PD-1/PD-L信号通路在慢性HBV感染免疫反应中的作用

陶丽琳; 赖欣; 韦嘉

doi:10.3969/j.issn.1001-5256.2016.12.031

PD-1/PD-L信号通路在慢性HBV感染免疫反应中的作用

DOI: 10.3969/j.issn.1001-5256.2016.12.031

昆明医科大学第四附属医院消化科

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中图分类号: R512.62
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出版历程
- 出版日期: 2016-12-20

PD-1/PD-L signaling pathway in chronic hepatitis B

摘要

摘要: 慢性乙型肝炎是影响我国人群健康的主要疾病之一,HBV的慢性感染可导致疾病的进展。程序性死亡因子（PD）1是近年来发现的属于B7/CD28家族的重要协同刺激分子,与其配体（PD-L）结合后在调节T淋巴细胞的活化、分化及增殖功能方面起着重要作用。在慢性HBV感染的不同阶段,PD-1及其配体的表达存在差异。PD-1及其配体在不同的免疫细胞上的相互作用引起机体的免疫耐受,最终导致HBV感染的慢性化。通过不同途径阻断PD-1/PD-L通路可以使耗竭的T淋巴细胞功能得到改善,提示可能是未来抗病毒治疗的方向之一。
- 肝炎病毒,乙型 /
- 肝炎,乙型,慢性 /
- 程序性死亡因子1 /
- 综述
Abstract: Hepatitis B is one of the major diseases that affect the health of Chinese people,and chronic hepatitis B virus( HBV) infection can lead to disease progression. Programmed death- 1( PD- 1) discovered in recent years is an important coordinated stimulus molecule which belongs to the B7/CD28 family. After its binding with programmed death ligand( PD- L),it can regulate the activation,differentiation,and proliferation of T lymphocytes. PD- 1 and its ligand are differently expressed in different stages of chronic HBV infection. The interaction between PD- 1 and its ligand in different immune cells induces immune tolerance in human body and finally leads to the chronicity of HBV infection. Blocking the PD- 1/PD- L signaling pathway through different ways can improve T cell exhaustion,suggesting that this might be one of the directions of antiviral therapy in future.
- hepatitis B,virus /
- hepatitis B,chronic /
- programmed death 1 /
- review

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参考文献(52)

[1]ISHIDA Y,AGATA Y,SIBAHARA K,et al.Induced expression of PDI,a novel member of the immunoglobulin gene superfamily upon programmed cell death[J].EMBO J,1992,11(11):3887-3895.

[2]GIBSON A,OGESE M,SULLIVAN A,et al.Negative regulation by PD-L1 during drug-specific priming of IL-22 secreting Tcells and the influence of PD-1 on effector T cell function[J].JImmunol,2014,192(6):2611-2621.

[3]CHEMNITZ JM,PARRY RV,NICHOLS KE,et al.SHP-1 and SHP-2 associate with immunoreceptor tyrosine-basd switch motif0f programmed death l upon primary human T cell stimulation,but only receptor ligation prevents T cell activation[J].J lmmunol,2004,173(2):945-954.

[4]WHERRY EJ,HA SJ,KAECH SM,et al.Molecular signature of CD8+T cell exhaustion during chronic viral infection[J].Immunity,2007,27(4):670-684.

[5]YANG W,LI H,CHEN PW,et al.PD-L1 expression on human ocular cells and its possible role in regulating immune-mediated ocular inflammation[J].Invest Ophthmol Vis Sci,2009,50(1):273-280.

[6]MARGARITE L,TARRIO N,GRABIE N,et al.PD-1 protects against inflammation and lymphocyte damage in T cell mediated myocarditis[J].J Immunol,2012,188(10):4876-4884.

[7]HAN YP,LI J,JIANG LF,et al.Hepatitis B e antigen from chronic hepatitis B patients induces Th1/Th2 cytokine imbalance in vitro[J].Chin J Hepatol,2013,21(8):584-589.(in Chinese)韩亚萍,李军,蒋龙凤,等.HBeA g导致慢性乙型肝炎患者外周血Thl/Th2型细胞因子失衡[J].中华肝脏病杂志,2013,21(8):584-589.

[8]HAN Y,LI J,JIANG L,et al.Regulation of B7-H1 expression on peripheral monocytes and IFN-gamma secretion in T lymphocytes by HBeA g[J].Cell Immunol,2013,283(1-2):25-30.

