共信号分子CD28、ICOS、PD-1、CTLA-4在系统性红斑狼疮患者外周血中的表达水平及意义
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摘要
目的:探讨共信号分子CD28、ICOS、PD-1、CTLA-4是否参与系统性红斑狼疮(systemic lupus erythematosus,SLE)的发病机制。方法:收集20例SLE患者与30名健康体检者外周血标本,通过免疫荧光标记及流式细胞术检测共信号分子CD28、ICOS、PD-1、CTLA-4在活跃期、非活跃期患者及健康对照者外周血CD4+T细胞表面的表达水平,同时将上述共信号分子与系统性红斑狼疮疾病活动性指数(SLEDAI)进行相关性分析。结果:在SLE患者中,CD28和ICOS的表达水平与健康组比较差异无统计学意义(P> 0. 05),PD-1较健康组明显高表达(P <0. 001),CTLA-4较健康组低表达(P <0. 01);在20例自身对照组中,CD28及PD-1在活跃期较非活跃期均高表达(P <0. 05,P <0. 01),而ICOS及CTLA-4的表达水平差异无统计学意义(P> 0. 05)。且4种共信号分子的表达水平与SLEDAI评分均无相关性。结论:PD-1及CTLA-4、CD28可能参与SLE的发病机制,而ICOS可能与SLE的发病机制关系不大。
Objective: To demonstrate whether the costimulatory molecules CD28,ICOS,PD-1 and CTLA-4 are participated in pathogenesis of systemic lupus erythematosus( SLE). Methods: Peripheral blood samples from 20 SLE patients and 30 healthy subjects were collected. The expression levels of costimulatory molecules CD28,ICOS,PD-1 and CTLA-4 on the surface of CD4+T cells in patients with active and inactive SLE and healthy controls were detected by immunofluorescence labeling and flow cytometry. At the same time,the correlation between the above costimulatory molecules and disease activity index of systemic lupus erythematosus( SLEDAI)was analyzed. Results: In patients with SLE,there were no significant difference between the expression levers of CD28 and ICOS which were compared with the health group( P > 0. 05),the expression of PD-1 was significantly higher than that of the health group( P <0. 001),and the expression of CTLA-4 was lower than of the healthy group( P < 0. 01). In the self-control group,the expression levers of CD28 and PD-1 were higher than non-active group( P < 0. 05,P < 0. 01),but there were no difference between the expression levers of ICOS and CTLA-4( P > 0. 05). Moreover,there was no relation between the expression levers of those four costimulatory molecules and SLEDAI. Conclusion: PD-1,CTLA-4 and CD28 may be involved in the pathogenesis of SLE,but ICOS may be less to do with the pathogenesis of SLE.
Objective: To demonstrate whether the costimulatory molecules CD28,ICOS,PD-1 and CTLA-4 are participated in pathogenesis of systemic lupus erythematosus( SLE). Methods: Peripheral blood samples from 20 SLE patients and 30 healthy subjects were collected. The expression levels of costimulatory molecules CD28,ICOS,PD-1 and CTLA-4 on the surface of CD4+T cells in patients with active and inactive SLE and healthy controls were detected by immunofluorescence labeling and flow cytometry. At the same time,the correlation between the above costimulatory molecules and disease activity index of systemic lupus erythematosus( SLEDAI)was analyzed. Results: In patients with SLE,there were no significant difference between the expression levers of CD28 and ICOS which were compared with the health group( P > 0. 05),the expression of PD-1 was significantly higher than that of the health group( P <0. 001),and the expression of CTLA-4 was lower than of the healthy group( P < 0. 01). In the self-control group,the expression levers of CD28 and PD-1 were higher than non-active group( P < 0. 05,P < 0. 01),but there were no difference between the expression levers of ICOS and CTLA-4( P > 0. 05). Moreover,there was no relation between the expression levers of those four costimulatory molecules and SLEDAI. Conclusion: PD-1,CTLA-4 and CD28 may be involved in the pathogenesis of SLE,but ICOS may be less to do with the pathogenesis of SLE.
引文
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[10]Bijl M,Horst G,Limburg PC,et al.Expression of costimulatory molecules on peripheral blood lymphocytes of patients with systemic lupus erythematosus[J].Ann Rheum Dis,2001,60(5):523-526.
