调节性T淋巴细胞/辅助性T淋巴细胞17在自身免疫性肝炎发生发展中的作用机制及其相关治疗靶点

董雯迪; 张海蓉; 李瑞; 张宇艳; 朱婕

doi:10.3969/j.issn.1001-5256.2021.10.042

调节性T淋巴细胞/辅助性T淋巴细胞17在自身免疫性肝炎发生发展中的作用机制及其相关治疗靶点

DOI: 10.3969/j.issn.1001-5256.2021.10.042

昆明医科大学第一附属医院消化内科，昆明 650032

详细信息

通信作者:
张海蓉，zhr919@sina.com

中图分类号: R575.1
计量
- 文章访问数: 920
- HTML全文浏览量: 200
- PDF下载量: 38
- 被引次数: 0
出版历程
- 收稿日期: 2021-03-10
- 录用日期: 2021-04-30
- 出版日期: 2021-10-20

Role of regulatory T/T helper 17 cells in the pathogenesis of autoimmune hepatitis and related therapeutic targets

Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China

摘要

摘要: 自身免疫性肝炎(AIH)病因及发病机制尚不明确，目前认为其与遗传易感性、环境因素等相互作用有关。调节性T淋巴细胞(Treg)主要通过分泌IL-10和TGFβ发挥免疫抑制功能，辅助性T淋巴细胞(Th)17主要促进炎症反应，提示Treg和Th17及两者动态平衡可能参与AIH的发生发展，但其参与机制仍需进一步探讨。综述了近年来Treg/Th17与AIH的相关性，并对其作用机制、治疗靶点作一阐述。
- 肝炎, 自身免疫性 /
- T淋巴细胞, 调节性 /
- T淋巴细胞, 辅助诱导
Abstract: The etiology and pathogenesis of autoimmune hepatitis (AIH) remain unclear and are currently considered to be associated with genetic susceptibility and environmental factors. Regulatory T (Treg) cells play an immunosuppressive role by secreting IL-10 and TGFβ, while T helper 17 (Th17) cells mainly promote inflammatory response, suggesting that Treg cells, Th17 cells, and the dynamic balance between them may be involved in the development and progression of AIH; however, further studies are needed to explore related participation mechanisms. This article reviews the association between Treg/Th17 cells and AIH in recent years and elaborates on their mechanism of action and therapeutic targets.
- Hepatitis, Autoimmune /
- T-Lymphocytes, Regulatory /
- T-Lymphocytes, Helper-Inducers

HTML全文

图 1 T淋巴细胞介导的免疫机制图

下载: 全尺寸图片幻灯片

参考文献(51)