[9]SHARPE AH,WHERRY EJ,AHMED R,et al.The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection[J].Nat Immunol,2007,8(3):239-245.

[10]BARBER DL,WHERRY EJ,MASOPUST D,et al.Restoring function in exhausted CD8 T cells during chronic viral infection[J].Nature,2006,439(7077):682-687.

[11]MICHEL ML,DENG Q,MANCINI-BOURGINE M.Therapeutic vaccines and Immune-based therapies for the treatment of chronic hepatitis B:perspectives and challenges[J].J Hepatol,2011,54(6):1286-1296.

[12]YE B,LIU X,LI X,et al.T-cell exhaustion in chronic hepatitis B infection:current knowledge and clinical significance[J].Cell Death Dis,2015,6:e1694.

[13]ISOGAWA M,TANAKA Y.Immunobiology of hepatitis B virus infection[J].Hepatol Res,2015,45(2):179-189.

[14]MAIER H,ISOGAWA M,FREEMAN GJ,et al.PD-1:PD-L1 interactions contribute to the functional suppression of virus-specific CD8+T lymphocytes in the liver[J].J Immunol,2007,178(5):2714-2720.

[15]ATTINA D,VALENTINO M,GALIE N,et al.Application of a new pulmonary artery obstruction score in the prognostic evaluation of acute pulmonary embolism:comparison with clinical and haemodynamic parameters[J].Radiol Med,2011,116(2):230-245.

[16]FAN R,LAN Y,CHEN J,et al.T-bet expression in CD8+Tcells associated with chronic hepatitis B virus infection[J].Virol J,2016,13:14.

[17]TANG ZS,HAO YH,ZHANG EJ,et al.CD28 family of receptors on T cells in chronic HBV infection:expression characteristics,clinical significance and correlations with PD-1 blockade[J].Mol Med Rep,2016,14(2):1107-1116.

[18]ZHANG YX,YAN SY,WANG HC,et al.PD-1 and PD-L1expression in different stages of chronic HBV infection varies[J].Ningxia Med J,2016,38(9):790-792.(in Chinese)张玉喜,闫树英,王惠成,等.PD-1和PD-L1表达在慢性乙型肝炎病毒不同感染阶段患者的表达[J].宁夏医学杂志,2016,38(9):790-792.

[19]PENG G,LI S,WU W,et al.Circulating CD4+CD25+regulatory T cells correlate with chronic hepatitis B infection[J].Immunology,2008,123(1):57-65.

[20]FENG C,CAO LJ,SONG HF,et al.Expression of PD-L1 on CD4+CD25+Foxp3+regulatory T cells of patients with chronic HBV infection and its correlation with clinical parameters[J].Viral Immunol,2015,28(8):418-424.

[21]PARK SJ,NAMKOONG H,DOH J,et al.Negative role of inducible PD-1 on survival of activated dendritic cells[J].J Leukoc Biol,2014,95(4):621-629.

[22]SELENKO-GEBAU N,MAJDIC O,SZEKERES A,et al.B7-H1(programmed death-1 ligand)on dendritic cells is involved in the induction and maintenance of T cell anergy[J].J Immunol,2003,170(7):3637-3644.

[23]PENG GP,SUN W,WU W,et al.PD-L1 expression in circulating dendritic cells of patients with chronic hepatitis B[J].J Zhejiang Univ:Med Sci,2008,37(4):364-372.(in Chinese)彭国平,孙雯,吴炜,等.慢性乙型肝炎患者外周血树突状细胞PD-L1表达的相关研究[J].浙江大学学报:医学版,2008,37(4):364-372.

[24]LIMA TS,CHEWB V,SIEOWA JL,et al.PD-1 expression on dendritic cells suppresses CD8+T cell function and antitumor immunity[J].OncoI mmunology,2016,5(3):e1085146.

[25]CHEN LE,LI YG,ZHANG H,et al.Effect of B7-H1 on T-cell stimulating capacity of dendritic cells in chronic hepatitis B infenction[J].J Prev Med Chin PLA,2007,25(5):320-323.

[26]LI M,SUN XH,JUN X,et al.HBcA g induces PD-1 upregulation on CD4+T cells through activation of JNK,ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients[J].Lab Invest,2012,92(2):295-304.

