类风湿关节炎抗炎治疗的新靶点：CD200/CD200R1

CD200/CD200R1 signaling has an immunoregulatory effect in activation threshold of inflammatory immune response and maintains immune homeostasis; moreover, emerging studies have emphasized the therapeutic importance of CD200/CD200R in experimental autoimmune diseases, such as CIA、EAE and EAU, thus, highlight themselves as a potential anti-inflammatory intervention in autoimmune diseases. However, information on the role of CD200/CD200R1 in human rheumatoid arthritis (RA) is very limited. We, therefore, evaluated the functional status of CD200/CD200R1 interactions in patients with RA and demonstrated that in RA patients, the numbers of CD200+ cells and CD200R1+ cells from CD14+ cells and CD4+ cells in peripheral blood mononuclear cells (PBMC) were lower than that in HCs, whereas the expressions of CD200+ cells was higher in RA synovium compared to that in HCs. These abnormal expressions were corrected after treatment with TNF-α blockage and correlated with less radiographic progression as evaluated by RAMRIS. All these evidence indicating that defective CD200/CD200R1 expression not only exists in RA but also has a clinical relevance in regulating the severity of such disease. Though the underlying mechnism is not certain, it might relate to the finding that the synovitis and bone erosion alleviation was observed with up-regulated expression of CD200/CD200R1. Here, we will further investigate the immunosuppressive function of this pathway on Th17 differentiation and osteoclastogenesis in RA patients, and try to explore the unique insight of modulating this signal to treat chronic inflammatory diseases, such as RA as well.

进行性、炎症性骨破坏是当前RA治疗的难点。 动物研究发现CD200及CD200R1信号可调节免疫应答阈值，维持机体免疫稳态；强化该信号在动物体内表达能够显著减轻CIA的滑膜炎症与骨侵蚀，有望成为关节炎治疗的新靶点。但是CD200/CD200R1在人类RA中的作用认识还十分有限。我们前期研究显示CD200/CD200R1在RA患者CD14+单核细胞、CD4+辅助性T细胞以及病变滑膜中存在明显表达异常,经TNF-α拮抗剂有效治疗后，该信号可在RA患者体内上调表达，炎症随之减轻，提示该信号可参与调控RA的免疫病理转归。T细胞和单核巨噬细胞是关节炎症反应的主要应答细胞，本研究将具体深入阐明CD200/CD200R1在调控RA中活化单核细胞介导的Th17应答、CD4+辅助性T细胞向Th17细胞增殖、分化、趋化、以及单核细胞诱导的破骨细胞形成中的免疫调节机制，为进一步操控该信号治疗RA提供方向和依据。

进行性、炎症性骨破坏是当前RA治疗的难点。 动物研究发现CD200及CD200R1信号可调节免疫应答阈值，维持机体免疫稳态；强化该信号在动物体内表达能够显著减轻CIA的滑膜炎症与骨侵蚀，有望成为关节炎治疗的新靶点。但是CD200/CD200R1在人类RA中的作用认识还十分有限。我们前期研究显示CD200/CD200R1在RA患者CD14+单核细胞、CD4+辅助性T细胞以及病变滑膜中存在明显表达异常,经TNF-α拮抗剂有效治疗后，该信号可在RA患者体内上调表达，炎症随之减轻，提示该信号可参与调控RA的免疫病理转归。. 本研究采用免疫组化法、流式细胞仪检测RA 滑膜、外周血细胞CD200CD200R1 表达水平，观察强化CD200CD200R1 信号对RA 破骨细胞分化及T 辅助17( Th17) 细胞增殖、分化的作用。发现RA 患者外周血CD200 + ( 3. 8%vs. 14. 8%，P ＜ 0. 0001) 及CD200R1 + ( 8.0% vs. 20. 6%，P ＜ 0. 0001) 细胞明显低于健康对照者；RA患者滑膜中CD200+高表达(2.74 vs 0.65, P ＜ 0. 0001)，而RA患者滑膜中CD200R1和健康对照无差异。经英夫利西单抗联合甲氨蝶呤治疗后，外周血CD200CD200R1 表达明显升高( P ＜ 0. 0001) ，且CD200R1 变化水平与血沉( ESR) 、C 反应蛋白( CRP) 、疾病活动性评分( DAS28) 呈负相关。细胞培养发现通过上调CD200/CD200R1 信号可以抑制CD4 + 辅助性T 细胞向Th17 细胞增殖分化，促进凋亡、坏死、并抑制趋化因子配体20( CCL20) -趋化因子受体6( chemokine receptor 6，CCR6) 介导的Th17 细胞的炎性趋化。此外，强化CD200/CD200R1 信号还可降低单核诱导的破骨细胞形成。因此得出结论：RA 滑膜及外周血CD200/CD200R1 信号存在表达与功能异常，通过调控Th17 细胞及破骨细胞免疫应答，有望成为RA 抗炎治疗的新靶点，本研究首次证实RA患者外周血和滑膜中的CD200/CD200R1的异常表达多途径参与调控RA患者的炎症和破骨活性，为筛选新的兼顾抗炎和抗骨侵蚀性RA药物提供理论依据和新方向。