CD200/CD200受体1在类风湿关节炎免疫病理机制中的作用  

Abberant CD200/CD200R1 Pathway Contribute to the Immunopathogenesis of Rheumatoid Arthritis

作　　者：任燕[1,2] 冷晓梅[1] 杨波[1,3] 赵岩[1] 张奉春[1] 张烜[1] 

机构地区：[1]中国医学科学院 北京协和医学院 北京协和医院风湿免疫科,北京100032 [2]卫生部中日友好医院干部保健病区,北京100029 [3]中国医学科学院 北京协和医学院 北京协和医院骨科,北京100032

出　　处：《中华临床免疫和变态反应杂志》2012年第4期247-256,F0002,共11页Chinese Journal of Allergy & Clinical Immunology

基　　金：国家自然科学基金(30972731);教育部博士点基金;国家重点基础研究发展计划(973计划)(2007CB512405)

摘　　要：目的探讨CD200/CD200受体1(CD200R1)信号轴在类风湿关节炎(RA)免疫病理机制中的作用。方法采用免疫组化法、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。结果 RA患者滑膜及外周血CD200+(3.55%±0.24%vs.14.37%±1.54%,P<0.0001)及CD200R1+(11.19%±1.23%vs.20.57%±1.26%,P<0.0001)细胞明显低于健康对照者,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(46.86%±1.08%vs.54.06%±1.80%,P<0.01),促进凋亡(1.21%±0.11%vs.0.82%±0.06%,P<0.0001)、坏死(13.54%±0.31%vs.3.82%±0.19%,P<0.0001),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(359.30±35.25vs.1992.00±318.00,P<0.0001)。此外,强化CD200/CD200R1信号还可降低单核诱导的破骨细胞形成。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。To evaluate the functional status of CD200/CD200R1 interactions in patients with rheumatoid arthritis （RA）. Methods The expression of CD200 and CD200R1 by CD4 ＋ cells, CD14＋ cells and synovium was examined by flowcytometry and immunohistochemistry, and compared between RA patients before and after treatment with infliximab （IFX） plus methotrexate （ MTX）, and also healthy controls （HCs）. Sorted CD4 ＋T cells were stained with CFSE and Annexin V/PI for evaluating the effect of CD200 on cell proliferation and apoptosis. Moreover, the effect of CD200 on osteoclastogenesis and on T helper 17 （Th17） differentiation and function was determined by immunocytochemistry, flowcytometry and transwell migration assay. Results In RA patients, the numbers of CD200 ± cells E （ 3.55% ± 0.24% ） vs.（14.37% ± 1.54%）, P 〈0.00011 and CD200R1 ＋ cells [（11.19%± 1.23%） vs. （20.57% ± 1.26% ）, P 〈 0. 0001 ] from peripheral blood mononuclear cells （ PBMC ） were significantly lower than those in HCs, whereas the expression of CD200 ＋ cells was higher in RA synovium compared to that in HCs. This abnormal expression could be corrected after treatment with IFX plus MTX （ P 〈 0. 0001 ） and was correlated with lower level of ESR, CRP and DAS28. Importantly, the engagement of CD200 receptor on CD14 ＋ T cells with CD200Fc fusion protein in vitro reduced the osteoclastogenesis. Whereas the engagement of CD200 receptor on CD4 ＋ T cells with CD200Fc fusion protein in vitro inhibited CD4 ＋ T cells proliferation [ （46.86% ± 1.08% ） vs. （ 54.06% ± 1.80% ）, P 〈 0.01 ], promoted its apoptosis [（1.21% ±0.11%） vs. （0.82% ±0.06%）, P〈0.00011 and necrocytosis [（13.54% ±0.31%） vs. （3.82% ±0. 19% ） , P 〈0. 0001 ] , reduced CD4 ＋ T cells differentiation into Thl7 cells as well as down- regulated CCL20-CCR6-mediated Thl7 ehemotaxis in RA [ （359.30 ±35.25 ） vs. （ 1992.00 ± 318.00）, P 〈0. 0001 ] . Conclusions CD200 and CD200R1 expression and function

关 键 词：CD200 CD200R1 类风湿关节炎 T辅助17细胞 破骨细胞 

分 类 号：R593.22[医药卫生—内科学] R392.3[医药卫生—临床医学]