ICOS/ICOSL在类风湿关节炎患者外周血淋巴细胞的表达及临床意义
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摘要
目的:检测初发类风湿关节炎(Rheumatoid arthritis,RA)患者外周血淋巴细胞表面共刺激分子ICOS和ICOSL的表达,并探讨其临床意义。方法:采用流式细胞术和RT-PCR的方法,检测85例初发RA患者和50例健康对照(Healthy control,HC)外周血CD4+T细胞表面ICOS及CD14+单核细胞和CD19+B细胞表面ICOSL的表达,比较15例初诊RA患者治疗前后ICOS和ICOSL表达水平变化,分析其临床意义。结果:RA患者外周血中ICOS/ICOSL的mRNA的表达水平显著高于HC。RA患者外周血CD4+T细胞表面ICOS表达显著增高[(7.08±4.72)%vs(3.01±1.39)%,P<0.0001]。RA患者外周血中CD14+单核细胞[(5.77±3.45)%vs(3.64±1.43)%,P<0.05]和CD19+B细胞[(5.78±4.52)%vs(3.97±1.63)%,P<0.05]表面ICOSL的表达均高于HC。活动期的RA患者外周血单核细胞和B细胞表面的ICOSL表达高于非活动期患者[(5.45±3.50)%vs(4.04±1.55)%,P=0.036]、[(6.59±5.74)%vs(5.63±4.30)%,P=0.016],治疗后CD4+T细胞表面ICOS的表达及CD14+单核细胞和CD19+B细胞表面ICOSL的表达均显著下降[(3.33±0.31)%vs(5.56±1.11)%,P=0.076]、[(5.12±1.23)%vs(9.99±2.02)%,P=0.045]、[(3.74±0.57)%vs(8.62±1.77)%,P=0.011]。结论:RA患者外周血单个核细胞表面ICOS和ICOSL异常高表达,且与疾病活动度和临床疗效密切相关。提示ICOS/ICOSL信号通路可能参与RA免疫病理进程。
Objective: To investigate the expression of inducible costimulatory( ICOS) and inducible costimulatory ligand( ICOSL) on peripheral blood mononuclear cells( PBMCs) and their clinical relationship with rheumatoid arthritis( RA)patients. Methods: Peripheral blood samples were collected from 85 RA patients and 50 HC in this study. Expression of ICOS and ICOSL on PBMC from the subjects were detected by flow cytometry and real-time polymerase chain reaction( RT-PCR). The alteration of ICOS and ICOSL were observed after hormone therapy in 15 patients with RA and the relationship between their expression level and patients' clinical manifestations were analysed. Results: The ICOS and ICOSL mRNA level of RA patients' PBMCs were significantly higher than that in HC. The expression level of ICOS on CD4+T cells was higher than than that in HC[( 7. 08 ± 4. 72) % vs( 3. 01 +1. 39) %,P<0. 0001]. The expression of ICOSL on monocytes[( 5. 77±3. 45) % vs( 3. 64±1. 43) %,P<0. 05] and B cells [( 5. 78 ±4. 52) % vs( 3. 97±1. 63) %,P<0. 05] were significantly elevated in RA patients. In RA patients with active disease,however,ICOSL expression on monocytes and B cells were increased as compared with those in inactive RA patients [( 5. 45 ± 3. 50) % vs( 4. 04 ±1. 55) %,P = 0. 036],[( 6. 59 ±5. 74) % vs( 5. 63 ± 4. 30) %,P = 0. 016]. Furthermore,after receiving immunosuppressive therapy,the expressions of ICOS and ICOSL were notably reduced as compared with pre-therapy levels on PBMCs from patients [( 5. 45 ±3. 50) % vs( 4. 04±1. 55) %,P = 0. 036],[( 6. 59 ±5. 74) % vs( 5. 63 ±4. 30) %,P = 0. 016]. Conclusion: The high levels of ICOS and ICOSL expression were closely correlated with the degree of disease and therapeutic response,suggesting that ICOS / ICOSL pathway may play a critical role in pathogenesis of RA.
