Immune response pattern varies with the natural history of chronic hepatitis B
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摘要
BACKGROUND Chronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant(IT), immune active(IA), inactive carrier(IC) and hepatitis B envelope antigen(HBeAg)-negative hepatitis(ENEG).AIM To investigate the immune status of natural killer(NK) and T cells in different phases of chronic hepatitis B.METHODS The frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus(HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects.RESULTS The ability of NK cells to produce IFN-γ was markedly attenuated in HBVinfected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-α production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEGphases, as evidenced by the upregulation of NKp44 in CD56~(bright) NK cells and CD69 in CD56~(dim) NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-γ and TNF-αexpression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases.CONCLUSION Our findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.
BACKGROUND Chronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant(IT), immune active(IA), inactive carrier(IC) and hepatitis B envelope antigen(HBeAg)-negative hepatitis(ENEG).AIM To investigate the immune status of natural killer(NK) and T cells in different phases of chronic hepatitis B.METHODS The frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus(HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects.RESULTS The ability of NK cells to produce IFN-γ was markedly attenuated in HBVinfected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-α production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEGphases, as evidenced by the upregulation of NKp44 in CD56~(bright) NK cells and CD69 in CD56~(dim) NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-γ and TNF-αexpression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases.CONCLUSION Our findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.
BACKGROUND Chronic hepatitis B is a highly heterogeneous disease that can be divided into four phases: Immune tolerant(IT), immune active(IA), inactive carrier(IC) and hepatitis B envelope antigen(HBeAg)-negative hepatitis(ENEG).AIM To investigate the immune status of natural killer(NK) and T cells in different phases of chronic hepatitis B.METHODS The frequency, phenotype and function of circulating NK cells, as well as nonantigen-specific and hepatitis B virus(HBV)-specific T cell responses were detected by flow cytometry in healthy and HBV-infected subjects.RESULTS The ability of NK cells to produce IFN-γ was markedly attenuated in HBVinfected patients overall but was less compromised in IC patients. Patients in the IT and IA phases also displayed significantly lower TNF-α production compared to healthy subjects. NK cells were phenotypically activated in the IA and ENEGphases, as evidenced by the upregulation of NKp44 in CD56~(bright) NK cells and CD69 in CD56~(dim) NK cells. Furthermore, global T-cells from the ENEG phase displayed a proinflammatory cytokine profile with upregulated IFN-γ and TNF-αexpression, while this profile was suppressed in IT and IA patients. Finally, core and S antigen-specific T cell responses were significantly stronger after in vitro expansion in the IC phase compared to other phases.CONCLUSION Our findings demonstrate the changes in immune response pattern during the natural history of HBV infection. Both NK and T cells are functionally impaired in the IT and IA phases. With the spontaneous clearance of HBeAg and hepatitis B surface antigen decline, NK cell cytokine production and HBV-specific T responses are partially restored in IC phase, and the ENEG phase is dominated by nonantigen-specific T cell responses.