[1]	HENNES EM, ZENIYA M, CZAJA AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis[J]. Hepatology, 2008, 48(1): 169-176. DOI: 10.1002/hep.22322.
[2]	European Association for the Study of Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis[J]. J Hepatol, 2015, 63(4): 971-1004. DOI: 10.1016/j.jhep.2015.06.030.
[3]	Chinese Society of Hepatology, Chinese Medical Association; Chinese Society of Gastroenterology, Chinese Medical Association; Chinese Society of Infectious Diseases, Chinese Medical Association. Consensus on the diagnosis and management of autoimmune hepatitis(2015)[J]. J Clin Hepatol, 2016, 32(1): 9-22. DOI: 10.3969/j.issn.1001-5256.2016.01.002. 中华医学会肝病学分会, 中华医学会消化病学分会, 中华医学会感染病学分会. 自身免疫性肝炎诊断和治疗共识(2015)[J]. 临床肝胆病杂志, 2016, 32(1): 9-22. DOI: 10.3969/j.issn.1001-5256.2016.01.002.
[4]	CAO YN, ZHOU GQ, WANG XB, et al. Research advances in the pathogenesis of autoimmune hepatitis[J]. J Clin Hepatol, 2019, 35(10): 2335-2338. DOI: 10.3969/j.issn.1001-5256.2019.10.045. 曹亦楠, 周桂琴, 王宪波, 等. 自身免疫性肝炎发病机制的研究现状[J]. 临床肝胆病杂志, 2019, 35(10): 2335-2338. DOI: 10.3969/j.issn.1001-5256.2019.10.045.
[5]	FLOREANI A, RESTREPO-JIMÉNEZ P, SECCHI MF, et al. Etiopathogenesis of autoimmune hepatitis[J]. J Autoimmun, 2018, 95: 133-143. DOI: 10.1016/j.jaut.2018.10.020.
[6]	CZAJA AJ. Examining pathogenic concepts of autoimmune hepatitis for cues to future investigations and interventions[J]. World J Gastroenterol, 2019, 25(45): 6579-6606. DOI: 10.3748/wjg.v25.i45.6579.
[7]	MEHRFELD C, ZENNER S, KORNEK M, et al. The contribution of non-professional antigen-presenting cells to immunity and tolerance in the liver[J]. Front Immunol, 2018, 9: 635. DOI: 10.3389/fimmu.2018.00635.
[8]	SUCHER E, SUCHER R, GRADISTANAC T, et al. Autoimmune hepatitis-immunologically triggered liver pathogenesis-diagnostic and therapeutic strategies[J]. J Immunol Res, 2019, 2019: 9437043. DOI: 10.1155/2019/9437043.
[9]	ARNDTZ K, HIRSCHFIELD GM. The pathogenesis of autoimmune liver disease[J]. Dig Dis, 2016, 34(4): 327-333. DOI: 10.1159/000444471.
[10]	HERBIN O, BONITO AJ, JEONG S, et al. Medullary thymic epithelial cells and CD8α(+) dendritic cells coordinately regulate central tolerance but CD8α(+) cells are dispensable for thymic regulatory T cell production[J]. J Autoimmun, 2016, 75: 141-149. DOI: 10.1016/j.jaut.2016.08.002.
[11]	RIEMANN M, ANDREAS N, FEDOSEEVA M, et al. Central immune tolerance depends on crosstalk between the classical and alternative NF-κB pathways in medullary thymic epithelial cells[J]. J Autoimmun, 2017, 81: 56-67. DOI: 10.1016/j.jaut.2017.03.007.
[12]	SOZZANI S, DEL PRETE A, BOSISIO D. Dendritic cell recruitment and activation in autoimmunity[J]. J Autoimmun, 2017, 85: 126-140. DOI: 10.1016/j.jaut.2017.07.012.
[13]	ZHANG C, TIAN Z. NK cell subsets in autoimmune diseases[J]. J Autoimmun, 2017, 83: 22-30. DOI: 10.1016/j.jaut.2017.02.005.
[14]	YU ZJ, HE ZB. Advances in research of autoimmune hepatitis[J]. Chin J Immunol, 2019, 35(22): 2813-2818. DOI: 10.3969/j.issn.1000-484X.2019.22.025. 余真君, 何泽宝. 自身免疫性肝炎研究进展[J]. 中国免疫学杂志, 2019, 35(22): 2813-2818. DOI: 10.3969/j.issn.1000-484X.2019.22.025.
[15]	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.
[16]	MOY L, LEVINE J. Autoimmune hepatitis: A classic autoimmune liver disease[J]. Curr Probl Pediatr Adolesc Health Care, 2014, 44(11): 341-346. DOI: 10.1016/j.cppeds.2014.10.005.
[17]	LIBERAL R, VERGANI D, MIELI-VERGANI G. Update on autoimmune hepatitis[J]. J Clin Transl Hepatol, 2015, 3(1): 42-52. DOI: 10.14218/JCTH.2014.00032.
