中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 40 Issue 5
May  2024
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(5): 1026-1031

Role of HBeAg-induced immune activition and immunosuppression in chronic hepatitis B

DOI: 10.12449/JCH240525

  • Laboratory of Tumor Immunology，The First Hospital of Jilin University，Changchun 130021，China

Research funding:

Jilin Province Science and Technology Development Plan Project Natural Science Foundation Project (20190201245JC)

More Information
  • Corresponding author: TU Zhengkun， tuzhengkun@hotmail.com （ORCID： 0000-0001-6803-2015）
  • Received Date: 2024-01-25
  • Accepted Date: 2024-02-22
  • Published Date: 2024-05-25
    Abstract
  • Chronic hepatitis B induced by HBV infection is a significant risk factor leading to liver cirrhosis and liver cancer. Half a century ago， HBeAg was first discovered in the serum of HBV infected individuals， and although HBeAg does not participate in HBV infection or replication in hepatocytes， studies have shown that it can interfere with the innate and adaptive immune responses of the host and play an important role in immune activation and immunosuppression during chronic HBV infection. HBV has no cytotoxicity to the infected hepatocytes， and the antiviral action and inflammatory response mediated by immune response determine whether HBV is cleared or induces liver inflammation-related diseases. Therefore， this article reviews the formation of HBeAg and its immune activation and immunosuppression mechanisms in chronic HBV infection， with a focus on the different immune effects caused by HBeAg on innate immune and adaptive immune cells， and this article also elaborates on the dual role of HBeAg in inducing immune responses and explores the conversion role of HBeAg in different stages of chronic HBV infection.

     