引文
1 Sarin SK,Kumar M,Lau GK,Abbas Z,Chan HL,Chen CJ,Chen DS,Chen HL,Chen PJ,Chien RN,Dokmeci AK,Gane E,Hou JL,Jafri W,Jia J,Kim JH,Lai CL,Lee HC,Lim SG,Liu CJ,Locarnini S,Al Mahtab M,Mohamed R,Omata M,Park J,Piratvisuth T,Sharma BC,Sollano J,Wang FS,Wei L,Yuen MF,Zheng SS,Kao JH.Asian-Pacific clinical practice guidelines on the management of hepatitis B:a2015 update.Hepatol Int 2016;10:1-98[PMID:26563120 DOI:10.1007/s12072-015-9675-4]
2 European Association for the Study of the Liver.EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol 2017;67:370-398[PMID:28427875 DOI:10.1016/j.jhep.2017.03.021]
3 Terrault NA,Lok ASF,McMahon BJ,Chang KM,Hwang JP,Jonas MM,Brown RS,Bzowej NH,Wong JB.Update on prevention,diagnosis,and treatment of chronic hepatitis B:AASLD 2018 hepatitis Bguidance.Hepatology 2018;67:1560-1599[PMID:29405329 DOI:10.1002/hep.29800]
4 Werle-Lapostolle B,Bowden S,Locarnini S,Wursthorn K,Petersen J,Lau G,Trepo C,Marcellin P,Goodman Z,Delaney WE 4th,Xiong S,Brosgart CL,Chen SS,Gibbs CS,Zoulim F.Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy.Gastroenterology 2004;126:1750-1758[PMID:15188170 DOI:10.1053/j.gastro.2004.03.018]
5 Zeng LY,Lian JS,Chen JY,Jia HY,Zhang YM,Xiang DR,Yu L,Hu JH,Lu YF,Zheng L,Li LJ,Yang YD.Hepatitis B surface antigen levels during natural history of chronic hepatitis B:A Chinese perspective study.World J Gastroenterol 2014;20:9178-9184[PMID:25083092]
6 Rehermann B.Pathogenesis of chronic viral hepatitis:Differential roles of T cells and NK cells.Nat Med2013;19:859-868[PMID:23836236 DOI:10.1038/nm.3251]
7 Peppa D,Micco L,Javaid A,Kennedy PT,Schurich A,Dunn C,Pallant C,Ellis G,Khanna P,Dusheiko G,Gilson RJ,Maini MK.Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.PLoS Pathog 2010;6:e1001227[PMID:21187913 DOI:10.1371/journal.ppat.1001227]
8 Zhang Z,Zhang S,Zou Z,Shi J,Zhao J,Fan R,Qin E,Li B,Li Z,Xu X,Fu J,Zhang J,Gao B,Tian Z,Wang FS.Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients.Hepatology 2011;53:73-85[PMID:21254163 DOI:10.1002/hep.23977]
9 Li Y,Wang JJ,Gao S,Liu Q,Bai J,Zhao XQ,Hao YH,Ding HH,Zhu F,Yang DL,Zhao XP.Decreased peripheral natural killer cells activity in the immune activated stage of chronic hepatitis B.PLoS One 2014;9:e86927[PMID:24520324 DOI:10.1371/journal.pone.0086927]
10 Ghosh S,Nandi M,Pal S,Mukhopadhyay D,Chakraborty BC,Khatun M,Bhowmick D,Mondal RK,Das S,Das K,Ghosh R,Banerjee S,Santra A,Chatterjee M,Chowdhury A,Datta S.Natural killer cells contribute to hepatic injury and help in viral persistence during progression of hepatitis B e-antigennegative chronic hepatitis B virus infection.Clin Microbiol Infect 2016;22:733.e9-733.e19[PMID:27208430 DOI:10.1016/j.cmi.2016.05.009]
11 Oliviero B,Varchetta S,Paudice E,Michelone G,Zaramella M,Mavilio D,De Filippi F,Bruno S,Mondelli MU.Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections.Gastroenterology 2009;137:1151-1160,1160.e1-1160.e7[PMID:19470388 DOI:10.1053/j.gastro.2009.05.047]
12 Tjwa ET,van Oord GW,Hegmans JP,Janssen HL,Woltman AM.Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B.J Hepatol 2011;54:209-218[PMID:21095036 DOI:10.1016/j.jhep.2010.07.009]