[18]	DOHERTY DG. Immunity, tolerance and autoimmunity in the liver: A comprehensive review[J]. J Autoimmun, 2016, 66: 60-75. DOI: 10.1016/j.jaut.2015.08.020.
[19]	SINGER BD, KING LS, D'ALESSIO FR. Regulatory T cells as immunotherapy[J]. Front Immunol, 2014, 5: 46. DOI: 10.3389/fimmu.2014.00046.
[20]	HORI S, NOMURA T, SAKAGUCHI S. Control of regulatory T cell development by the transcription factor Foxp3[J]. Science, 2003, 299(5609): 1057-1061. DOI: 10.1126/science.1079490.
[21]	KARIM M, KINGSLEY CI, BUSHELL AR, et al. Alloantigen-induced CD25⁺CD4⁺ regulatory T cells can develop in vivo from CD25^-CD4⁺ precursors in a thymus-independent process[J]. J Immunol, 2004, 172(2): 923-928. DOI: 10.4049/jimmunol.172.2.923.
[22]	LAN Q, FAN H, QUESNIAUX V, et al. Induced Foxp3(+) regulatory T cells: A potential new weapon to treat autoimmune and inflammatory diseases?[J]. J Mol Cell Biol, 2012, 4(1): 22-28. DOI: 10.1093/jmcb/mjr039.
[23]	WAN YY, FLAVELL RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression[J]. Nature, 2007, 445(7129): 766-770. DOI: 10.1038/nature05479.
[24]	CHEN J, LIU W, ZHU W. Foxp3⁺ treg cells are associated with pathological process of autoimmune hepatitis by activating methylation modification in autoimmune hepatitis patients[J]. Med Sci Monit, 2019, 25: 6204-6212. DOI: 10.12659/MSM.915408.
[25]	WANG WZ, XIANG XX. Immunological mechanismof Treg/Th17 and Th1/Th2 balance in autoimmune hepatitisand new targets for diagnosis and treatment[J]. J Clin Hepatol, 2019, 35(8): 1874-1877. DOI: 10.3969/j.issn.1001-5256.2019.08.051. 王维钊, 向晓星. Treg/Th17、Th1 /Th2平衡在自身免疫性肝炎中的免疫学机制及诊疗新靶点[J]. 临床肝胆病杂志, 2019, 35(8): 1874-1877. DOI: 10.3969/j.issn.1001-5256.2019.08.051.
[26]	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.
[27]	LIANG M, LIWEN Z, YUN Z, et al. The imbalance between Foxp3(+)tregs and Th1/Th17/Th22 cells in patients with newly diagnosed autoimmune hepatitis[J]. J Immunol Res, 2018, 2018: 3753081. DOI: 10.1155/2018/3753081.
[28]	JOHN K, HARDTKE-WOLENSKI M, JAECKEL E, et al. Increased apoptosis of regulatory T cells in patients with active autoimmune hepatitis[J]. Cell Death Dis, 2017, 8(12): 3219. DOI: 10.1038/s41419-017-0010-y.
[29]	HAO X, LI Y, WANG J, et al. Deficient O-GlcNAc glycosylation impairs regulatory T cell differentiation and notch signaling in autoimmune hepatitis[J]. Front Immunol, 2018, 9: 2089. DOI: 10.3389/fimmu.2018.02089.
[30]	LIU Y, YAN W, YUAN W, et al. Treg/Th17 imbalance is associated with poor autoimmune hepatitis prognosis[J]. Clin Immunol, 2019, 198: 79-88. DOI: 10.1016/j.clim.2018.11.003.
[31]	PEISELER M, SEBODE M, FRANKE B, et al. FOXP3+ regulatory T cells in autoimmune hepatitis are fully functional and not reduced in frequency[J]. J Hepatol, 2012, 57(1): 125-132. DOI: 10.1016/j.jhep.2012.02.029.
[32]	QIU R, ZHOU L, MA Y, et al. Regulatory T cell plasticity and stability and autoimmune diseases[J]. Clin Rev Allergy Immunol, 2020, 58(1): 52-70. DOI: 10.1007/s12016-018-8721-0.
[33]	SHARABI A, TSOKOS MG, DING Y, et al. Regulatory T cells in the treatment of disease[J]. Nat Rev Drug Discov, 2018, 17(11): 823-844. DOI: 10.1038/nrd.2018.148.
[34]	OO YH, ACKRILL S, COLE R, et al. Liver homing of clinical grade Tregs after therapeutic infusion in patients with autoimmune hepatitis[J]. JHEP Rep, 2019, 1(4): 286-296. DOI: 10.1016/j.jhepr.2019.08.001.
[35]	HARRINGTON LE, HATTON RD, MANGAN PR, et al. Interleukin 17-producing CD4⁺ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages[J]. Nat Immunol, 2005, 6(11): 1123-1132. DOI: 10.1038/ni1254.