Objective: To investigate the expression of inducible costimulatory( ICOS) and inducible costimulatory ligand( ICOSL) on peripheral blood mononuclear cells( PBMCs) and their clinical relationship with rheumatoid arthritis( RA)patients. Methods: Peripheral blood samples were collected from 85 RA patients and 50 HC in this study. Expression of ICOS and ICOSL on PBMC from the subjects were detected by flow cytometry and real-time polymerase chain reaction( RT-PCR). The alteration of ICOS and ICOSL were observed after hormone therapy in 15 patients with RA and the relationship between their expression level and patients' clinical manifestations were analysed. Results: The ICOS and ICOSL mRNA level of RA patients' PBMCs were significantly higher than that in HC. The expression level of ICOS on CD4+T cells was higher than than that in HC[( 7. 08 ± 4. 72) % vs( 3. 01 +1. 39) %,P<0. 0001]. The expression of ICOSL on monocytes[( 5. 77±3. 45) % vs( 3. 64±1. 43) %,P<0. 05] and B cells [( 5. 78 ±4. 52) % vs( 3. 97±1. 63) %,P<0. 05] were significantly elevated in RA patients. In RA patients with active disease,however,ICOSL expression on monocytes and B cells were increased as compared with those in inactive RA patients [( 5. 45 ± 3. 50) % vs( 4. 04 ±1. 55) %,P = 0. 036],[( 6. 59 ±5. 74) % vs( 5. 63 ± 4. 30) %,P = 0. 016]. Furthermore,after receiving immunosuppressive therapy,the expressions of ICOS and ICOSL were notably reduced as compared with pre-therapy levels on PBMCs from patients [( 5. 45 ±3. 50) % vs( 4. 04±1. 55) %,P = 0. 036],[( 6. 59 ±5. 74) % vs( 5. 63 ±4. 30) %,P = 0. 016]. Conclusion: The high levels of ICOS and ICOSL expression were closely correlated with the degree of disease and therapeutic response,suggesting that ICOS / ICOSL pathway may play a critical role in pathogenesis of RA.
引文
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[4]Fan X,Quezada SA,Sepulveda MA,et al.Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy[J].J Exp Med,2014,211(4):715-725.
[5]Dong C,Juedes AE,Temann UA,et al.ICOS co-stimulatory receptor is essential for T-cell activation and function[J].Nature,2001,4(09):97-101.
[6]Amett FC,Edworthy SM,Bloch DA,et al.The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthtitis[J].Arthritis Rheum,1988,31(3):315-324.
[7]Pinals RS,Baum J,Bland,et al.Preliminary criteria for the clinical remission in rheumatois arthritis[J].Bull Rheum Dis,1982(1),32:7-10.
[8]Spolski R,Leonard WJ.IL21 and T follicular helper cells[J].Int Immunol,2009,22:7-12.
[9]King C,Tangye SG,Mackay CR.T follicular helper(TFH)cells in normal and dysregulated immune responses[J].Ann Rev Immunol,2008,26:741-766.
[10]Nurieva RI,Chung Y,Hwang D,et al.Generation of T follicular helper cells is mediated by IL-21 but independent of T helper 1,2,or 17 cell lineages[J].Immunity,2008,29(1):138-149.
[11]Sliver JS,Hunter CA.With a little help from their friends interleukin-21,T cells and B cells[J].Immunity,2008,29(1):7-9.
[12]Akiba H,Takeda K,Kojima Y,et al.The role of ICOS in the CXCR5+follicular B helper T cell maintenance in vivo[J].J Immunol,2005,175(4):2340-2348.
[13]Wang F,Yan T,Chen L,et al.Involvement of inducible costimulator ligand(ICOSL)expression in thyroid tissue in hyperthyroidism of graves'disease patients[J].Clin Immunol,2012,32(6):1253-1261.
[14]Minoru H,Manabu F,Takashi M,et al.Augmented ICOS expression in patients with early diffuse cutaneous systemic sclerosis[J].Rheumatology,2013,52(2):242-251.
[15]Yanaba K,Asano Y,Noda S,et al.Increased production of soluble inducible costimulator in patients with diffuse cutaneous systemic sclerosis[J].Arch Dermatol Res,2013,305(5):17-23.
[16]Frey O,Meisel J,Hutloff A,et al.Inducible costimulator(ICOS)blockade inhibits accumulation of polyfunctional T helper 1/T helper 17 cells and mitigates autoimmune arthritis[J].Ann Rheum Dis,2010,69(8):1495-1501.
[17]Jie M,Chenlu Z,Bin M,et al.Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis[J].Clin Dev Immunol,2012,2012:827480.
[18]Hamel KM,Cao Y,Olalekan SA,et al.B cell specific expression of ICOSL is necessary for the induction of arthritis[J].Arthritis Rheumatism,2014.66(1):60-67.
