Th1-Induced CD106 Expression Mediates Leukocytes Adhesion on Synovial Fibroblasts from Juvenile Idiopathic Arthritis Patients

This study tested the hypothesis that subsets of human T helper cells can orchestrate leukocyte adhesion to synovial fibroblasts (SFbs), thus regulating the retention of leukocytes in the joints of juvenile idiopathic arthritis (JIA) patients. Several cell types, such as monocytes/macrophages, granulocytes, T and B lymphocytes, SFbs and osteoclasts participate in joint tissue damage JIA. Among T cells, an enrichment of classic and non-classic Th1 subsets, has been found in JIA synovial fluid (SF), compared to peripheral blood (PB). Moreover, it has been shown that IL-12 in the SF of inflamed joints mediates the shift of Th17 lymphocytes towards the non-classic Th1 subset. Culture supernatants of Th17, classic and non-classic Th1 clones, have been tested for their ability to stimulate proliferation, and to induce expression of adhesion molecules on SFbs, obtained from healthy donors. Culture supernatants of both classic and non-classic Th1, but not of Th17, clones, were able to induce CD106 (VCAM-1) up-regulation on SFbs. This effect, mediated by tumor necrosis factor (TNF)-α, was crucial for the adhesion of circulating leukocytes on SFbs. Finally, we found that SFbs derived from SF of JIA patients expressed higher levels of CD106 than those from healthy donors, resembling the phenotype of SFbs activated in vitro with Th1-clones supernatants. On the basis of these findings, we conclude that classic and non-classic Th1 cells induce CD106 expression on SFbs through TNF-α, an effect that could play a role in leukocytes retention in inflamed joints.本研究验证了如下假说：人类辅助性T细胞亚群可介导白细胞黏附至滑膜成纤维细胞（synovial fibroblasts, SFbs），从而调控白细胞在幼年特发性关节炎（juvenile idiopathic arthritis, JIA）患者关节内的滞留。幼年特发性关节炎（JIA）患者的关节组织损伤涉及多种细胞类型，包括单核细胞/巨噬细胞、粒细胞、T与B淋巴细胞、滑膜成纤维细胞（SFbs）以及破骨细胞。在T细胞中，与外周血（peripheral blood, PB）相比，经典型与非经典型Th1细胞亚群在JIA患者滑膜液（synovial fluid, SF）中呈现富集现象。此外，已有研究证实，炎症关节滑膜液中的白细胞介素-12（interleukin-12, IL-12）可介导Th17淋巴细胞向非经典型Th1细胞亚群转化。本研究检测了Th17、经典型及非经典型Th1克隆的培养上清液，评估其刺激细胞增殖以及诱导健康供体来源的SFbs表达黏附分子的能力。实验结果显示，经典型与非经典型Th1克隆的培养上清液，而非Th17克隆的培养上清液，可诱导SFbs表面CD106（血管细胞黏附分子-1, VCAM-1）的表达上调。该效应由肿瘤坏死因子-α（tumor necrosis factor, TNF-α）介导，是循环白细胞黏附至SFbs的关键环节。最终我们发现，JIA患者滑膜液来源的SFbs，其CD106表达水平高于健康供体来源的SFbs，这与经Th1克隆培养上清液体外活化的SFbs表型一致。基于上述研究发现，我们得出结论：经典型与非经典型Th1细胞可通过TNF-α诱导SFbs表面CD106的表达，这一效应可能在炎症关节内的白细胞滞留过程中发挥作用。