ICOS/ICOSL、OX40/OX40L及CD40/CD40L在系统性红斑狼疮患者外周血表达水平及其临床意义
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摘要
本研究旨在检测SLE患者外周CD4+T细胞表面ICOS、OX40、CD40L及B细胞表面ICOSL、OX40L、CD40分子的表达情况,并探索其临床意义。采用流式细胞术,我们检测SLE患者及健康对照外周CD4+T细胞表面ICOS、OX40、CD40L及B细胞表面ICOSL、OX40L、CD40分子的表达,并分析其与SLE临床指标的相关性。结果显示,SLE患者外周CD4+T细胞上ICOS、OX40、CD40L及B细胞上ICOSL、OX40L、CD40分子的表达均明显高于健康对照组(均P<0.05),且SLE患者CD4+T细胞表面ICOS的表达与患者血清IgG水平呈现正相关,B细胞表面ICOSL的表达与患者血清抗dsDNA抗体水平正相关,B细胞表面OX40L的表达与患者血清抗核抗体水平正相关(均P<0.05)。上述结果表明SLE患者外周CD4+T细胞上ICOS、OX40、CD40L及B细胞上ICOSL、OX40L、CD40分子均发生上调,并与SLE自身抗体水平呈现正相关,提示分别表达于T细胞和B细胞表面的ICOS/ICOSL、OX40/OX40L及CD40/CD40L分子,通过相互作用参与SLE的致病过程。
To investigate the role of ICOS/ICOSL,OX40/OX40 Land CD40/CD40 Lin systemic lupus erythematosus(SLE),we have compared ICOS,OX40,CD40 Lexpressions on the surface of CD4+T cells and ICOSL,OX40 L,CD40on B cells between SLE patients and healthy controls by flow cytometry.The clinical significance of them was further analyzed.The results indicated that both ICOS,OX40,CD40 Lon CD4+T cells and ICOSL,OX40 L,CD40on B cells were up-regulated in SLE patients when compared with healthy controls(P <0.05).In the patients,we found that the expression level of ICOS on CD4+T cells positively correlated with IgG levels(P <0.05),whereas,the expression level of ICOSL on B cells positively correlated with anti-dsDNA levels(P <0.05).In addition,The expression level of OX40 Lon B cells positively correlated with ANA levels(P<0.05).Taken together,our results demonstrate that ICOS/ICOSL,OX40/OX40 Land CD40/CD40 L were up-regulated on the peripheral lymphocytes of SLE patients with significant correlation to disease severity and autoantibody production.The interaction between ICOS/ICOSL,OX40/OX40 Land CD40/CD40 Lmight mediate important roles in the pathogenesis of SLE.
To investigate the role of ICOS/ICOSL,OX40/OX40 Land CD40/CD40 Lin systemic lupus erythematosus(SLE),we have compared ICOS,OX40,CD40 Lexpressions on the surface of CD4+T cells and ICOSL,OX40 L,CD40on B cells between SLE patients and healthy controls by flow cytometry.The clinical significance of them was further analyzed.The results indicated that both ICOS,OX40,CD40 Lon CD4+T cells and ICOSL,OX40 L,CD40on B cells were up-regulated in SLE patients when compared with healthy controls(P <0.05).In the patients,we found that the expression level of ICOS on CD4+T cells positively correlated with IgG levels(P <0.05),whereas,the expression level of ICOSL on B cells positively correlated with anti-dsDNA levels(P <0.05).In addition,The expression level of OX40 Lon B cells positively correlated with ANA levels(P<0.05).Taken together,our results demonstrate that ICOS/ICOSL,OX40/OX40 Land CD40/CD40 L were up-regulated on the peripheral lymphocytes of SLE patients with significant correlation to disease severity and autoantibody production.The interaction between ICOS/ICOSL,OX40/OX40 Land CD40/CD40 Lmight mediate important roles in the pathogenesis of SLE.
引文
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[2]邵康,张晨星,赵莉,等.PD-1/PD-L1在系统性红斑狼疮患者外周血表达水平及其临床意义[J].现代免疫学,2014,34:386-390。
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[6]GreenwaId RJ,McAdam AJ,Woude DV,et al.Inducible costimulator protein regulates both Th1and Th2responses to cutaneous Leishamaniasis[J].J lmmunol,2002,168:991-995.
