自身免疫性肝炎发病机制进展与临床干预新靶点

胡明礼; 王绮夏; 马雄

doi:10.3969/j.issn.1001-5256.2022.04.002

自身免疫性肝炎发病机制进展与临床干预新靶点

DOI: 10.3969/j.issn.1001-5256.2022.04.002

上海交通大学医学院附属仁济医院消化内科，上海市消化疾病研究所，上海 200001

基金项目:

国家自然科学基金 (82130017);

国家自然科学基金 (82070581);

国家自然科学基金 (81790634);

上海市卫生计生系统优秀青年医学人才培养计划 (2017YQ037);

上海市青年科技启明星计划 (18QA1402700)

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：胡明礼负责查找文献、分析资料、撰写文稿；马雄和王绮夏负责确定写作思路、指导文章撰写及最后定稿。

详细信息

通信作者:
王绮夏，wqx0221155@126.com

马雄，maxiongmd@163.com

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- 被引次数: 0
出版历程
- 收稿日期: 2021-11-30
- 录用日期: 2022-01-13
- 出版日期: 2022-04-20

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

Mingli HU,
Qixia WANG^{,
,},
Xiong MA^{,
,}

Shanghai Institute of Digestive Disease, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China

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)

摘要

摘要: 自身免疫性肝炎(AIH)是一种以肝细胞受损为主的免疫介导性肝病，以高免疫球蛋白G血症及自身抗体阳性为特征，组织学可见汇管区大量淋巴-浆细胞浸润所致的界面性肝炎。AIH发病机制尚未完全阐明，目前主要以糖皮质激素联合硫唑嘌呤进行非特异性免疫抑制治疗，多数患者应答良好。但在药物减量过程中以及停药后容易出现反跳或复发，故而大多数患者需长期维持治疗。本文就AIH发病机制进展及临床干预的潜在新靶点进行简要综述，以期为临床转化研究提供参考。
- 肝炎, 自身免疫性 /
- 病理过程 /
- 治疗学 /
- 靶点
Abstract: 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.
- Hepatitis, Autoimmune /
- Pathologic Processes /
- Therapeutics /
- Targets

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参考文献(39)

[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.