中文English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 38 Issue 4
Apr.  2022
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Article Contents

Advances in the pathogenesis of autoimmune hepatitis and new targets for clinical intervention

DOI: 10.3969/j.issn.1001-5256.2022.04.002
Research funding:

National Natural Science Foundation of China (82130017);

National Natural Science Foundation of China (82070581);

National Natural Science Foundation of China (81790634);

The Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2017YQ037);

Shanghai Rising-Star Program (18QA1402700)

More Information
  • Corresponding author: WANG Qixia, wqx0221155@126.com(ORCID: 0000-0002-8300-6314); MA Xiong, maxiongmd@163.com(ORCID: 0000-0001-9616-4672)
  • Received Date: 2021-11-30
  • Accepted Date: 2022-01-13
  • Published Date: 2022-04-20
  • Autoimmune hepatitis (AIH) is an immune-mediated liver disease with hepatocytes as the main target cells. It is characterized by the high immunoglobulin G level and the presence of autoantibodies, and histological observation shows interface hepatitis at the portal area caused by a large amount of lymphoplasmacytic infiltration. The pathogenesis of AIH has not been fully elucidated. At present, glucocorticoid combined with azathioprine is mainly used as non-specific immunosuppressive therapy, and most patients tend to have good response; however, rebound or relapse is often observed during dose reduction or after drug withdrawal, so most patients need long-term maintenance therapy. This article briefly reviews the advances in the pathogenesis of AIH and the potential new targets for clinical intervention, in order to provide a reference for clinical translational research.

     