13 Chang JJ,Lewin SR.Immunopathogenesis of hepatitis B virus infection.Immunol Cell Biol 2007;85:16-23[PMID:17130898 DOI:10.1038/sj.icb.7100009]
14 Thimme R,Wieland S,Steiger C,Ghrayeb J,Reimann KA,Purcell RH,Chisari FV.CD8(+)T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection.J Virol 2003;77:68-76[PMID:12477811 DOI:10.1128/JVI.77.1.68-76.2003]
15 Tan AT,Koh S,Goh V,Bertoletti A.Understanding the immunopathogenesis of chronic hepatitis B virus:An Asian prospective.J Gastroenterol Hepatol 2008;23:833-843[PMID:18565018 DOI:10.1111/j.1440-1746.2008.05385.x]
16 Webster GJ,Reignat S,Brown D,Ogg GS,Jones L,Seneviratne SL,Williams R,Dusheiko G,Bertoletti A.Longitudinal analysis of CD8+T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B:Implications for immunotherapy.J Virol 2004;78:5707-5719[PMID:15140968 DOI:10.1128/JVI.78.11.5707-5719.2004]
17 Nguyen T,Thompson AJ,Bowden S,Croagh C,Bell S,Desmond PV,Levy M,Locarnini SA.Hepatitis Bsurface antigen levels during the natural history of chronic hepatitis B:A perspective on Asia.J Hepatol2010;52:508-513[PMID:20206400 DOI:10.1016/j.jhep.2010.01.007]
18 Yoshioka T,Tatsumi T,Miyagi T,Mukai K,Nishio K,Nishio A,Yokoyama Y,Suda T,Kegasawa T,Shigekawa M,Hikita H,Sakamori R,Takehara T.Frequency and role of NKp46 and NKG2A in hepatitis B virus infection.PLoS One 2017;12:e0174103[PMID:28328926 DOI:10.1371/journal.pone.0174103]
19 Sun C,Fu B,Gao Y,Liao X,Sun R,Tian Z,Wei H.TGF-β1 down-regulation of NKG2D/DAP10 and2B4/SAP expression on human NK cells contributes to HBV persistence.PLoS Pathog 2012;8:e1002594[PMID:22438812 DOI:10.1371/journal.ppat.1002594]
20 Wang XX,Luo BF,Jiang HJ,Cong X,Jin Q,Ma DL,Wei L,Feng B.Recovery of natural killer cells is mainly in post-treatment period in chronic hepatitis C patients treated with sofosbuvir plus ledipasvir.World J Gastroenterol 2018;24:4554-4564[PMID:30386105 DOI:10.3748/wjg.v24.i40.4554]
21 Xia Y,Stadler D,Lucifora J,Reisinger F,Webb D,H?sel M,Michler T,Wisskirchen K,Cheng X,Zhang K,Chou WM,Wettengel JM,Malo A,Bohne F,Hoffmann D,Eyer F,Thimme R,Falk CS,Thasler WE,Heikenwalder M,Protzer U.Interferon-γand Tumor Necrosis Factor-αProduced by T Cells Reduce the HBV Persistence Form,cccDNA,Without Cytolysis.Gastroenterology 2016;150:194-205[PMID:26416327 DOI:10.1053/j.gastro.2015.09.026]
22 Zou Z,Li B,Xu D,Zhang Z,Zhao JM,Zhou G,Sun Y,Huang L,Fu J,Yang Y,Jin L,Zhang W,Zhao J,Sun Y,Xin S,Wang FS.Imbalanced intrahepatic cytokine expression of interferon-gamma,tumor necrosis factor-alpha,and interleukin-10 in patients with acute-on-chronic liver failure associated with hepatitis Bvirus infection.J Clin Gastroenterol 2009;43:182-190[PMID:18633332 DOI:10.1097/MCG.0b013e3181624464]
23 Liang M,Ma S,Hu X,Zhou B,Zhang J,Chen J,Wang Z,Sun J,Zhu X,Abbott W,Hou J.Cellular immune responses in patients with hepatitis B surface antigen seroclearance induced by antiviral therapy.Virol J 2011;8:69[PMID:21320337 DOI:10.1186/1743-422X-8-69]
