TIGIT在自身免疫性肝炎免疫机制中的作用及治疗前景

韩琳; 张明月; 孙颖

doi:10.3969/j.issn.1001-5256.2022.03.034

TIGIT在自身免疫性肝炎免疫机制中的作用及治疗前景

DOI: 10.3969/j.issn.1001-5256.2022.03.034

韩琳¹,
张明月^{1, 2},
孙颖^{1, 2, , ,}

1.
解放军总医院第五医学中心肝病医学部肝病科，北京 100039
2.
解放军医学院研究生院，北京 100039

基金项目:

国家自然科学基金面上项目 (82170538)

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：韩琳、张明月负责资料分析，撰写论文；孙颖负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
孙颖，sunying_302@yahoo.com

韩琳、张明月对本文贡献等同，同为第一作者

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出版历程
- 收稿日期: 2021-07-22
- 录用日期: 2021-09-27
- 出版日期: 2022-03-20

Role of T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain in the immune mechanism of autoimmune hepatitis and its prospects in treatment

Lin HAN¹,
Mingyue ZHANG^{1, 2},
Ying SUN^{1, 2
, ,
,}

1.
Department of Liver Disease, Senior Department of Hepatology, The Fifth Medical Center of PLA General Hospital, Beijing 100039, China
2.
Graduate School, Medical School of Chinese PLA, Beijing 100039, China

Research funding:

General Project of National Natural Science Foundation of China (82170538)

More Information

Corresponding author: SUN Ying, sunying_302@yahoo.com(ORCID: 0000-0002-2570-9206)

摘要

摘要: 免疫耐受失衡在自身免疫性肝炎(AIH)的发病过程中发挥关键作用。免疫调节性T淋巴细胞(Treg)的共抑制信号分子表达异常可能是导致自身抗原耐受性破坏的重要原因之一。共抑制信号分子T淋巴细胞免疫球蛋白和免疫受体酪氨酸抑制基序结构域(TIGIT)是一种主要表达在Treg上的抑制性受体。本文阐述了Treg与AIH相关的免疫机制以及TIGIT在自身免疫性疾病发生、发展及治疗中的作用，以寻找TIGIT作为AIH候选靶点的治疗策略。
- 肝炎, 自身免疫性 /
- 治疗学 /
- T淋巴细胞免疫球蛋白和免疫受体酪氨酸抑制基序结构域
Abstract: The imbalance of immune tolerance plays a key role in the pathogenesis of autoimmune hepatitis (AIH), and the abnormal expression of coinhibitory signal molecules for regulatory T cells (Treg) may be one of the important reasons for the destruction of autoantigen tolerance. As a coinhibitory signal molecule, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an inhibitory receptor mainly expressed on Treg. This article elaborates on the immune mechanism of Treg associated with AIH and the role of TIGIT in the development, progression, and treatment of autoimmune diseases, so as to find the treatment strategy with TIGIT as the candidate target for AIH.
- Hepatitis, Autoimmune /
- Therapeutics /
- TIGIT

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表 1 Treg及TIGIT与自身免疫性肝病治疗的相关研究

