IL-12 和 IL-18 分别诱导 T 细胞中转录因子 STAT4 和 NF-kB 的激活。这些发现表明，IL-18R+ CD4+ T 细胞在滑膜组织中积累，其中部分细胞中的功能性 IL-12R 可能通过 CD 3 激活和 IL-18 等刺激而被诱导。 RA中Th1细胞产生IFN-γ可能需要IL-12R和IL-18R的共表达。此外，我们发现RA滑膜T细胞CXCR3趋化因子受体的表达增加，并且RA中CD4+T细胞表达Th2相关表面分子CD30的能力减弱，并且RA的CD30+CD4+T细胞在通过凋亡激活时可以被去除。较少的