24 Park JJ,Wong DK,Wahed AS,Lee WM,Feld JJ,Terrault N,Khalili M,Sterling RK,Kowdley KV,Bzowej N,Lau DT,Kim WR,Smith C,Carithers RL,Torrey KW,Keith JW,Levine DL,Traum D,Ho S,Valiga ME,Johnson GS,Doo E,Lok AS,Chang KM;Hepatitis B Research Network.Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B.Gastroenterology 2016;150:684-695.e5[PMID:26684441 DOI:10.1053/j.gastro.2015.11.050]
25 Boni C,Laccabue D,Lampertico P,Giuberti T,ViganòM,Schivazappa S,Alfieri A,Pesci M,Gaeta GB,Brancaccio G,Colombo M,Missale G,Ferrari C.Restored function of HBV-specific T cells after longterm effective therapy with nucleos(t)ide analogues.Gastroenterology 2012;143:963-973.e9[PMID:22796241 DOI:10.1053/j.gastro.2012.07.014]
26 Mueller SN,Ahmed R.High antigen levels are the cause of T cell exhaustion during chronic viral infection.Proc Natl Acad Sci USA 2009;106:8623-8628[PMID:19433785 DOI:10.1073/pnas.0809818106]
27 Vanwolleghem T,Hou J,van Oord G,Andeweg AC,Osterhaus AD,Pas SD,Janssen HL,Boonstra A.Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells.Hepatology 2015;62:87-100[PMID:25808668 DOI:10.1002/hep.27805]
28 Das A,Hoare M,Davies N,Lopes AR,Dunn C,Kennedy PT,Alexander G,Finney H,Lawson A,Plunkett FJ,Bertoletti A,Akbar AN,Maini MK.Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection.J Exp Med 2008;205:2111-2124[PMID:18695005 DOI:10.1084/jem.20072076]
29 Croagh CM,Lubel JS.Natural history of chronic hepatitis B:phases in a complex relationship.World JGastroenterol 2014;20:10395-10404[PMID:25132755 DOI:10.3748/wjg.v20.i30.10395]
30 Fisicaro P,Valdatta C,Massari M,Loggi E,Biasini E,Sacchelli L,Cavallo MC,Silini EM,Andreone P,Missale G,Ferrari C.Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B.Gastroenterology 2010;138:682-693,693.e1-693.e4[PMID:19800335 DOI:10.1053/j.gastro.2009.09.052]
2 European Association for the Study of the Liver.EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.J Hepatol 2017;67:370-398[PMID:28427875 DOI:10.1016/j.jhep.2017.03.021]
3 Terrault NA,Lok ASF,McMahon BJ,Chang KM,Hwang JP,Jonas MM,Brown RS,Bzowej NH,Wong JB.Update on prevention,diagnosis,and treatment of chronic hepatitis B:AASLD 2018 hepatitis Bguidance.Hepatology 2018;67:1560-1599[PMID:29405329 DOI:10.1002/hep.29800]
4 Werle-Lapostolle B,Bowden S,Locarnini S,Wursthorn K,Petersen J,Lau G,Trepo C,Marcellin P,Goodman Z,Delaney WE 4th,Xiong S,Brosgart CL,Chen SS,Gibbs CS,Zoulim F.Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy.Gastroenterology 2004;126:1750-1758[PMID:15188170 DOI:10.1053/j.gastro.2004.03.018]
5 Zeng LY,Lian JS,Chen JY,Jia HY,Zhang YM,Xiang DR,Yu L,Hu JH,Lu YF,Zheng L,Li LJ,Yang YD.Hepatitis B surface antigen levels during natural history of chronic hepatitis B:A Chinese perspective study.World J Gastroenterol 2014;20:9178-9184[PMID:25083092]
6 Rehermann B.Pathogenesis of chronic viral hepatitis:Differential roles of T cells and NK cells.Nat Med2013;19:859-868[PMID:23836236 DOI:10.1038/nm.3251]
7 Peppa D,Micco L,Javaid A,Kennedy PT,Schurich A,Dunn C,Pallant C,Ellis G,Khanna P,Dusheiko G,Gilson RJ,Maini MK.Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection.PLoS Pathog 2010;6:e1001227[PMID:21187913 DOI:10.1371/journal.ppat.1001227]
