Disruption of peripheral blood B-cell homeostasis and variation of surface receptors occur with certain infections and autoimmune diseases. However, the impact of antiviral therapy on B-cell alteration during chronic hepatitis B (CHB) infection remains unclear. Our study aims to document the effects of B-cell alteration in CHB patients treated with tenofovir or adefovir. A total of 21 CHB patients and 10 healthy donors were recruited into the study. We identified B-cell subsets by flow cytometry and observed changes in the B-cell repertoire of CHB patients upon tenofovir or adefovir antiviral treatment. The total and percent of B cells and CD5 + B-cell subsets were significantly increased in CHB patients compared to healthy donors. Total and percent of CD5 + B cells gradually decreased following the diminution of the HBV DNA load after tenofovir and adefovir treatment. Upon tenofovir treatment, the percent of memory CD27 + B cells was increased but the absolute number declined, whereas naïve CD27− B cells declined in both percent and absolute number. In the adefovir treatment group, neither naïve nor memory B cells were altered by the treatment. Furthermore, CHB patients displayed higher levels of activation markers (CD69 and CD24) and trended towards restored B-cell homeostasis after antiviral treatment. In conclusion, disrupted B-cell homeostasis is an important feature of CHB patients and is partially restored after control of viral replication by antiviral treatment. B-cell antiviral immunity is improved by restoring B-cell homeostasis and activation.
NebbiaGPeppaDMainiMK. Hepatitis B infection: current concepts and future challenges. QJM2012; 105: 109–13.
2.
LiawYFChuCM. Hepatitis B virus infection. Lancet2009; 373: 582–92.
3.
MatthewsGVCooperDADoreGJ. Improvements in parameters of end-stage liver disease in patients with HIV/HBV-related cirrhosis treated with tenofovir. Antivir Ther2007; 12: 119–22.
4.
LeeYSSuhDJLimYSJungSWKimKMLeeHCChungYHYooWKimSO. Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy. Hepatology2006; 43: 1385–91.
5.
MarcellinPLadaOAsselahT. Treatment of chronic hepatitis B with the combination of pegylated interferon with lamivudine. Hepatol Res2007; 37: S55–61.
6.
SonneveldMJZoutendijkRFlinkHJZwangLHansenBEJanssenHL. Close monitoring of Hepatitis B surface antigen levels helps classify flares during peginterferon therapy and predicts treatment response. Clin Infect Dis2013; 56: 100–05.
7.
SarinSKKumarMHissarSSharmaBC. Combination of pegylated interferon and lamivudine for patients with chronic hepatitis B who have failed treatment. Hepatobiliary Pancreat Dis Int2006; 5: 374–80.
8.
MarcellinPHeathcoteEJButiMGaneEde ManRAKrastevZGermanidisGLeeSSFlisiakRKaitaKMannsMKotzevITchernevKBuggischPWeilertFKurdasOOShiffmanMLTrinhHWashingtonMKSorbelJAndersonJSnow-LampartAMondouEQuinnJRousseauF. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med2008; 359: 2442–55.
9.
PapatheodoridisGVManolakopoulosSDusheikoGArchimandritisAJ. Therapeutic strategies in the management of patients with chronic hepatitis B virus infection. Lancet Infect Dis2008; 8: 167–78.
10.
LapinskiTWPogorzelskaJFlisiakR. HBV mutations and their clinical significance. Adv Med Sci2012; 57: 18–22.
11.
HuiCKLieAAuWYLeungYHMaSYCheungWWZhangHYChimCSKwongYLLiangRLauGK. A long-term follow-up study on hepatitis B surface antigen-positive patients undergoing allogeneic hematopoietic stem cell transplantation. Blood2005; 106: 464–69.
12.
GottoJWebsterGJBrownDJenkinsJDusheikoGMBertolettiA. The impact of HBV-DNA fluctuations on virus-specific CD8 + T cells in HBeAg + chronic hepatitis B patients treated with a steroid and lamivudine. J Viral Hepat2006; 13: 415–25.
13.
TrehanPatiNKotillilSHissarSSShrivastavaSKhanamASukritiSMishraSKSarinSK. Circulating tregs correlate with viral load reduction in chronic HBV-treated patients with tenofovir disoproxil fumarate. J Clin Immunol2011; 31: 509–20.
14.
JiangYLiWYuLLiuJXinGYanHSunPZhangHXuDNiuJ. Enhancing the antihepatitis B virus immune response by adefovir dipivoxil and entecavir therapies. Cell Mol Immunol2011; 8: 75–82.
15.
LeeCKHanKHSuhJHChoYSWonSYChonCYMoonYMParkIS. [HBV-specific CD8 + T cells for sustained HBeAg seroconversion after lamivudine therapy]. Korean J Hepatol2005; 11: 34–42.
16.
BoniCPennaABertolettiALamonacaVRaptiIMissaleGPilliMUrbaniSCavalliACerioniSPanebiancoRJenkinsJFerrariC. Transient restoration of anti-viral T cell responses induced by lamivudine therapy in chronic hepatitis B. J Hepatol2003; 39: 595–605.
17.
ShokrgozarMASamMRAmirkhaniAShokriF. Frequency analysis of HBsAg-specific B lymphocytes in high-responder individuals to recombinant hepatitis B vaccine: comparison of LDA and ELISPOT assays. Scand J Immunol2006; 64: 536–43.
18.