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[12]Wu Q,Gardiner GJ,Berry E,et al.ICOS-expressing lymphocytes promote resolution of CD8-mediated lung injury in a mouse model of lung rejection[J].PLoS One,2013,8:e72955.
[13]Hutloff A,Buchner K,Reiter K,et al.Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus[J].Arthr Rheum,2004,50:3211-3220.
[14]Iwai H,Abe M,Hirose S,et al.Involvement of inducible costimulator-B7homologous protein costimulatory pathway in murine lupus nephritis[J].J Immunol,2003,171:2848-2854.
[15]Patschan S,Dolff S,Kribben A,et al.CD134expression on CD4+T cells is associated with nephritis and disease activity in patients with systemic lupus erythematosus[J].Clin Exp Immunol,2006,145:235-242.
[16]Cunninghame Graham DS,Graham RR,Manku H,et al.Polymorphism at the TNF superfamily gene TNFSF4confers susceptibility to systemic lupus erythematosus[J].Nat Genet,2008,40:83-89.
[17]Chang YK,Yang W,Zhao M,et al.Association of BANK1and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese[J].Genes Immun,2009,10:414-420.
[18]Rogers PR,Song J,Gramaglia I,et al.OX40promotes BclxL and Bcl-2expression and is essential for long-term survival of CD4Tcells[J].Immunity,2001,15:445-455.
[19]Zhang W1,Shi Q,Xu X,et al.Aberrant CD40-induced NF-κB activation in human lupus B lymphocytes[J].PLoS One,2012:7:e41644.
[20]Yellin MJ,Dagati V,Parkinson C,et al.Immunohistologic analysis of renal CD40and CD40Lexpression in lupus nephritis and other glomerulonephritides[J].Arthr Rheum,1997,40:124.
[21]Christadoss P1,Poussin M,Deng C.Animal models of myasthenia gravis[J].Clin Immunol,2000,94:75-87.
[22]Volmar CH,Ait-Ghezala G,Frieling J,et al.CD40/CD40L interaction induces Abeta production and increases gamma secretase activity independently of tumor necrosis factor receptor associated factor(TRAF)signaling[J].Exp Cell Res,2009,315:2265-2274.
[23]Saijo S,Asano M,Horai R,et al.Suppression of autoimmune arthritis in interleukin1-1-deficient mice in which T cell activation is impaired due to low levels of CD40ligand and OX40expression on T cells[J].Arthr Rheum,2002,46:533-544.
[24]Jeurissen A,Wuyts M,Kasran A,et al.Essential role for CD40ligand interactions in T lymphocyte-mediated modulation of the murine immune response to pneumococcal capsular poly saccharides[J].J Immunol,2002,168:2773-2781.
[25]Mohan C,Shi Y,Laman JD,et al.Interaction between CD40and its ligand gp39in the development of murine lupus nephritis[J].J Immunol,1995,154:1470-1480.
[2]邵康,张晨星,赵莉,等.PD-1/PD-L1在系统性红斑狼疮患者外周血表达水平及其临床意义[J].现代免疫学,2014,34:386-390。
[3]Kidd P.Th1/Th2balance:the hypothesis,its limitations,and implications for health and disease[J].Alternat Medi Rev,2003,8:223-246.
[4]Klaus SJ,Pinchuk LM,Ochs HD,et al.Costimulation through CD28enhances T cell-dependent B cell activation via CD40-CD40Linteraction[J].J Immunol,1994,152:5643-5652.
[5]Zhang Y,Yasuda T,Wang CR,et al.A pivotal role of cellbound but not soluble CD4 molecules in full development of lupus-like manifestations in MRL-Fas(lprcg)/Fas(lprcg)mice[J].Clin Exp Immunol,2000,122:124-132.
[6]GreenwaId RJ,McAdam AJ,Woude DV,et al.Inducible costimulator protein regulates both Th1and Th2responses to cutaneous Leishamaniasis[J].J lmmunol,2002,168:991-995.