    • FullText(HTML)
  • loading
    • References(45)
  • [1]
    TANG LSY, COVERT E, WILSON E, et al. Chronic hepatitis B infection: A review[J]. JAMA, 2018, 319( 17): 1802- 1813. DOI: 10.1001/jama.2018.3795.
    [2]
    CHANG ML, LIAW YF. Hepatitis B flare in hepatitis B e antigen-negative patients: A complicated cascade of innate and adaptive immune responses[J]. Int J Mol Sci, 2022, 23( 3): 1552. DOI: 10.3390/ijms23031552.
    [3]
    MILICH DR. Is the function of the HBeAg really unknown?[J]. Hum Vaccin Immunother, 2019, 15( 9): 2187- 2191. DOI: 10.1080/21645515.2019.1607132.
    [4]
    PADARATH K, DEROUBAIX A, KRAMVIS A. The complex role of HBeAg and its precursors in the pathway to hepatocellular carcinoma[J]. Viruses, 2023, 15( 4): 857. DOI: 10.3390/v15040857.
    [5]
    XIE XY, LV HR, LIU CX, et al. HBeAg mediates inflammatory functions of macrophages by TLR2 contributing to hepatic fibrosis[J]. BMC Med, 2021, 19( 1): 247. DOI: 10.1186/s12916-021-02085-3.
    [6]
    TSUKUDA S, WATASHI K. Hepatitis B virus biology and life cycle[J]. Antiviral Res, 2020, 182: 104925. DOI: 10.1016/j.antiviral.2020.104925.
    [7]
    ITO K, KIM KH, LOK ASF, et al. Characterization of genotype-specific carboxyl-terminal cleavage sites of hepatitis B virus e antigen precursor and identification of furin as the candidate enzyme[J]. J Virol, 2009, 83( 8): 3507- 3517. DOI: 10.1128/JVI.02348-08.
    [8]
    KRAMVIS A, CHANG KM, DANDRI M, et al. A roadmap for serum biomarkers for hepatitis B virus: Current status and future outlook[J]. Nat Rev Gastroenterol Hepatol, 2022, 19( 11): 727- 745. DOI: 10.1038/s41575-022-00649-z.
    [9]
    TSAI KN, OU JH J. Hepatitis B virus e antigen and viral persistence[J]. Curr Opin Virol, 2021, 51: 158- 163. DOI: 10.1016/j.coviro.2021.10.003.
    [10]
    European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2017, 67( 2): 370- 398. DOI: 10.1016/j.jhep.2017.03.021.
    [11]
    European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection[J]. J Hepatol, 2012, 57( 1): 167- 185. DOI: 10.1016/j.jhep.2012.02.010.
    [12]
    HSU YS, CHIEN RN, YEH CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B[J]. Hepatology, 2002, 35( 6): 1522- 1527. DOI: 10.1053/jhep.2002.33638.
    [13]
    NI YH, CHANG MH, CHEN PJ, et al. Viremia profiles in children with chronic hepatitis B virus infection and spontaneous e antigen seroconversion[J]. Gastroenterology, 2007, 132( 7): 2340- 2345. DOI: 10.1053/j.gastro.2007.03.111.
    [14]
    LIAW YF, LAU GKK, KAO JH, et al. Hepatitis B e antigen seroconversion: A critical event in chronic hepatitis B virus infection[J]. Dig Dis Sci, 2010, 55( 10): 2727- 2734. DOI: 10.1007/s10620-010-1179-4.
    [15]
    WANG WW, BIAN HJ, LI FF, et al. HBeAg induces the expression of macrophage miR-155 to accelerate liver injury via promoting production of inflammatory cytokines[J]. Cell Mol Life Sci, 2018, 75( 14): 2627- 2641. DOI: 10.1007/s00018-018-2753-8.
    [16]
    THOMSON AW, KNOLLE PA. Antigen-presenting cell function in the tolerogenic liver environment[J]. Nat Rev Immunol, 2010, 10( 11): 753- 766. DOI: 10.1038/nri2858.
    [17]
    LIU J, JIANG M, MA ZY, et al. TLR1/2 ligand-stimulated mouse liver endothelial cells secrete IL-12 and trigger CD8+ T cell immunity in vitro[J]. J Immunol, 2013, 191( 12): 6178- 6190. DOI: 10.4049/jimmunol.1301262.
    [18]
    XIE XH, LUO JZ, BROERING R, et al. HBeAg induces liver sinusoidal endothelial cell activation to promote intrahepatic CD8 T cell immunity and HBV clearance[J]. Cell Mol Immunol, 2021, 18( 11): 2572- 2574. DOI: 10.1038/s41423-021-00769-7.
    [19]
    YANG CL, LI N, WANG YW, et al. Serum levels of B-cell activating factor in chronic hepatitis B virus infection: Association with clinical diseases[J]. J Interferon Cytokine Res, 2014, 34( 10): 787- 794. DOI: 10.1089/jir.2014.0032.
    [20]
    LI HJ, ZHAI NC, SONG HX, et al. The role of immune cells in chronic HBV infection[J]. J Clin Transl Hepatol, 2015, 3( 4): 277- 283. DOI: 10.14218/JCTH.2015.00026.
    [21]
    LU BR, ZHANG BC, WANG LC, et al. Hepatitis B virus e antigen regulates monocyte function and promotes B lymphocyte activation[J]. Viral Immunol, 2017, 30( 1): 35- 44. DOI: 10.1089/vim.2016.0113.
    [22]
    MÖCKEL T, BASTA F, WEINMANN-MENKE J, et al. B cell activating factor(BAFF): Structure, functions, autoimmunity and clinical implications in Systemic Lupus Erythematosus(SLE)[J]. Autoimmun Rev, 2021, 20( 2): 102736. DOI: 10.1016/j.autrev.2020.102736.
    [23]
    WANG L, ZENG XQ, WANG ZD, et al. Recent advances in understanding T cell activation and exhaustion during HBV infection[J]. Virol Sin, 2023, 38( 6): 851- 859. DOI: 10.1016/j.virs.2023.10.007.
    [24]
    JORGOVANOVIC D, SONG MJ, WANG LP, et al. Roles of IFN-γ in tumor progression and regression: A review[J]. Biomark Res, 2020, 8: 49. DOI: 10.1186/s40364-020-00228-x.
    [25]
    CHISARI FV, ISOGAWA M, WIELAND SF. Pathogenesis of hepatitis B virus infection[J]. Pathol Biol(Paris), 2010, 58( 4): 258- 266. DOI: 10.1016/j.patbio.2009.11.001.
    [26]