[36]	PARK H, LI Z, YANG XO, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17[J]. Nat Immunol, 2005, 6(11): 1133-1141. DOI: 10.1038/ni1261.
[37]	WU B, WAN Y. Molecular control of pathogenic Th17 cells in autoimmune diseases[J]. Int Immunopharmacol, 2020, 80: 106187. DOI: 10.1016/j.intimp.2020.106187.
[38]	GAGLIANI N, AMEZCUA VESELY MC, ISEPPON A, et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation[J]. Nature, 2015, 523(7559): 221-225. DOI: 10.1038/nature14452.
[39]	LIU YJ, WANG GC. Relationship of MCP-1, chronic hepatic disease and its complications[J/CD]. Chin J Hepatol(Electronic Version), 2017, 9(4): 31-37. DOI: 10.3969/j.issn.1674-7380.2017.04.005. 刘英娇, 王拱辰. 单核细胞趋化蛋白-1与慢性肝病及其并发症的相关性[J/CD]. 中国肝脏病杂志(电子版), 2017, 9(4): 31-37. DOI: 10.3969/j.issn.1674-7380.2017.04.005.
[40]	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.
[41]	OO YH, BANZ V, KAVANAGH D, et al. CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver[J]. J Hepatol, 2012, 57(5): 1044-1051. DOI: 10.1016/j.jhep.2012.07.008.
[42]	KI SH, PARK O, ZHENG M, et al. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: Role of signal transducer and activator of transcription 3[J]. Hepatology, 2010, 52(4): 1291-1300. DOI: 10.1002/hep.23837.
[43]	BETTELLI E, CARRIER Y, GAO W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J]. Nature, 2006, 441(7090): 235-238. DOI: 10.1038/nature04753.
[44]	LIBERAL R, GRANT CR, MA Y, et al. CD39 mediated regulation of Th17-cell effector function is impaired in juvenile autoimmune liver disease[J]. J Autoimmun, 2016, 72: 102-112. DOI: 10.1016/j.jaut.2016.05.005.
[45]	HU ED, CHEN DZ, WU JL, et al. High fiber dietary and sodium butyrate attenuate experimental autoimmune hepatitis through regulation of immune regulatory cells and intestinal barrier[J]. Cell Immunol, 2018, 328: 24-32. DOI: 10.1016/j.cellimm.2018.03.003.
[46]	KOMATSU N, OKAMOTO K, SAWA S, et al. Pathogenic conversion of Foxp3⁺ T cells into TH17 cells in autoimmune arthritis[J]. Nat Med, 2014, 20(1): 62-68. DOI: 10.1038/nm.3432.
[47]	FENG TT, ZOU T, WANG X, et al. Clinical significance of changes in the Th17/Treg ratio in autoimmune liver disease[J]. World J Gastroenterol, 2017, 23(21): 3832-3838. DOI: 10.3748/wjg.v23.i21.3832.
[48]	ZHA XJ, XIAN YT. Expressions of miR-21 and miR-155 in peripheral blood of patients with autoimmune liver disease and their relationships with Th17 and Treg cell balance[J]. Chin J Gastroenterol Hepatol, 2020, 29(5): 581-586. DOI: 10.3969/j.issn.1006-5709.2020.05.022. 扎西吉, 咸育婷. 自身免疫性肝病患者外周血miR-21、miR-155表达及其与Th17、Treg细胞平衡的关系[J]. 胃肠病学和肝病学杂志, 2020, 29(5): 581-586. DOI: 10.3969/j.issn.1006-5709.2020.05.022.
[49]	GAO LP, MAO XR. Study on the imbalance between T helper cell 17 and regulatory cells in autoimmune hepatitis model of rats[J]. Chin J Clin Pharmacol, 2020, 36(19): 3021-3025. https://www.cnki.com.cn/Article/CJFDTOTAL-GLYZ202019017.htm 高丽萍, 毛小荣. 辅助性T细胞17/调节性T细胞失衡在大鼠自身免疫性肝炎模型中的研究[J]. 中国临床药理学杂志, 2020, 36(19): 3021-3025. https://www.cnki.com.cn/Article/CJFDTOTAL-GLYZ202019017.htm
[50]	HUANG H, DENG Z. Adoptive transfer of regulatory T cells stimulated by Allogeneic Hepatic Stellate Cells mitigates liver injury in mice with concanavalin A-induced autoimmune hepatitis[J]. Biochem Biophys Res Commun, 2019, 512(1): 14-21. DOI: 10.1016/j.bbrc.2019.02.147.
[51]	XIA G, WU S, WANG X, et al. Inhibition of microRNA-155 attenuates concanavalin-A-induced autoimmune hepatitis by regulating Treg/Th17 cell differentiation[J]. Can J Physiol Pharmacol, 2018, 96(12): 1293-1300. DOI: 10.1139/cjpp-2018-0467.