活动性类风湿关节炎调节性T细胞程序性细胞死亡蛋白-1/程序性死亡配体1表达及与临床指标的相关性
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摘要
目的探讨程序性细胞死亡蛋白-1/程序性死亡配体1(PD-1/PD-L1)在活动性类风湿关节炎(rheumatoid arthritis,RA)患者外周血调节性T细胞表面表达变化及临床意义。方法用流式细胞术分别检测62例活动期RA患者外周血CD4~+CD25~+T细胞和CD4~+CD25~-T细胞群PD-1和PD-L1的阳性率,并设立39例健康体检者作为健康对照组,分析PD-1/PD-L1与实验室各指标和病情活动性的相关性。结果 PD-1在24例高度活动组和38例中低度活动组RA患者CD4~+CD25~+T细胞的表达水平分别为[(2.27±0.56)%和(1.83±1.08)%],高于健康对照组(1.42±0.49)%,差异有统计学意义(P<0.01)。PD-L1在高度活动组和中低度活动组RA患者CD4~+CD25~+T细胞的表达水平分别为[(2.06±0.62)%和(1.83±0.63)%],亦高于健康对照组(0.80±0.43)%,与对照组相比差异有统计学意义(P<0.001)。PD-1在CD4~+CD25~+T细胞表达水平与DAS28呈正相关(r=0.477,P<0.01),PD-L1在CD4~+CD25~-T细胞表达水平与DAS28无相关性(r=0.078,P=0.549)。结论 PD-1/PD-L1在活动性RA患者调节性T细胞表达存在差异,其与DAS28相关性提示PD-1/PD-L1信号通路可经调节性T细胞调控参与RA的发生。
Objective To investigate the significance of PD-1/PD-L1 expression on the surface of CD4~+CD25~+ T cells from peripheral blood of patients with rheumatoid arthritis(RA).Methods The positive rate of PD-1/PD-L1 on CD4~+CD25~+ T cells from peripheral blood of 62 cases of activity RA and 39 healthy human were detected by flow cytometry, and the correlation between them with the laboratory indexes and the activity of the disease was analyzed. Results The PD-1 expression levels of CD4~+CD25~+T cells in the 24 RA patients from high activity groups and 38 patients from moderate and low activity groups were(2.27±0.56)% and(1.83±1.08)%,respectively, while the level of healthy control group was(1.42±0.49)%, and there was significant difference between each group(P<0.01).The PD-L1 expression levels in the RA patients from the high activity group and moderate and low activity groups activity group was(2.06±0.62)% and(1.83±0.63)%,respectively, higher than that of the healthy control group(0.80±0.43)%, and the difference was statistically significant(P<0.001). The expression level of PD-1 in CD4~+CD25~+T cells was positively correlated with DAS28(r=0.477, P<0.01). Conclusions Our findings suggested that expression of PD-1/PD-L1 on regulatory T cells of patients with active RA was up-regulated and correlated with DAS28. Thus, it led to the fact that PD-1/PD-L1 pathway might participate in the pathogenesis of RA through Treg regulation.
Objective To investigate the significance of PD-1/PD-L1 expression on the surface of CD4~+CD25~+ T cells from peripheral blood of patients with rheumatoid arthritis(RA).Methods The positive rate of PD-1/PD-L1 on CD4~+CD25~+ T cells from peripheral blood of 62 cases of activity RA and 39 healthy human were detected by flow cytometry, and the correlation between them with the laboratory indexes and the activity of the disease was analyzed. Results The PD-1 expression levels of CD4~+CD25~+T cells in the 24 RA patients from high activity groups and 38 patients from moderate and low activity groups were(2.27±0.56)% and(1.83±1.08)%,respectively, while the level of healthy control group was(1.42±0.49)%, and there was significant difference between each group(P<0.01).The PD-L1 expression levels in the RA patients from the high activity group and moderate and low activity groups activity group was(2.06±0.62)% and(1.83±0.63)%,respectively, higher than that of the healthy control group(0.80±0.43)%, and the difference was statistically significant(P<0.001). The expression level of PD-1 in CD4~+CD25~+T cells was positively correlated with DAS28(r=0.477, P<0.01). Conclusions Our findings suggested that expression of PD-1/PD-L1 on regulatory T cells of patients with active RA was up-regulated and correlated with DAS28. Thus, it led to the fact that PD-1/PD-L1 pathway might participate in the pathogenesis of RA through Treg regulation.