[11]Kawamoto M,Harigai M,Hara M,et al.Expression and function of inducible co-stimulator in patients with systemic lupus erythematosus:possible involvement in excessive interferon-γand anti-doublestranded DNA antibody production[J].Arthritis Research and Therapy,2006,8(3):1-14.
[12]Zhiping C,Zhenfu L,Shunhua Z,et al.Expression of Inducible Costimulator in Peripheral Blood T Lymphocytes in the Patients with Systemic Lupus Erythematosus[J].Journal of Huazhong University of Science and Technology:Medical Sciences,2005,25(3):357-359.
[13]Yang JH.Expression and function of inducible costimulator on peripheral blood T cells in patients with systemic lupus erythematosus[J].Rheumatology,2005,44(10):1245-1254.
[14]Shinohara T,Taniwaki M,Ishida Y,et al.Structure and chromosomal localization of the human PD-1 gene(PDCD1)[J].Genomics,1994,23(3):704-706.
[15]Chemnitz JM,Parry RV,Nichols KE,et al.SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon primary Human T Cell Stimulation,but Only Receptor Ligation Prevents T Cell Activation[J].The Journal of Immunology:Official Journal of the American Association of Immunologist,2004,173(2):945-954.
[16]Ishida Y,Agata Y,Shibahara K,et al.Induced expression of PD-1,a novel member of the immunoglobulin gene superfamily,upon programmed cell death[J].The EMBO journal,1992,11(11):3887-3895.
[17]Dolff S,Quandt D,Feldkamp T,et al.Increased percentages of PD-1 on CD4+T cells is associated with higher INF-γproduction and altered IL-17 production in patients with systemic lupus erythematosus[J].Scandinavian Journal of Rheumatology,2014,43(4):307-313.
[18]Teft WA,Chau TA,Madrenas J.Structure-Function analysis of the CTLA-4 interaction with PP2A[J].BMC Immunol,2009,10(1):10-23.
[19]Liu MF,Liu HS,Wang CR,et al.Expression of CTLA-4 Molecule in Peripheral Blood T Lymphocytes from Patients with Systemic Lupus Erythematosus[J].Journal of Clinical Immunology,1998,18(6):392-398.
[20]Liu MF,Wang CR,Chen PC,et al.Increased Expression of Soluble Cytotoxic T-Lymphocyte-Associated Antigen-4 Molecule in Patients with Systemic Lupus Erythematosus[J].Scandinavian Journal of Immunology,2003,57(6):568-572.
[21]Lee JH,Wang LC,Lin YT,et al.Inverse correlation between CD4+regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus[J].Immunology,2006,117(2):280-286.
[22]Alegre ML,Noel PJ,Eisfelder BJ,et al.Regulation of Surface and Intracellular Expression of CTLA4 on Mouse T Cells[J].The Journal of Immunology,1996,157(11):4762-4770.
[23]Chuang E,Alegre ML,Duckett CS,et al.Interaction of CTLA-4with the Clathrin-Associated Protein AP50 Results in Ligand-Independent Endocytosis That Limits Cell Surface Expression[J].Journal Of Immunology(Baltimore,Md.:1950),1997,159(1):144-151.
[24]Shiratori T,Miyatake S,Ohno H,et al.Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2[J].Immunity,1997,6(5):583-589.
[2]Sherlock JP,Taylor PC,Buckley CD.The biology of IL-23 and IL-17 and their therapeutic targeting in rheumatic diseases[J].Current Opinion in Rheumatology,2015,27(1):71-75.
[3]Hutloff A,Dittrich AM,Beier KC,et al.ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28[J].Nature,1999,397(6716):263-266.
[4]Parry RV,Chemnitz JM.CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms[J].Molecular and Cellular Biology,2005,25(21):9543-9553.
[5]Marc C,Hochberg MDM.Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus[J].Arthritis and Rheumatology,1997,40(9):1725.
[6]Sharpe AH,Freeman GJ.The B7-CD28 superfamily[J].Nature Reviews Immunology,2002,2(2):116-126.