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  • [1]
    MIELI-VERGANI G, VERGANI D, CZAJA AJ, et al. Autoimmune hepatitis[J]. Nat Rev Dis Primers, 2018, 4: 18017. DOI: 10.1038/nrdp.2018.17.
    [2]
    TERZIROLI BERETTA-PICCOLI B, MIELI-VERGANI G, VERGANI D. Autoimmmune hepatitis[J]. Cell Mol Immunol, 2021. DOI: 10.1038/s41423-021-00768-8.[Online ahead of print]
    [3]
    MACK CL, ADAMS D, ASSIS DN, et al. Diagnosis and management of autoimmune hepatitis in adults and children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases[J]. Hepatology, 2020, 72(2): 671-722. DOI: 10.1002/hep.31065.
    [4]
    THAN NN, HODSON J, SCHMIDT-MARTIN D, et al. Efficacy of rituximab in difficult-to-manage autoimmune hepatitis: Results from the International Autoimmune Hepatitis Group[J]. JHEP Rep, 2019, 1(6): 437-445. DOI: 10.1016/j.jhepr.2019.10.005.
    [5]
    LIBERAL R, de BOER YS, HENEGHAN MA. Established and novel therapeutic options for autoimmune hepatitis[J]. Lancet Gastroenterol Hepatol, 2021, 6(4): 315-326. DOI: 10.1016/S2468-1253(20)30328-9.
    [6]
    de BOER YS, van GERVEN NM, ZWIERS A, et al. Genome-wide association study identifies variants associated with autoimmune hepatitis type 1[J]. Gastroenterology, 2014, 147(2): 443-452.e5. DOI: 10.1053/j.gastro.2014.04.022.
    [7]
    OLIVEIRA LC, PORTA G, MARIN ML, et al. Autoimmune hepatitis, HLA and extended haplotypes[J]. Autoimmun Rev, 2011, 10(4): 189-193. DOI: 10.1016/j.autrev.2010.09.024.
    [8]
    WEBB G, CHEN YY, LI KK, et al. Single-gene association between GATA-2 and autoimmune hepatitis: A novel genetic insight highlighting immunologic pathways to disease[J]. J Hepatol, 2016, 64(5): 1190-1193. DOI: 10.1016/j.jhep.2016.01.017.
    [9]
    COOKSON S, CONSTANTINI PK, CLARE M, et al. Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis[J]. Hepatology, 1999, 30(4): 851-856. DOI: 10.1002/hep.510300412.
    [10]
    TERZIROLI BERETTA-PICCOLI B, DI BARTOLOMEO C, DELEONARDI G, et al. Autoimmune liver serology before and after successful treatment of chronic hepatitis C by direct acting antiviral agents[J]. J Autoimmun, 2019, 102: 89-95. DOI: 10.1016/j.jaut.2019.04.019.
    [11]
    WEILER-NORMANN C, SCHRAMM C. Drug induced liver injury and its relationship to autoimmune hepatitis[J]. J Hepatol, 2011, 55(4): 747-749. DOI: 10.1016/j.jhep.2011.02.024.
    [12]
    WEI Y, LI Y, YAN L, et al. Alterations of gut microbiome in autoimmune hepatitis[J]. Gut, 2020, 69(3): 569-577. DOI: 10.1136/gutjnl-2018-317836.
    [13]
    BOVENSIEPEN CS, SCHAKAT M, SEBODE M, et al. TNF-producing Th1 cells are selectively expanded in liver infiltrates of patients with autoimmune hepatitis[J]. J Immunol, 2019, 203(12): 3148-3156. DOI: 10.4049/jimmunol.1900124.
    [14]
    JARUGA B, HONG F, KIM WH, et al. IFN-gamma/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: A critical role of IRF-1[J]. Am J Physiol Gastrointest Liver Physiol, 2004, 287(5): G1044-G1052. DOI: 10.1152/ajpgi.00184.2004.
    [15]
    LIBERAL R, GRANT CR, HOLDER BS, et al. The impaired immune regulation of autoimmune hepatitis is linked to a defective galectin-9/tim-3 pathway[J]. Hepatology, 2012, 56(2): 677-686. DOI: 10.1002/hep.25682.
    [16]
    MURATORI L, PAROLA M, RIPALTI A, et al. Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane[J]. Gut, 2000, 46(4): 553-561. DOI: 10.1136/gut.46.4.553.
    [17]
    TERZIROLI BERETTA-PICCOLI B, MIELI-VERGANI G, VERGANI D. The clinical usage and definition of autoantibodies in immune-mediated liver disease: A comprehensive overview[J]. J Autoimmun, 2018, 95: 144-158. DOI: 10.1016/j.jaut.2018.10.004.
    [18]
    MA Y, BOGDANOS DP, HUSSAIN MJ, et al. Polyclonal T-cell responses to cytochrome P450ⅡD6 are associated with disease activity in autoimmune hepatitis type 2[J]. Gastroenterology, 2006, 130(3): 868-882. DOI: 10.1053/j.gastro.2005.12.020.
    [19]
    ZHAO L, TANG Y, YOU Z, et al. Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression[J]. PLoS One, 2011, 6(4): e18909. DOI: 10.1371/journal.pone.0018909.
    [20]
    LIBERAL R, GRANT CR, YUKSEL M, et al. Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis[J]. Hepatology, 2017, 66(5): 1570-1584. DOI: 10.1002/hep.29307.
    [21]