[19]崔冉,徐建华,帅宗文,等.滤泡辅助性T细胞及白细胞介素-21CXCL13在类风湿关节炎中的作用[J].中华风湿学杂志,2012,16(5):300-304.
[20]Herber D,Brown TP,Liang S,et al.IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21 R.Fc reduces disease progression[J].J Immunol,2007,178(6):3822-3830.
[21]Iwai H,Abe M,Hirose S,et al.Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis[J].J Immunol,2003,171(6):2848-2854.
[2]Merrill JT.Co-stimulatory molecules as targets for treatment of lupus[J].Clin Immunol,2013,148(3):369-375.
[3]Wang F,Zhu W,Liu T,et al.The expression analysis of ICOS-L on activated T cells and immature dendritic cells as well as malignant B cells and Grave's-disease-derived thyroid tissues by two novel m Abs against human ICOS-L[J].Tissue Antigens,2007,69(1):62-72.
[4]Fan X,Quezada SA,Sepulveda MA,et al.Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy[J].J Exp Med,2014,211(4):715-725.
[5]Dong C,Juedes AE,Temann UA,et al.ICOS co-stimulatory receptor is essential for T-cell activation and function[J].Nature,2001,4(09):97-101.
[6]Amett FC,Edworthy SM,Bloch DA,et al.The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthtitis[J].Arthritis Rheum,1988,31(3):315-324.
[7]Pinals RS,Baum J,Bland,et al.Preliminary criteria for the clinical remission in rheumatois arthritis[J].Bull Rheum Dis,1982(1),32:7-10.
[8]Spolski R,Leonard WJ.IL21 and T follicular helper cells[J].Int Immunol,2009,22:7-12.
[9]King C,Tangye SG,Mackay CR.T follicular helper(TFH)cells in normal and dysregulated immune responses[J].Ann Rev Immunol,2008,26:741-766.
[10]Nurieva RI,Chung Y,Hwang D,et al.Generation of T follicular helper cells is mediated by IL-21 but independent of T helper 1,2,or 17 cell lineages[J].Immunity,2008,29(1):138-149.
[11]Sliver JS,Hunter CA.With a little help from their friends interleukin-21,T cells and B cells[J].Immunity,2008,29(1):7-9.
[12]Akiba H,Takeda K,Kojima Y,et al.The role of ICOS in the CXCR5+follicular B helper T cell maintenance in vivo[J].J Immunol,2005,175(4):2340-2348.
[13]Wang F,Yan T,Chen L,et al.Involvement of inducible costimulator ligand(ICOSL)expression in thyroid tissue in hyperthyroidism of graves'disease patients[J].Clin Immunol,2012,32(6):1253-1261.
[14]Minoru H,Manabu F,Takashi M,et al.Augmented ICOS expression in patients with early diffuse cutaneous systemic sclerosis[J].Rheumatology,2013,52(2):242-251.
[15]Yanaba K,Asano Y,Noda S,et al.Increased production of soluble inducible costimulator in patients with diffuse cutaneous systemic sclerosis[J].Arch Dermatol Res,2013,305(5):17-23.
[16]Frey O,Meisel J,Hutloff A,et al.Inducible costimulator(ICOS)blockade inhibits accumulation of polyfunctional T helper 1/T helper 17 cells and mitigates autoimmune arthritis[J].Ann Rheum Dis,2010,69(8):1495-1501.
[17]Jie M,Chenlu Z,Bin M,et al.Increased frequency of circulating follicular helper T cells in patients with rheumatoid arthritis[J].Clin Dev Immunol,2012,2012:827480.
[18]Hamel KM,Cao Y,Olalekan SA,et al.B cell specific expression of ICOSL is necessary for the induction of arthritis[J].Arthritis Rheumatism,2014.66(1):60-67.
[19]崔冉,徐建华,帅宗文,等.滤泡辅助性T细胞及白细胞介素-21CXCL13在类风湿关节炎中的作用[J].中华风湿学杂志,2012,16(5):300-304.
[20]Herber D,Brown TP,Liang S,et al.IL-21 has a pathogenic role in a lupus-prone mouse model and its blockade with IL-21 R.Fc reduces disease progression[J].J Immunol,2007,178(6):3822-3830.
[21]Iwai H,Abe M,Hirose S,et al.Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis[J].J Immunol,2003,171(6):2848-2854.