    XIE XH, LUO JZ, ZHU D, et al. HBeAg is indispensable for inducing liver sinusoidal endothelial cell activation by hepatitis B virus[J]. Front Cell Infect Microbiol, 2022, 12: 797915. DOI: 10.3389/fcimb.2022.797915.
    [27]
    CHEN WJ, BIAN HJ, XIE XY, et al. Negative feedback loop of ERK/CREB/miR-212-3p inhibits HBeAg-induced macrophage activation[J]. J Cell Mol Med, 2020, 24( 18): 10935- 10945. DOI: 10.1111/jcmm.15723.
    [28]
    TIAN YJ, KUO CF, AKBARI O, et al. Maternal-derived hepatitis B virus e antigen alters macrophage function in offspring to drive viral persistence after vertical transmission[J]. Immunity, 2016, 44( 5): 1204- 1214. DOI: 10.1016/j.immuni.2016.04.008.
    [29]
    HATIPOGLU I, ERCAN D, ACILAN C, et al. Hepatitis B virus e antigen(HBeAg) may have a negative effect on dendritic cell generation[J]. Immunobiology, 2014, 219( 12): 944- 949. DOI: 10.1016/j.imbio.2014.07.020.
    [30]
    SIOUD M, FLØISAND Y. TLR agonists induce the differentiation of human bone marrow CD34+ progenitors into CD11c+ CD80/86+ DC capable of inducing a Th1-type response[J]. Eur J Immunol, 2007, 37( 10): 2834- 2846. DOI: 10.1002/eji.200737112.
    [31]
    WANG FC, SONG MY, HU YH, et al. The relation of the frequency and functional molecules expression on plasmacytoid dendritic cells to postpartum hepatitis in women with HBeAg-positive chronic hepatitis B virus infection[J]. Front Immunol, 2022, 13: 1062123. DOI: 10.3389/fimmu.2022.1062123.
    [32]
    LEU CM, LU YC, PENG WL, et al. The hepatitis B virus e antigen suppresses the respiratory burst and mobility of human monocytes and neutrophils[J]. Immunobiology, 2014, 219( 11): 880- 887. DOI: 10.1016/j.imbio.2014.07.008.
    [33]
    YANG SS, LIAN GJ. ROS and diseases: Role in metabolism and energy supply[J]. Mol Cell Biochem, 2020, 467( 1-2): 1- 12. DOI: 10.1007/s11010-019-03667-9.
    [34]
    YANG FF, YU XP, ZHOU CL, et al. Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection[J]. PLoS Pathog, 2019, 15( 4): e1007690. DOI: 10.1371/journal.ppat.1007690.
    [35]
    RACANELLI V, REHERMANN B. The liver as an immunological organ[J]. Hepatology, 2006, 43(2 Suppl 1): S54- S62. DOI: 10.1002/hep.21060.
    [36]
    SUN C, FU BQ, GAO YF, et al. TGF-β1 down-regulation of NKG2D/DAP10 and 2B4/SAP expression on human NK cells contributes to HBV persistence[J]. PLoS Pathog, 2012, 8( 3): e1002594. DOI: 10.1371/journal.ppat.1002594.
    [37]
    MA QQ, DONG XY, LIU SY, et al. Hepatitis B e antigen induces NKG2A+ natural killer cell dysfunction via regulatory T cell-derived interleukin 10 in chronic hepatitis B virus infection[J]. Front Cell Dev Biol, 2020, 8: 421. DOI: 10.3389/fcell.2020.00421.
    [38]
    JEGASKANDA S, AHN SH, SKINNER N, et al. Downregulation of interleukin-18-mediated cell signaling and interferon gamma expression by the hepatitis B virus e antigen[J]. J Virol, 2014, 88( 18): 10412- 10420. DOI: 10.1128/JVI.00111-14.
    [39]
    FERRANDO-MARTINEZ S, HUANG K, BENNETT AS, et al. HBeAg seroconversion is associated with a more effective PD-L1 blockade during chronic hepatitis B infection[J]. JHEP Rep, 2019, 1( 3): 170- 178. DOI: 10.1016/j.jhepr.2019.06.001.
    [40]
    PARKER KH, BEURY DW, OSTRAND-ROSENBERG S. Myeloid-derived suppressor cells: Critical cells driving immune suppression in the tumor microenvironment[J]. Adv Cancer Res, 2015, 128: 95- 139. DOI: 10.1016/bs.acr.2015.04.002.
    [41]
    MUNN DH, MELLOR AL. IDO in the tumor microenvironment: Inflammation, counter-regulation, and tolerance[J]. Trends Immunol, 2016, 37( 3): 193- 207. DOI: 10.1016/j.it.2016.01.002.
    [42]
    KRAMVIS A, KOSTAKI EG, HATZAKIS A, et al. Immunomodulatory function of HBeAg related to short-sighted evolution, transmissibility, and clinical manifestation of hepatitis B virus[J]. Front Microbiol, 2018, 9: 2521. DOI: 10.3389/fmicb.2018.02521.
    [43]
    LEE WM, KING WC, JANSSEN HLA, et al. Hepatitis B e antigen loss in adults and children with chronic hepatitis B living in North America: A prospective cohort study[J]. J Viral Hepat, 2021, 28( 11): 1526- 1538. DOI: 10.1111/jvh.13591.
    [44]
    TSAI SL, CHEN PJ, LAI MY, et al. Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion[J]. J Clin Invest, 1992, 89( 1): 87- 96. DOI: 10.1172/JCI115590.
    [45]
    YANG HC, KAO JH. Revisiting the natural history of chronic HBV infection[J]. Curr Hepatol Rep, 2016, 15( 3): 141- 149. DOI: 10.1007/s11901-016-0304-z.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(1)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (359) PDF downloads(67) Cited by()
    Proportional views
    Related
        

    The first journal specializing in hepatobiliary and pancreatic diseases in China

    Supervisor：Ministry of Education of the People's Republic of China

    Sponsor：Jilin University

    Academic Support: Chinese Society of Hepatology，Chinese Medical Association

    Address: 461 Xinjiang Road, Changchun

    Submit：0431-88782044

    Peer review：0431-88783542

    Email：lcgdb@vip.163.com

    About Journal

    Submission Guideline

    Journal Online

    Hepatobiliary College

    Guidelines

    YesterdayIP[]YesterdayPV[]TodayIP[]TodayPV[]Online[]

    Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return