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HBeAg诱导的免疫激活和免疫抑制在慢性乙型肝炎中的作用

李欣阳 涂正坤

引用本文:
Citation:

HBeAg诱导的免疫激活和免疫抑制在慢性乙型肝炎中的作用

DOI: 10.12449/JCH240525
基金项目: 

吉林省科技发展计划项目自然科学基金 (20190201245JC)

利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:李欣阳负责查阅文献,撰写文章;涂正坤负责拟定文章思路,指导撰写文章并最后定稿。
详细信息
    通信作者:

    涂正坤, tuzhengkun@hotmail.com (ORCID: 0000-0001-6803-2015)

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

Research funding: 

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

More Information
  • 摘要: HBV感染诱导的慢性乙型肝炎是导致肝硬化和肝癌的重要危险因素。半个世纪前,HBeAg在HBV感染者血清中首次被发现,尽管HBeAg并不参与HBV在肝细胞中的感染或复制,但其已被证实可干扰宿主先天性和适应性免疫反应,在慢性HBV感染的过程中发挥着重要的免疫激活和免疫抑制作用。HBV对于感染的肝细胞并没有细胞毒性,免疫应答介导的抗病毒作用和炎症反应决定HBV是否被清除或者诱导肝脏炎症相关疾病。因此,本文对HBeAg的形成及其在慢性HBV感染中引起的免疫激活和免疫抑制机制进行综述,重点论述HBeAg对先天免疫和适应性免疫细胞所引起的不同免疫效应,阐述了其诱导免疫反应的两面性,并探讨HBeAg在慢性HBV感染不同阶段间的转换作用。

     

  • 图  1  CHB感染各时期特征及免疫反应

    注: ERK,细胞外调节蛋白激酶;pDC,浆细胞样树突状细胞;ROS,活性氧;TLR,Toll样受体;IFN,干扰素;IL,白细胞介素;NLRP3,NOD样受体蛋白3;MDSC,骨髓源性抑制细胞;IDO,吲哚胺2,3-双加氧酶;BAFF,B淋巴细胞激活因子;TNF,肿瘤坏死因子。

    Figure  1.  Characteristics and immune responses of different stages of CHB infection

  • [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.
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  • 收稿日期:  2024-01-25
  • 录用日期:  2024-02-22
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