8 Zhang Z,Zhang S,Zou Z,Shi J,Zhao J,Fan R,Qin E,Li B,Li Z,Xu X,Fu J,Zhang J,Gao B,Tian Z,Wang FS.Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients.Hepatology 2011;53:73-85[PMID:21254163 DOI:10.1002/hep.23977]
9 Li Y,Wang JJ,Gao S,Liu Q,Bai J,Zhao XQ,Hao YH,Ding HH,Zhu F,Yang DL,Zhao XP.Decreased peripheral natural killer cells activity in the immune activated stage of chronic hepatitis B.PLoS One 2014;9:e86927[PMID:24520324 DOI:10.1371/journal.pone.0086927]
10 Ghosh S,Nandi M,Pal S,Mukhopadhyay D,Chakraborty BC,Khatun M,Bhowmick D,Mondal RK,Das S,Das K,Ghosh R,Banerjee S,Santra A,Chatterjee M,Chowdhury A,Datta S.Natural killer cells contribute to hepatic injury and help in viral persistence during progression of hepatitis B e-antigennegative chronic hepatitis B virus infection.Clin Microbiol Infect 2016;22:733.e9-733.e19[PMID:27208430 DOI:10.1016/j.cmi.2016.05.009]
11 Oliviero B,Varchetta S,Paudice E,Michelone G,Zaramella M,Mavilio D,De Filippi F,Bruno S,Mondelli MU.Natural killer cell functional dichotomy in chronic hepatitis B and chronic hepatitis C virus infections.Gastroenterology 2009;137:1151-1160,1160.e1-1160.e7[PMID:19470388 DOI:10.1053/j.gastro.2009.05.047]
12 Tjwa ET,van Oord GW,Hegmans JP,Janssen HL,Woltman AM.Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B.J Hepatol 2011;54:209-218[PMID:21095036 DOI:10.1016/j.jhep.2010.07.009]
13 Chang JJ,Lewin SR.Immunopathogenesis of hepatitis B virus infection.Immunol Cell Biol 2007;85:16-23[PMID:17130898 DOI:10.1038/sj.icb.7100009]
14 Thimme R,Wieland S,Steiger C,Ghrayeb J,Reimann KA,Purcell RH,Chisari FV.CD8(+)T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection.J Virol 2003;77:68-76[PMID:12477811 DOI:10.1128/JVI.77.1.68-76.2003]
15 Tan AT,Koh S,Goh V,Bertoletti A.Understanding the immunopathogenesis of chronic hepatitis B virus:An Asian prospective.J Gastroenterol Hepatol 2008;23:833-843[PMID:18565018 DOI:10.1111/j.1440-1746.2008.05385.x]
16 Webster GJ,Reignat S,Brown D,Ogg GS,Jones L,Seneviratne SL,Williams R,Dusheiko G,Bertoletti A.Longitudinal analysis of CD8+T cells specific for structural and nonstructural hepatitis B virus proteins in patients with chronic hepatitis B:Implications for immunotherapy.J Virol 2004;78:5707-5719[PMID:15140968 DOI:10.1128/JVI.78.11.5707-5719.2004]
17 Nguyen T,Thompson AJ,Bowden S,Croagh C,Bell S,Desmond PV,Levy M,Locarnini SA.Hepatitis Bsurface antigen levels during the natural history of chronic hepatitis B:A perspective on Asia.J Hepatol2010;52:508-513[PMID:20206400 DOI:10.1016/j.jhep.2010.01.007]
18 Yoshioka T,Tatsumi T,Miyagi T,Mukai K,Nishio K,Nishio A,Yokoyama Y,Suda T,Kegasawa T,Shigekawa M,Hikita H,Sakamori R,Takehara T.Frequency and role of NKp46 and NKG2A in hepatitis B virus infection.PLoS One 2017;12:e0174103[PMID:28328926 DOI:10.1371/journal.pone.0174103]
19 Sun C,Fu B,Gao Y,Liao X,Sun R,Tian Z,Wei H.TGF-β1 down-regulation of NKG2D/DAP10 and2B4/SAP expression on human NK cells contributes to HBV persistence.PLoS Pathog 2012;8:e1002594[PMID:22438812 DOI:10.1371/journal.ppat.1002594]
20 Wang XX,Luo BF,Jiang HJ,Cong X,Jin Q,Ma DL,Wei L,Feng B.Recovery of natural killer cells is mainly in post-treatment period in chronic hepatitis C patients treated with sofosbuvir plus ledipasvir.World J Gastroenterol 2018;24:4554-4564[PMID:30386105 DOI:10.3748/wjg.v24.i40.4554]