引文
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[14] Liu CP,JiangJA,Gao L,et al.Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathwayse[J].Arthritis Res Ther,2015,17:340.
[15] 黄自坤,李雪,罗忠勤,等.类风湿性关节炎外周血中性粒细胞PD-L1表达及意义[J].免疫学杂志,2017,7:586-590.
[16] Okazaki T,Honjo T.The PD-1-PD-L pathway in immunological tolerance[J].Trends Immunol,2006,27:195-201.
[17] Guo G,Shang Y,Zhu G,et al.The expression and distribution of immunomodulatory proteins B7-H1,B7-DC,B7-H3,and B7-H4 in rheumatoid synovium[J].Clin Rheumatol,2012;31:271-281.
[18] Ceeraz S,Hall C,Choy EH,et al.Defective CD8+CD28+ regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy[J].Clin Exp Immunol,2013,174:18-26.
[19] Pedoeem AI.Azoulay-Alfaguter M,Strazza GJ,et al.Program-med death-1 pathway in cancer andautoimmunity[J].Clin Immunol,2014,153:145-152.
[2] Dai S JR,Zhang X.The PD-1/PD-Ls pathway and autoimmune diseases[J].Cellular Immunology,2014,290:72-79.
[3] Zamani MR,Aslani S,Salmaninejad A,et al.PD-1/PD-L and autoimmunity:A growing relationship[J].Cell Immunol,2016,310:27-41.
[4] Yang Lf,Qiao GL,Hassan Y,et al.Program death-1 suppresses autoimmune arthritis by inhibiting Th17 response[J].Arch Immunol Ther Exp,2016,64:417-423.
[5] 杨丰钒,张欣,朱平.活动期强直性脊柱炎患者外周血效应性 T 细胞的比例增加且程序性死亡蛋白配-1水平降低[J].细胞与分子免疫学杂志,2016,32:676-679.
[6] Pedoeem AI,Azoulay-Alfaguter M,Strazza GJ,et al,Programmed death-1 pathway in cancer and autoimmunity[J].Clin Immunol,2014,153:145-152.
[7] Tarrio ML,Grabie N,Bu DX,et al.PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis[J].J Immunol,2012,188:4876-4884.
[8] Saresella M,Rainone V,Al-Daghri NM,et al.The PD-1/PD-L1 pathway in human pathology[J].Curr Mol Med,2012,12:259-267.
[9] Greisen SR,Rasmussen TK,Stengaard-Pedersen K,et al.Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis[J].Scand J Rheumatol,2010,43:101-108.
[10] Govindaraj C,Scalzo-Inguanti K,Madondo M,et al.Impaired Th1 immunity in ovarian cancer patients is mediated by TNFR2+ Tregs within the tumor microenvironment[J].Clin Immunol,2013,149:97-110.
[11] Raptopoulou AP,Bertsias G,Makrygiannakis D,et al.The programmed death1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis[J].Arthritis Rheum,2010,62:1870-1880.
[12] Wan B,Nie H,Liu A,et al.Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis[J].J Immunol,2006,177:8844-8850.
[13] Hassan WA,Baraka EA.Fouad NA.Clinical signifificance of soluble programmed death-1(sPD-1) in rheumatoid arthritis patients:Relation to disease activity and functional status[J].Egyptian Rheumatol,2015,37:165-169.
[14] Liu CP,JiangJA,Gao L,et al.Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathwayse[J].Arthritis Res Ther,2015,17:340.
[15] 黄自坤,李雪,罗忠勤,等.类风湿性关节炎外周血中性粒细胞PD-L1表达及意义[J].免疫学杂志,2017,7:586-590.
[16] Okazaki T,Honjo T.The PD-1-PD-L pathway in immunological tolerance[J].Trends Immunol,2006,27:195-201.
[17] Guo G,Shang Y,Zhu G,et al.The expression and distribution of immunomodulatory proteins B7-H1,B7-DC,B7-H3,and B7-H4 in rheumatoid synovium[J].Clin Rheumatol,2012;31:271-281.
[18] Ceeraz S,Hall C,Choy EH,et al.Defective CD8+CD28+ regulatory T cell suppressor function in rheumatoid arthritis is restored by tumour necrosis factor inhibitor therapy[J].Clin Exp Immunol,2013,174:18-26.
[19] Pedoeem AI.Azoulay-Alfaguter M,Strazza GJ,et al.Program-med death-1 pathway in cancer andautoimmunity[J].Clin Immunol,2014,153:145-152.
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