[7]Hebbar M,Jeannin P,Magistrelli G,et al.Detection of circulating soluble CD28 in patients with systemic lupus erythematosus,primary Sj9gren’s syndrome and systemic sclerosis[J].Clin Exp Immunol,2004,136(2):382-388.
[8]Brambila-Tapia AJL,Gámez-Nava JI,Salazar-Páramo M,et al.Increased CD28 serum levels are not associated with specific clinical activity in systemic lupus erythematosus[J].Rheumatology International,2011,31(10):1321-1324.
[9]Kaneko H,Saito K,Hashimoto H,et al.Preferential elimination of CD28+T cells in systemic lupus erythematosus(SLE)and the relation with activation-induced apoptosis[J].Clin Exp Immunol,1996,106(2):218-229.
[10]Bijl M,Horst G,Limburg PC,et al.Expression of costimulatory molecules on peripheral blood lymphocytes of patients with systemic lupus erythematosus[J].Ann Rheum Dis,2001,60(5):523-526.
[11]Kawamoto M,Harigai M,Hara M,et al.Expression and function of inducible co-stimulator in patients with systemic lupus erythematosus:possible involvement in excessive interferon-γand anti-doublestranded DNA antibody production[J].Arthritis Research and Therapy,2006,8(3):1-14.
[12]Zhiping C,Zhenfu L,Shunhua Z,et al.Expression of Inducible Costimulator in Peripheral Blood T Lymphocytes in the Patients with Systemic Lupus Erythematosus[J].Journal of Huazhong University of Science and Technology:Medical Sciences,2005,25(3):357-359.
[13]Yang JH.Expression and function of inducible costimulator on peripheral blood T cells in patients with systemic lupus erythematosus[J].Rheumatology,2005,44(10):1245-1254.
[14]Shinohara T,Taniwaki M,Ishida Y,et al.Structure and chromosomal localization of the human PD-1 gene(PDCD1)[J].Genomics,1994,23(3):704-706.
[15]Chemnitz JM,Parry RV,Nichols KE,et al.SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon primary Human T Cell Stimulation,but Only Receptor Ligation Prevents T Cell Activation[J].The Journal of Immunology:Official Journal of the American Association of Immunologist,2004,173(2):945-954.
[16]Ishida Y,Agata Y,Shibahara K,et al.Induced expression of PD-1,a novel member of the immunoglobulin gene superfamily,upon programmed cell death[J].The EMBO journal,1992,11(11):3887-3895.
[17]Dolff S,Quandt D,Feldkamp T,et al.Increased percentages of PD-1 on CD4+T cells is associated with higher INF-γproduction and altered IL-17 production in patients with systemic lupus erythematosus[J].Scandinavian Journal of Rheumatology,2014,43(4):307-313.
[18]Teft WA,Chau TA,Madrenas J.Structure-Function analysis of the CTLA-4 interaction with PP2A[J].BMC Immunol,2009,10(1):10-23.
[19]Liu MF,Liu HS,Wang CR,et al.Expression of CTLA-4 Molecule in Peripheral Blood T Lymphocytes from Patients with Systemic Lupus Erythematosus[J].Journal of Clinical Immunology,1998,18(6):392-398.
[20]Liu MF,Wang CR,Chen PC,et al.Increased Expression of Soluble Cytotoxic T-Lymphocyte-Associated Antigen-4 Molecule in Patients with Systemic Lupus Erythematosus[J].Scandinavian Journal of Immunology,2003,57(6):568-572.
[21]Lee JH,Wang LC,Lin YT,et al.Inverse correlation between CD4+regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus[J].Immunology,2006,117(2):280-286.
[22]Alegre ML,Noel PJ,Eisfelder BJ,et al.Regulation of Surface and Intracellular Expression of CTLA4 on Mouse T Cells[J].The Journal of Immunology,1996,157(11):4762-4770.
[23]Chuang E,Alegre ML,Duckett CS,et al.Interaction of CTLA-4with the Clathrin-Associated Protein AP50 Results in Ligand-Independent Endocytosis That Limits Cell Surface Expression[J].Journal Of Immunology(Baltimore,Md.:1950),1997,159(1):144-151.
[24]Shiratori T,Miyatake S,Ohno H,et al.Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2[J].Immunity,1997,6(5):583-589.