21 Xia Y,Stadler D,Lucifora J,Reisinger F,Webb D,H?sel M,Michler T,Wisskirchen K,Cheng X,Zhang K,Chou WM,Wettengel JM,Malo A,Bohne F,Hoffmann D,Eyer F,Thimme R,Falk CS,Thasler WE,Heikenwalder M,Protzer U.Interferon-γand Tumor Necrosis Factor-αProduced by T Cells Reduce the HBV Persistence Form,cccDNA,Without Cytolysis.Gastroenterology 2016;150:194-205[PMID:26416327 DOI:10.1053/j.gastro.2015.09.026]
22 Zou Z,Li B,Xu D,Zhang Z,Zhao JM,Zhou G,Sun Y,Huang L,Fu J,Yang Y,Jin L,Zhang W,Zhao J,Sun Y,Xin S,Wang FS.Imbalanced intrahepatic cytokine expression of interferon-gamma,tumor necrosis factor-alpha,and interleukin-10 in patients with acute-on-chronic liver failure associated with hepatitis Bvirus infection.J Clin Gastroenterol 2009;43:182-190[PMID:18633332 DOI:10.1097/MCG.0b013e3181624464]
23 Liang M,Ma S,Hu X,Zhou B,Zhang J,Chen J,Wang Z,Sun J,Zhu X,Abbott W,Hou J.Cellular immune responses in patients with hepatitis B surface antigen seroclearance induced by antiviral therapy.Virol J 2011;8:69[PMID:21320337 DOI:10.1186/1743-422X-8-69]
24 Park JJ,Wong DK,Wahed AS,Lee WM,Feld JJ,Terrault N,Khalili M,Sterling RK,Kowdley KV,Bzowej N,Lau DT,Kim WR,Smith C,Carithers RL,Torrey KW,Keith JW,Levine DL,Traum D,Ho S,Valiga ME,Johnson GS,Doo E,Lok AS,Chang KM;Hepatitis B Research Network.Hepatitis B Virus--Specific and Global T-Cell Dysfunction in Chronic Hepatitis B.Gastroenterology 2016;150:684-695.e5[PMID:26684441 DOI:10.1053/j.gastro.2015.11.050]
25 Boni C,Laccabue D,Lampertico P,Giuberti T,ViganòM,Schivazappa S,Alfieri A,Pesci M,Gaeta GB,Brancaccio G,Colombo M,Missale G,Ferrari C.Restored function of HBV-specific T cells after longterm effective therapy with nucleos(t)ide analogues.Gastroenterology 2012;143:963-973.e9[PMID:22796241 DOI:10.1053/j.gastro.2012.07.014]
26 Mueller SN,Ahmed R.High antigen levels are the cause of T cell exhaustion during chronic viral infection.Proc Natl Acad Sci USA 2009;106:8623-8628[PMID:19433785 DOI:10.1073/pnas.0809818106]
27 Vanwolleghem T,Hou J,van Oord G,Andeweg AC,Osterhaus AD,Pas SD,Janssen HL,Boonstra A.Re-evaluation of hepatitis B virus clinical phases by systems biology identifies unappreciated roles for the innate immune response and B cells.Hepatology 2015;62:87-100[PMID:25808668 DOI:10.1002/hep.27805]
28 Das A,Hoare M,Davies N,Lopes AR,Dunn C,Kennedy PT,Alexander G,Finney H,Lawson A,Plunkett FJ,Bertoletti A,Akbar AN,Maini MK.Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection.J Exp Med 2008;205:2111-2124[PMID:18695005 DOI:10.1084/jem.20072076]
29 Croagh CM,Lubel JS.Natural history of chronic hepatitis B:phases in a complex relationship.World JGastroenterol 2014;20:10395-10404[PMID:25132755 DOI:10.3748/wjg.v20.i30.10395]
30 Fisicaro P,Valdatta C,Massari M,Loggi E,Biasini E,Sacchelli L,Cavallo MC,Silini EM,Andreone P,Missale G,Ferrari C.Antiviral intrahepatic T-cell responses can be restored by blocking programmed death-1 pathway in chronic hepatitis B.Gastroenterology 2010;138:682-693,693.e1-693.e4[PMID:19800335 DOI:10.1053/j.gastro.2009.09.052]