研究内容	作者	年份	研究对象	例数	细胞类型	研究结果
Treg频率与AIH疾病活动的关系研究	Longhi等^[18]	2004	AIH患者	41	Treg	AIH疾病活动期患者Treg频率显著低于缓解期
Treg频率与AIH疾病活动的关系研究	Taubert等^[19]	2014	1型AIH患者	76	Treg	1型AIH患者获得生化缓解者，其肝内Treg/Teff和Treg/B淋巴细胞比率较未缓解患者更高
基于恢复Treg功能的AIH治疗研究	Buitrago-Molina等^[20]	2021	AIH小鼠模型		Treg	在AIH疾病晚期阶段给予IL-2/抗-IL-2复合物治疗，经过治疗后的小鼠模型肝内和全身Treg数量增加，肝内激活的Teff减少
	Lapierre等^[21]	2013	2型AIH 小鼠模型		Treg	在AIH的小鼠体内过继转移体外扩增的CXCR3⁺Treg，可有效靶向肝脏炎症，诱导AIH的缓解
	Xia等^[22]	2018	AIH小鼠模型		Treg/ Th17	ConA诱导的AIH小鼠模型，经antagomir-155处理后，其ALT、AST和ALP显著下降，antagomir-155可通过调节Treg和Th17的分化来预防AIH
	Hardtke-Wolenski等^[23]	2015	AIH小鼠模型	5	Treg	对AIH模型小鼠进行特异性Treg的过继治疗，结果发现特异性Treg过继治疗的AIH模型小鼠肝脏可获得组织学缓解
	Longhi等^[24]	2011	2型AIH患者	17	Treg	从2型AIH患者中获得CYP2D6特异性Treg，当其与半成熟树突状细胞共培养时，Treg能够发挥高效抑制自身反应性T淋巴细胞的作用
	Vuerich等^[25]	2021	AIH患者	49	Treg/ Th17	在AIH患者中，芳香烃受体途径的功能障碍能够影响Treg和Th17诱导细胞表面酶CD39的表达，导致Treg抑制功能缺陷，阻断这些抑制性和/或非典型芳香烃受体途径可恢复Treg和Th17的功能失衡
TIGIT与自身免疫性肝病的相关研究	Deng等^[12]	2020	PBC患者	42	TIGIT⁺ CD8⁺ T淋巴细胞	在PBC患者中CD8⁺TIGIT⁺ T淋巴细胞频率与肝功能损伤程度呈负相关，TIGIT高表达时可抑制CD226⁺CD8⁺T淋巴细胞亚群活性，有助于缓解疾病的活动状态
TIGIT与自身免疫性肝病的相关研究	Akiyama等^[13]	2021	IgG4相关疾病患者	23	TIGIT⁺Tfh	外周血TIGIT⁺Tfh通过OX40途径促进IL-21的分泌，TIGIT⁺Tfh频率与疾病活动相关
TIGIT与自身免疫性疾病治疗的研究	Liu等^[11]	2019	狼疮小鼠模型	60	TIGIT-Ig	经TIGIT-Ig融合蛋白腹腔注射的狼疮小鼠模型，发生蛋白尿的时间推迟，自身抗体(如抗核抗体)的血清浓度降低，存活率显著提高

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参考文献(27)

