Adhesion molecules and soluble factors specifically regulate T lymphocyte function in patients with rheumatoid arthritis.

类风湿关节炎(RA)的滑膜炎以T细胞的滑膜浸润和滑膜衬里细胞的增殖为特征。我们从黏附分子、细胞因子和蛋白多糖的角度研究了循环T细胞向滑膜组织的迁移机制以及T细胞与滑膜细胞的相互作用。1.T细胞向类风湿滑膜的侵袭机制。为了阐明T细胞向滑膜组织迁移的机制，我们评估了外周T细胞与从类风湿滑膜中纯化的内皮细胞的粘附性。内皮细胞表达硫酸乙酰肝素蛋白多糖以及ICAM-1、VCAM-1和E-选择素等黏附分子。滑膜中的T细胞产生大量炎性细胞因子MIP-1β。当固定在硫酸乙酰肝素…上时，mip-1β最有效更多的表达在类风湿内皮细胞上，从而触发T细胞整合素，从而诱导T细胞与内皮细胞的高亲和力黏附。我们推测，由于体内的细胞因子会被血流迅速冲走，MIP-1β可以以其固定的形式诱导T细胞黏附。抗VLA-4/LFA-1抗体、抑制硫酸肝素合成的木糖苷、阻断G蛋白偶联MIP-1β受体信号转导的百日咳毒素均可抑制诱导的T细胞黏附。这些结果表明，滑膜T细胞产生的MIP-1β通过其固定化形式与滑膜内皮上的硫酸肝素结合，诱导整合素介导的T细胞与内皮细胞的黏附。因此，细胞因子、蛋白多糖和黏附分子参与了T细胞向滑膜的迁移，从而导致T细胞在类风湿滑膜中的聚集。2.T细胞与滑膜细胞的细胞相互作用机制在类风湿滑膜炎中起着核心作用。我们研究了T细胞与滑膜成纤维细胞之间的相互作用。T细胞主要通过LFA-1/ICAM-1与滑膜细胞黏附。组织化学研究表明，LFA-1阳性T细胞聚集在ICAM-1阳性滑膜细胞周围。我们发现T细胞激活滑膜细胞，通过LFA-1/ICAM-1的细胞黏附诱导IL-1β的产生。为了阐明ICAM-1本身对滑膜细胞是否诱导激活信号，将建立的滑膜成纤维细胞系上的ICAM-1进行了交联，并对IL-1β的产生进行了评估。CAT分析显示，交联型ICAM-1通过含有核因子AP-1结合位点的增强子区域诱导IL-1β基因组DNA转录。通过带移实验证实AP-1参与了ICAM-1诱导的IL-1β转录。这些结果表明，黏附分子在类风湿滑膜细胞中不仅起到胶粘剂的作用，而且还传递激活信号，通过核因子诱导细胞因子产生。提示T细胞通过LFA-1/ICAM-1途径与滑膜细胞的黏附在滑膜炎发病机制中的意义，可能为滑膜炎的控制提供新的途径。较少

Synovitis in rheumatoid arthritis (RA) is characterized by infiltration of synovium by T cells as well as the proliferation of synovial lining cells. We have studied the mechanism of circulating T cell migration into synovial tissue and interaction of T cells with synovial cells from the standpoints of adhesion molecules, cytokines and proteoglycan.1.The mechanisms of T cell infiltration into rheumatoid synovium.We have studied the mechanism of T cell adhesion to endothelium and have proposed that it consists of inflammatory adhesion cascade. To clarify the mechanism of T cell migration into synovial tissue, we assessed the adhesion of peripheral T cells to endothelial cells purified from rheumatoid synovium. The endothelial cells expressed heparan sulfate proteoglycan as well as adhesion molecules such as ICAM-1, VCAM-1 and E-selectin. T cells in synovium produced large amounts of inflammatory cytokine MIP-1beta. The MIP-1beta was most effective when immobilized on the heparan sulfate … More expressed on the rheumatoid endothelium to trigger T cell integrin which lead to the induction of high affinity adhesion of T cells to the endothelium. We reasoned that, as cytokines in vivo will be rapidly washed away by blood flow, MIP-1beta can induce T cell adhesion in its immobilized form. The induced T cell adhesion was inhibited by either, the mixture of anti-VLA-4/LFA-1 antibodies, xyloside which inhibits the synthesis of heparan sulfate, or pertussis toxin which blocks signal transduction through G-protein coupled MIP-1beta receptor. These results indicate that MIP-1beta produced from synovial T cells induces integrin-mediated T cell adhesion to endothelium by its immobilized form on heparan sulfate on synovial endothelium. Thus, cytokines and proteoglycan as well as adhesion molecules are involved in T cell migration into synovium, which leads to accumulation of T cells in rheumatoid synovium. Extrapolation to include the results would bring new approaches to clarification of pathogenesis and pharmacological agents in RA.2.The mechanisms of cellular interaetion of T cells with synovial cellsSynovial lining cells and T cells play a central role in rheumatoid synovitis. We studied the interaction between T cells and synovial fibroblasts. T cells adhered to the synovial cells mainly through LFA-1/ICAM-1. Histochemical studies indicated that LFA-1-positive T cells accumulated around ICAM-1-positive synovial cells. We found that T cells activated synovial cells to induce IL-1beta production through the cellular adhesion via LFA-1/ICAM-1. To clarify if ICAM-1 per se on the synovial cells induce activation signals, ICAM-1 on a synovial fibroblast cell line established rocally was cross-linked and IL-1beta production was assessed. Cross-linked ICAM-1 induced transcription of IL-1beta genomic DNA through enhancer regions containing nuclear factor AP-1-binding sites by CAT analysis. The involvement of AP-1 in ICAM-1-induced IL-1beta transcription was confirmed by bandshift assay. These results indicate that adhesion molecules not only function as glue but transduce activation signals which induce cytokine production through nuclear factor in rheumatoid synovial cells. Thus, the significance of T cell adhesion to synovial cells by LFA-1/ICAM-1 pathway in the pathogenesis of synovitis is suggested, which may bring new approaches to the control of synovitis. Less