[27]LIANG XS,ZHOU Y,LI CZ,et al.Natural course of chronic hepatitis B is characterized by changing patterns of programmed death type-1 of CD8-positive T cells[J].World J Gastroenterol,2010,16(5):618-624.

[28]PENG G,LI S,WU W,et al.PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients[J].Mol Immunol,2008,45(4):963-970.

[29]GAO YQ,ZHOU ZH,SUN XH,et al.PD-1/PD-L1 expression in different stages of chronic HBV infection varies[C]//The twenty-third National Academic Conference of Chinese traditional and Western Medicine,2014.(in Chinese)高月求,周振华,孙学华,等.慢性乙型肝炎不同感染状态患者PD-1和PD-L1表达的差异[C]//第二十三次全国中西医结合肝病学术会议,2014.

[30] ZHOU JY,ZHOU DF,LI JQ.PD-1 expression in HBcA g-specific CD8+T cells of adolescents with chronic HBV infection[J].Chin J Hepatol,2013,21(1):27-32.(in Chinese)周俊英,周东方,李俊卿.青少年慢性乙型肝炎患者乙型肝炎病毒特异性CD8+T淋巴细胞程序性死亡分子-1的表达[J].中华肝脏病杂志,2013,21(1):27-32.

[31]TENG XY,WANG P,ZHOU XG,et al.PD-I/PD-L1 expressions in liver tissues of patients with chronic HBV infection[J].Chin J Hepatol,2011,19(5):345-348.(in Chinese)滕晓英,王鹏,周新刚,等.慢性乙型肝炎病毒感染者肝组织中程序性死亡分子-1及其配体的表达[J].中华肝脏病杂志,2011,19(5):345-348.

[32]SHERMAN AC,TREHANPATI N,DAUCHER M,et al.Augmentation of hepatitis B virus-specific cellular immunity with programmed death receptor-1/programmed death receptor-L1 blockade in hepatitis B virusand HIV/hepatitis B virus coinfected patients treated with adefovir[J].AIDS Res Hum Retrovimses,2013,29(4):665-672.

[33]LIU J,ZHANGE,MA Z,et al.Enhancing virus-specific immunity in vivo by combining therapeutic vaccination and PD-L1 blockade in chronic hepadnaviral infection[J].PLoS Pathog,2014,10(1):e1003856.

[34]HOU FQ,WU XJ,WANG Y,et al.Rapid downregulation of programmed Death-1 and interferon-gamma-inducible protein-10expression is associated with favourable outcome during antiviral treatment of chronic hepatitis B[J].J Viral Hepat,2013,20(Suppl 1):18-26.

[35]XIE DY,LIN BL,CHEN FJ,et al.Programmed death-1(PD-1)and PD-L1 expression during antiviral treatment of chronic hepatitis B[J].Chin J Hepatol,2010,18(9):646-650.(in Chinese)谢冬英,林炳亮,陈风娟,等.慢性乙型肝炎患者抗病毒治疗过程程序性死亡分子1及其配体表达的变化[J].中华肝脏病杂志,2010,18(9):646-650.

[36]NAN XP,ZHANG Y,TAO H,et al.Inhibition of viral replication downregulates CD4+CD25highregulatory T cells and programmed death-1 ligand in chronic hepatitis B[J].Viral Immunol,2012,25(1):21-28.

[37]SU Y,BAO JF,LIANG XL,et al.The impact of entecavir on Tlymphocytes PD-1 levels in peripheral blood and liver function of CHB patients[J].Chin J Microecol,2015,27(3):354-357.(in Chinese)苏毅,包剑锋,梁学琳,等.恩替卡韦对CHB患者外周血T淋巴细胞PD-1水平及肝功能的影响[J].中国微生态学杂志,2015,27(3):354-357.