[1]	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.
[2]	WANG QX, MA X. Current status and perspectives of autoimmune hepatitis[J]. J Clin Hepatol, 2020, 36(4): 721-723. DOI: 10.3969/j.issn.1001-5256.2020.04.001. 王绮夏, 马雄. 自身免疫性肝炎的研究现状与展望[J]. 临床肝胆病杂志, 2020, 36(4): 721-723. DOI: 10.3969/j.issn.1001-5256.2020.04.001.
[3]	LONGHI MS, MIELI-VERGANI G, VERGANI D. Regulatory T cells in autoimmune hepatitis: An updated overview[J]. J Autoimmun, 2021, 119: 102619. DOI: 10.1016/j.jaut.2021.102619.
[4]	WANG H, FENG X, YAN W, et al. Regulatory T cells in autoimmune hepatitis: Unveiling their roles in mouse models and patients[J]. Front Immunol, 2020, 11: 575572. DOI: 10.3389/fimmu.2020.575572.
[5]	CHAUVIN JM, ZAROUR HM. TIGIT in cancer immunotherapy[J]. J Immunother Cancer, 2020, 8(2): e000957. DOI: 10.1136/jitc-2020-000957.
[6]	JI W, PENG X, LOU T, et al. Total flavonoids from Tetrastigma hemsleyanum ameliorates inflammatory stress in concanavalin A-induced autoimmune hepatitis mice by regulating Treg/Th17 immune homeostasis[J]. Inflammopharmacology, 2019, 27(6): 1297-1307. DOI: 10.1007/s10787-019-00599-0.
[7]	WU HY, YANG JL. TIGIT and anti-tumor immunity[J]. Chin J Immunol, 2020, 36(11): 1407-1408, inside back cover. DOI: 10.3969/j.issn.1000-484X.2020.11.025. 吴红艳, 杨建林. TIGIT与抗肿瘤免疫[J]. 中国免疫学杂志, 2020, 36(11): 1407-1408, 封3. DOI: 10.3969/j.issn.1000-484X.2020.11.025.
[8]	YANG ZZ, KIM HJ, WU H, et al. TIGIT expression is associated with T-cell suppression and exhaustion and predicts clinical outcome and anti-PD-1 response in follicular lymphoma[J]. Clin Cancer Res, 2020, 26(19): 5217-5231. DOI: 10.1158/1078-0432.CCR-20-0558.
[9]	ANDERSON AC, JOLLER N, KUCHROO VK. Lag-3, Tim-3, and TIGIT: Co-inhibitory receptors with specialized functions in immune regulation[J]. Immunity, 2016, 44(5): 989-1004. DOI: 10.1016/j.immuni.2016.05.001.
[10]	ZHOU H, LI B, LI J, et al. Dysregulated T cell activation and aberrant cytokine expression profile in systemic lupus erythematosus[J]. Mediators Inflamm, 2019, 2019: 8450947. DOI: 10.1155/2019/8450947.
[11]	LIU S, SUN L, WANG C, et al. Treatment of murine lupus with TIGIT-Ig[J]. Clin Immunol, 2019, 203: 72-80. DOI: 10.1016/j.clim.2019.04.007.
[12]	DENG C, LI W, FEI Y, et al. Imbalance of the CD226/TIGIT immune checkpoint is involved in the pathogenesis of primary biliary cholangitis[J]. Front Immunol, 2020, 11: 1619. DOI: 10.3389/fimmu.2020.01619.
[13]	AKIYAMA M, SUZUKI K, YOSHIMOTO K, et al. Peripheral TIGIT⁺ T follicular helper cells that produce high levels of interleukin-21 via OX40 represent disease activity in IgG4-related disease[J]. Front Immunol, 2021, 12: 651357. DOI: 10.3389/fimmu.2021.651357.
[14]	NAGAI K. Co-inhibitory receptor signaling in T-cell-mediated autoimmune glomerulonephritis[J]. Front Med (Lausanne), 2020, 7: 584382. DOI: 10.3389/fmed.2020.584382.
[15]	PING YQ, MAO C, XIAO P, et al. Structures of the glucocorticoid-bound adhesion receptor GPR97-Go complex[J]. Nature, 2021, 589(7843): 620-626. DOI: 10.1038/s41586-020-03083-w.
[16]	BUTTGEREIT F, GABER T. New insights into the fascinating world of glucocorticoids: The dexamethasone-miR-342-Rictor axis in regulatory T cells[J]. Cell Mol Immunol, 2021, 18(3): 520-522. DOI: 10.1038/s41423-020-00598-0.
[17]	WANG R, WANG QX, MA X. Standard therapy and potential therapeutic targets for autoimmune hepatitis[J]. J Clin Hepatol, 2020, 36(4): 737-742. DOI: 10.3969/j.issn.1001-5256.2020.04.005. 王睿, 王绮夏, 马雄. 自身免疫性肝炎的标准治疗和潜在治疗靶点[J]. 临床肝胆病杂志, 2020, 36(4): 737-742. DOI: 10.3969/j.issn.1001-5256.2020.04.005.
[18]	LONGHI MS, MA Y, BOGDANOS DP, et al. Impairment of CD4(+) CD25(+) regulatory T-cells in autoimmune liver disease[J]. J Hepatol, 2004, 41(1): 31-37. DOI: 10.1016/j.jhep.2004.03.008.
[19]	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.
[20]	BUITRAGO-MOLINA LE, PIETREK J, NOYAN F, et al. Treg-specific IL-2 therapy can reestablish intrahepatic immune regulation in autoimmune hepatitis[J]. J Autoimmun, 2021, 117: 102591. DOI: 10.1016/j.jaut.2020.102591.
[21]	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.
[22]	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.
[23]	HARDTKE-WOLENSKI M, TAUBERT R, NOYAN F, et al. Autoimmune hepatitis in a murine autoimmune polyendocrine syndrome type 1 model is directed against multiple autoantigens[J]. Hepatology, 2015, 61(4): 1295-1305. DOI: 10.1002/hep.27639.
[24]	LONGHI MS, HUSSAIN MJ, KWOK WW, et al. Autoantigen-specific regulatory T cells, a potential tool for immune-tolerance reconstitution in type-2 autoimmune hepatitis[J]. Hepatology, 2011, 53(2): 536-547. DOI: 10.1002/hep.24039.
[25]	VUERICH M, HARSHE R, FRANK LA, et al. Altered aryl-hydrocarbon-receptor signalling affects regulatory and effector cell immunity in autoimmune hepatitis[J]. J Hepatol, 2021, 74(1): 48-57. DOI: 10.1016/j.jhep.2020.06.044.
[26]	RAFFIN C, VO LT, BLUESTONE JA. Treg cell-based therapies: Challenges and perspectives[J]. Nat Rev Immunol, 2020, 20(3): 158-172. DOI: 10.1038/s41577-019-0232-6.
[27]	LUCCA LE, AXISA PP, SINGER ER, et al. TIGIT signaling restores suppressor function of Th1 Tregs[J]. JCI Insight, 2019, 4(3): e124427. DOI: 10.1172/jci.insight.124427.