    GRANT CR, LIBERAL R, HOLDER BS, et al. Dysfunctional CD39(POS) regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis[J]. Hepatology, 2014, 59(3): 1007-1015. DOI: 10.1002/hep.26583.
    [22]
    MA L, QIN J, JI H, et al. Tfh and plasma cells are correlated with hypergammaglobulinaemia in patients with autoimmune hepatitis[J]. Liver Int, 2014, 34(3): 405-415. DOI: 10.1111/liv.12245.
    [23]
    YOU Z, LI Y, WANG Q, et al. The clinical significance of hepatic CD69+ CD103+ CD8+ resident-memory T cells in autoimmune hepatitis[J]. Hepatology, 2021, 74(2): 847-863. DOI: 10.1002/hep.31739.
    [24]
    BÉLAND K, MARCEAU G, LABARDY A, et al. Depletion of B cells induces remission of autoimmune hepatitis in mice through reduced antigen presentation and help to T cells[J]. Hepatology, 2015, 62(5): 1511-1523. DOI: 10.1002/hep.27991.
    [25]
    LIU X, JIANG X, LIU R, et al. B cells expressing CD11b effectively inhibit CD4+ T-cell responses and ameliorate experimental autoimmune hepatitis in mice[J]. Hepatology, 2015, 62(5): 1563-1575. DOI: 10.1002/hep.28001.
    [26]
    ERHARDT A, BIBURGER M, PAPADOPOULOS T, et al. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice[J]. Hepatology, 2007, 45(2): 475-485. DOI: 10.1002/hep.21498.
    [27]
    LONGHI MS, MA Y, MITRY RR, et al. Effect of CD4+ CD25+ regulatory T-cells on CD8 T-cell function in patients with autoimmune hepatitis[J]. J Autoimmun, 2005, 25(1): 63-71. DOI: 10.1016/j.jaut.2005.05.001.
    [28]
    LIBERAL R, GRANT CR, HOLDER BS, et al. In autoimmune hepatitis type 1 or the autoimmune hepatitis-sclerosing cholangitis variant defective regulatory T-cell responsiveness to IL-2 results in low IL-10 production and impaired suppression[J]. Hepatology, 2015, 62(3): 863-875. DOI: 10.1002/hep.27884.
    [29]
    JEFFERY HC, BRAITCH MK, BAGNALL C, et al. Changes in natural killer cells and exhausted memory regulatory T Cells with corticosteroid therapy in acute autoimmune hepatitis[J]. Hepatol Commun, 2018, 2(4): 421-436. DOI: 10.1002/hep4.1163.
    [30]
    TAUBERT R, HARDTKE-WOLENSKI M, NOYAN F, et al. Intrahepatic regulatory T cells in autoimmune hepatitis are associated with treatment response and depleted with current therapies[J]. J Hepatol, 2014, 61(5): 1106-1114. DOI: 10.1016/j.jhep.2014.05.034.
    [31]
    ZHANG H, LIAN M, ZHANG J, et al. A functional characteristic of cysteine-rich protein 61: Modulation of myeloid-derived suppressor cells in liver inflammation[J]. Hepatology, 2018, 67(1): 232-246. DOI: 10.1002/hep.29418.
    [32]
    LIAN M, ZHANG J, ZHAO L, et al. Interleukin-35 regulates immune microenvironment of autoimmune hepatitis through inducing the expansion of myeloid-derived suppressor cells[J]. Front Immunol, 2019, 10: 2577. DOI: 10.3389/fimmu.2019.02577.
    [33]
    ZHANG H, LIU Y, BIAN Z, et al. The critical role of myeloid-derived suppressor cells and FXR activation in immune-mediated liver injury[J]. J Autoimmun, 2014, 53: 55-66. DOI: 10.1016/j.jaut.2014.02.010.
    [34]
    LI B, LIAN M, LI Y, et al. Myeloid-derived suppressive cells deficient in liver X receptor α protected from autoimmune hepatitis[J]. Front Immunol, 2021, 12: 732102. DOI: 10.3389/fimmu.2021.732102.
    [35]
    ARVANITI P, GIANNOULIS G, GABETA S, et al. Belimumab is a promising third-line treatment option for refractory autoimmune hepatitis[J]. JHEP Rep, 2020, 2(4): 100123. DOI: 10.1016/j.jhepr.2020.100123.
    [36]
    LAPIERRE P, BÉLAND K, YANG R, et al. Adoptive transfer of ex vivo expanded regulatory T cells in an autoimmune hepatitis murine model restores peripheral tolerance[J]. Hepatology, 2013, 57(1): 217-227. DOI: 10.1002/hep.26023.
    [37]
    ROSENZWAJG M, LORENZON R, CACOUB P, et al. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial[J]. Ann Rheum Dis, 2019, 78(2): 209-217. DOI: 10.1136/annrheumdis-2018-214229.
    [38]
    WEILER-NORMANN C, SCHRAMM C, QUAAS A, et al. Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis[J]. J Hepatol, 2013, 58(3): 529-534. DOI: 10.1016/j.jhep.2012.11.010.
    [39]
    HSU MC, LIU SH, WANG CW, et al. JKB-122 is effective, alone or in combination with prednisolone in Con A-induced hepatitis[J]. Eur J Pharmacol, 2017, 812: 113-120. DOI: 10.1016/j.ejphar.2017.07.012.
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