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

白介素12(IL-12)可诱导类风湿关节炎(RA)滑膜组织T细胞产生干扰素-γ(干扰素-γ)。IL-18不具有直接的干扰素-γ诱导活性，但IL-18可促进IL-12诱导的干扰素-γ的产生，而抗IL-18抗体可显著抑制IL-12诱导的干扰素-DNA的产生。因此，RA关节中丰富的IL-18可增强Th1细胞对IL-12的反应性，从而在缺乏IL-12的情况下诱导局部干扰素-γ的合成。外周血中未检测到IL-12受体(IL-12R)CD4+T细胞表面IL-12Rβ1/2链的表达，但在抗CD3Ab刺激后可诱导表达。类风湿关节炎患者IL-12R的诱生作用强于正常人。在滑膜组织中，部分β+T细胞表达IL-12RCD1/2链，并检测到诱导型β2链的转录。抗CD3抗体和IL-18共刺激后，滑膜组织CD4+T细胞上IL-12R的表达增强。在…上α/β链在外周血中呈结构性表达，且在RA患者中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-12βL/2链主要在表达IL-18R的α+T细胞中诱导，滑膜组织中的CD+T细胞激活后主要表达IL-18Rα并主要产生干扰素-γ。IL-12和IL-18分别诱导T细胞转录因子STAT4和NF-kB的激活。这些发现表明，IL-18R+CD4+T细胞聚集在滑膜组织中，其中一部分细胞可能在CD3激活和IL-18等刺激下诱导产生功能性的IL-12R。IL-12R和IL-18R的共同表达可能是RA患者Th1细胞产生干扰素-γ-所必需的。此外，我们还发现RA滑膜T细胞表达趋化因子受体CXCR3的增加，并且RA患者的CD4+T细胞表达Th2相关表面分子CD30的能力减弱，当通过细胞凋亡激活时，RA的CD30+CD4+T细胞可以被清除。较少

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