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

白细胞介素-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没有直接诱导IFN-γ的活性，但IL-18可以增强il -12诱导的IFN-γ的产生，而在抗IL-18抗体（Ab）存在时，IFN-γ的产生明显减弱。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。白细胞介素-12受体(IL-12R) β1/2链在外周血CD4+ T细胞表面未见表达，但经抗cd3 Ab刺激后可诱导表达。RA患者IL-12R的诱导作用强于正常人。在滑膜组织中，IL-12Rβ1/2链在一定比例的CD4+ T细胞中表达，并检测到诱导β2链的mRNA转录物。抗cd3 Ab和IL-18共同刺激滑膜组织CD4+ T细胞，IL-12R表达增强。另一方面，dl - 18r α/β链在外周血CD4+ T细胞中组成性表达，RA患者的表达水平高于正常人，在RA滑膜组织中的表达水平进一步升高。il -12β 1 /2链主要在表达IL-18Rα的CD4+ T细胞中被诱导，滑膜组织CD4+ T细胞在激活后大部分表达IL-18Rα，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细胞积聚在滑膜组织中，其中一部分细胞可能通过cd3激活和IL-18等刺激诱导出功能性IL-12R。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细胞中CXCR3趋化因子受体的表达增加。CD4+T细胞表达th2相关表面分子CD30的能力在RA中减弱，RA的CD30+ CD4+T细胞通过凋亡激活后可被清除。少

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