DasAEllisGPallantCLopesARKhannaPPeppaDChenABlairPDusheikoGGillUKennedyPTBrunettoMLamperticoPMauriCMainiMK. IL-10-Producing regulatory B Cells in the pathogenesis of chronic Hepatitis B virus infection. J Immunol2012; 189: 3925–35.
19.
CaoTLazdinaUDesombereIVanlandschootPMilichDRSallbergMLeroux-RoelsG. Hepatitis B virus core antigen binds and activates naive human B cells in vivo: studies with a human PBL-NOD/SCID mouse model. J Virol2001; 75: 6359–66.
20.
WuCLiuYZhaoQChenGChenJYanXZhouYHHuangZ. Soluble CD40 ligand-activated human peripheral B cells as surrogated antigen presenting cells: a preliminary approach for anti-HBV immunotherapy. Virol J2010; 7: 370–370.
21.
LeBienTWTedderTF. B lymphocytes: how they develop and function. Blood2008; 112: 1570–80.
22.
RacanelliVFrassanitoMALeonePGalianoMDe ReVSilvestrisFDammaccoF. Antibody production and in vitro behavior of CD27-defined B-cell subsets: persistent hepatitis C virus infection changes the rules. J Virol2006; 80: 3923–34.
23.
MoirSFauciAS. Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. J Allergy Clin Immunol2008; 122: 12–19; quiz 20–21.
24.
YanabaKBouazizJDMatsushitaTMagroCMSt ClairEWTedderTF. B-lymphocyte contributions to human autoimmune disease. Immunol Rev2008; 223: 284–99.
25.
SuarezFLortholaryOHermineOLecuitM. Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood2006; 107: 3034–44.
26.
HoyerBFMumtazIMLoddenkemperKBrunsASenglerCHermannKGMazaSKeitzerRBurmesterGRButtgereitFRadbruchAHiepeF. Takayasu arteritis is characterised by disturbances of B cell homeostasis and responds to B cell depletion therapy with rituximab. Ann Rheum Dis2012; 71: 75–79.
27.
SarantopoulosSStevensonKEKimHTWashelWSBhuiyaNSCutlerCSAlyeaEPHoVTSoifferRJAntinJHRitzJ. Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease. Blood2011; 117: 2275–83.
28.
OlivieroBCerinoAVarchettaSPaudiceEPaiSLudovisiSZaramellaMMicheloneGPugnalePNegroFBarnabaVMondelliMU. Enhanced B-cell differentiation and reduced proliferative capacity in chronic hepatitis C and chronic hepatitis B virus infections. J Hepatol2011; 55: 53–60.
29.
SugalskiJMRodriguezBMoirSAnthonyDD. Peripheral blood B cell subset skewing is associated with altered cell cycling and intrinsic resistance to apoptosis and reflects a state of immune activation in chronic hepatitis C virus infection. J Immunol2010; 185: 3019–27.
30.
ZouZXuDLiBXinSZhangZHuangLFuJYangYJinLZhaoJMShiMZhouGSunYWangFS. Compartmentalization and its implication for peripheral immunologically-competent cells to the liver in patients with HBV-related acute-on-chronic liver failure. Hepatol Res2009; 39: 1198–207.
31.
NiJHembradorEDi BisceglieAMJacobsonIMTalalAHButeraDRiceCMChambersTJDustinLB. Accumulation of B lymphocytes with a naive, resting phenotype in a subset of hepatitis C patients. J Immunol2003; 170: 3429–39.
32.
MohamadkhaniABastaniFSotoudehMSayehmiriKShahnazariPMontazeriGPoustchiH. Influence of B cells in liver fibrosis associated with hepatitis B virus harboring basal core promoter mutations. J Med Virol2012; 84: 1889–96.
BouazizJDLe BuanecHSaussineABensussanABagotM. IL-10 producing regulatory B cells in mice and humans: state of the art. Curr Mol Med2012; 12: 519–27.
39.
WardSMPhaloraPBradshawDLeyendeckersHKlenermanP. Direct ex vivo evaluation of long-lived protective antiviral memory B cell responses against hepatitis B virus. J Infect Dis2008; 198: 813–17.
40.
RosadoMMScarsellaMPandolfiECascioliSGiordaEChionnePMadonneEGesualdoFRomanoMAusielloCMRapicettaMZanettiARTozziACarsettiR. Switched memory B cells maintain specific memory independently of serum antibodies: the hepatitis B example. Eur J Immunol2011; 41: 1800–08.
41.
BauerTJilgW. Hepatitis B surface antigen-specific T and B cell memory in individuals who had lost protective antibodies after hepatitis B vaccination. Vaccine2006; 24: 572–77.
42.
ZuckermanESlobodinGKesselASaboEYeshurunDHalasKToubiE. Peripheral B-cell CD5 expansion and CD81 overexpression and their association with disease severity and autoimmune markers in chronic hepatitis C virus infection. Clin Exp Immunol2002; 128: 353–58.
43.
RosaDSalettiGDe GregorioEZoratFComarCD'OroUNutiSHoughtonMBarnabaVPozzatoGAbrignaniS. Activation of naive B lymphocytes via CD81, a pathogenetic mechanism for hepatitis C virus-associated B lymphocyte disorders. Proc Natl Acad Sci U S A2005; 102: 18544–49.
44.
AnolikJHBarnardJCappioneAPugh-BernardAEFelgarRELooneyRJSanzI. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus. Arthritis Rheum2004; 50: 3580–90.