[7]Katri EH,Jukka AP,Pivi MH.Genetic polymorphism of the human ICOS gene[J].Immunogenetics,2002,53:1028-1032.
[8]Smith KM,Brewer JM,Webb P,et al.Inducible costimulatory molecule-B7-related protein 1interactions are important for the clonal expansion and helper functions of nave,Th1,and Th2TceIIs[J].J Immunol,2003,170:2310-2315.
[9]Witsch EJ,Peiser M,Hutloff A,et a1.ICOS and CD28reversely regulate IL-10on re-activation of human effector T cells with mature dendritic cells[J].Immunol,2002,32:2680-2686.
[10]Lohning M,Hutloff A,Kallinich T,et a1.Expression of ICOS in vivo defines CD4-effector T cells with high inflanmmory potential and a strong bias for secretion of intedeukin 10[J].J Exp Med,2003,197:181-193.
[11]Qnintero-Del-Rio AI,Kelly JA,Kilpatrick J,et al.The genetics of systemic lupus erythematesus stratified by renal disease:linkage at 10q22.3(SLEN1),2Q34-35(SLEN2)and llpl5.6(SLEN3)[J].Gene Immun,2002,3:S57-S62.
[12]Wu Q,Gardiner GJ,Berry E,et al.ICOS-expressing lymphocytes promote resolution of CD8-mediated lung injury in a mouse model of lung rejection[J].PLoS One,2013,8:e72955.
[13]Hutloff A,Buchner K,Reiter K,et al.Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus[J].Arthr Rheum,2004,50:3211-3220.
[14]Iwai H,Abe M,Hirose S,et al.Involvement of inducible costimulator-B7homologous protein costimulatory pathway in murine lupus nephritis[J].J Immunol,2003,171:2848-2854.
[15]Patschan S,Dolff S,Kribben A,et al.CD134expression on CD4+T cells is associated with nephritis and disease activity in patients with systemic lupus erythematosus[J].Clin Exp Immunol,2006,145:235-242.
[16]Cunninghame Graham DS,Graham RR,Manku H,et al.Polymorphism at the TNF superfamily gene TNFSF4confers susceptibility to systemic lupus erythematosus[J].Nat Genet,2008,40:83-89.
[17]Chang YK,Yang W,Zhao M,et al.Association of BANK1and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese[J].Genes Immun,2009,10:414-420.
[18]Rogers PR,Song J,Gramaglia I,et al.OX40promotes BclxL and Bcl-2expression and is essential for long-term survival of CD4Tcells[J].Immunity,2001,15:445-455.
[19]Zhang W1,Shi Q,Xu X,et al.Aberrant CD40-induced NF-κB activation in human lupus B lymphocytes[J].PLoS One,2012:7:e41644.
[20]Yellin MJ,Dagati V,Parkinson C,et al.Immunohistologic analysis of renal CD40and CD40Lexpression in lupus nephritis and other glomerulonephritides[J].Arthr Rheum,1997,40:124.
[21]Christadoss P1,Poussin M,Deng C.Animal models of myasthenia gravis[J].Clin Immunol,2000,94:75-87.
[22]Volmar CH,Ait-Ghezala G,Frieling J,et al.CD40/CD40L interaction induces Abeta production and increases gamma secretase activity independently of tumor necrosis factor receptor associated factor(TRAF)signaling[J].Exp Cell Res,2009,315:2265-2274.
[23]Saijo S,Asano M,Horai R,et al.Suppression of autoimmune arthritis in interleukin1-1-deficient mice in which T cell activation is impaired due to low levels of CD40ligand and OX40expression on T cells[J].Arthr Rheum,2002,46:533-544.
[24]Jeurissen A,Wuyts M,Kasran A,et al.Essential role for CD40ligand interactions in T lymphocyte-mediated modulation of the murine immune response to pneumococcal capsular poly saccharides[J].J Immunol,2002,168:2773-2781.
[25]Mohan C,Shi Y,Laman JD,et al.Interaction between CD40and its ligand gp39in the development of murine lupus nephritis[J].J Immunol,1995,154:1470-1480.