[38]WU LX,LIN SM,ZHANG X,et al.Dyanmic changes in B7-H1expression on peripheral blood mononuclear cells in chronic hepatitis B patients treated with entecavir[J].J Clin hepatol,2014,30(9):929-931.(in Chinese)吴列秀,蔺淑梅,张曦,等.接受恩替卡韦治疗的慢性乙型肝炎患者外周血单个核细胞B7-H1表达的动态变化[J].临床肝胆病杂志,2014,30(9):929-931.(in Chinese)

[39]SHEN HY,HANG SX,TONG XC,et al.The effect of antiviral therapy PD-1 and PD-L1 in peripheral blood of patients with chronic HBV infection and its relationship with serum HBV DNA[J].Guangdong Med J,2015,36(6):870-873.(in Chinese)申红玉,杭双熊,童学成,等.抗病毒治疗对慢性HBV感染者外周血中PD-1和PD-L1的影响及其与血清HBV DNA的关系[J].广东医学,2015,36(6):870-873.

[40]XIN JJ,PAN XC,MAO JJ,et al.The effect of interferon-α-therapy on the variations and the significance of Treg percentage and PD-L1 expression on monocytes in the peripheral blood in patients with chronic hepatitis B[J].Acta Acad Med Xuzhou,2011,31(3):163-165.(in Chinese)辛杰晶,潘修成,毛娟娟,等.α-干扰素治疗慢性乙型肝炎患者外周血调节性T细胞比例及单核细胞程序性死亡受体-1配体表达的变化及意义[J].徐州医学院学报,2011,31(3):163-165.

[41]JIN Y,QIU T,LYU YF,et al.Effect of the sequential therapy of lamivudine andα-interferon on cellular immune function as well as serum PD-1 and Tin-1 levels in patients B[J].J Hainan Med Coll,2016,22(14):1515-1517.(in Chinese)金燕,邱婷,吕颐菲,等.拉米夫定和α-干扰素序贯治疗对慢性乙肝患者细胞免疫功能以及血清中PD-1和Tin-3含量的影响[J].海南医学院学报,2016,22(14):1515-1517.

[42]LIU MK,LYU WL,ZHAO HH,et al.TCM about etiology and pathogenesis of chronic hepatitis B[J].J Changchun Univ Chin Med,2015,31(4):735-737.(in Chinese)刘明坤,吕文良,赵慧慧,等.慢性乙型肝炎病因病机再探[J].长春中医药大学学报,2015,31(4):735-737.

[43]SHEN H,NIE HM,CHEN YY,et al.Status of treatments of traditional Chinese medicine on chronic hepatitis B[J].J Changchun Univ Tradit Chin Med,2015,3(4):873-876.(in Chinese)申弘,聂红明,陈逸云,等.慢性乙型肝炎的中医药治疗[J].长春中医药大学学报,2015,3(4):873-876.

[44]ZHOU ZH,SUN XH,LI M,et al.Effect of kidney-tonifying and spleen-strengthening prescription on PD-1 and PD-L1 expression in HBeA g-positive chronic hepatitis B patients with slightly increased ALT levels[J].J Clin Hepatol,2015,31(1):58-62.(in Chinese)周振华,孙学华,李曼,等.补肾健脾方对ALT轻度升高的HBeA g阳性慢性乙型肝炎患者程序性死亡受体1/程序性死亡配体1表达的影响[J].临床肝胆病杂志,2015,31(1):58-62.

[45]MASHIMA E,INOUE A,SAKURAGI Y,et al.Nivolumab in the treatment of malignant melanoma:review of the literature[J].Onco Targets Ther,2015,8:2045-2051.

[46]TZENG HT,TSAI HF,LIAO HJ,et al.PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model[J].PLoS One,2012,7(6):e39179.

[47]BENGSCH B,MARTIN B,THIMME R.Restoration of HBV-specific CD8+T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation[J].J Hepatol,2014,61(6):1212-1219.

[48]FISICARO P,VALDTTA C,MASSARI M,et al.Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B[J].Gastroenterology,2010,138(2):682-693.

[49]HA SJ,MUELLER SN,WHERRY EJ,et al.Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection[J].J Exp Med,2008,205(3):543-555.

[50]ONLAMOON N,ROGERS K,MAYNE AE,et al.Soluble PD-1 rescues the proliferative response of simian immunodeficiency virusspecific CD4 and CD8 T cells during chronic infection[J].Immunology,2008,124(2):277-293.

[51]MOON EK,WANG LC,DOLFI DV,et al.Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors[J].Clin Cancer Res,2014,20(16):4262-4273.

[52]WHERRY EJ,BLATTMAN JN,MURALI-KRISHNA K,et al.Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment[J].J Virol,2003,77(8):4911-4927.

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