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. 2022 Dec 28;47(12):1748–1753. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2022.220205

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Research progress in Th17 cells and the relevant cytokines in Graves’ ophthalmopathy

JIANG Minmin ^1,¹, ZHAO Jingxiao ¹, WANG Ping ¹, YAN Shuxun ^2,^✉, WANG Ying ^3,^✉

Editor: 傅希文

PMCID: PMC10930278 PMID: 36748387

Abstract

Graves’ ophthalmopathy is the most common clinical orbital disease, and T helper (Th) cells play an important role in the development of Graves’ ophthalmopathy. Th17 cells are a major subpopulation of Th cells and abnormally highly expressed in patients with Graves’ ophthalmopathy. Th17 cells and the related cytokines interleukin (IL)-17A, IL-21 and IL-23 are involved in regulating the inflammatory response, fibrosis and adipogenesis. Th17 cells are unstable and exhibit a degree of plasticity, and they can differentiate into IL-17A and interferon (IFN)-γ dual-producing Th17.1 cells, which exacerbate the pathogenicity of Th17 cells. In addition, Th17 cells and the relevant factors are strongly associated with disease activity and severity in Graves’ ophthalmopathy.

Keywords: Graves’ ophthalmopathy, Th17 cells, cytokines

目前临床上最常见的眼眶疾病是Graves眼病(Graves’ ophthalmopathy，GO)，它也被称之为甲状腺相关性眼病(thyroid associated ophthalmopathy，TAO)和甲亢突眼^[1]。GO主要与Graves病(Graves’ disease，GD)病有关，研究^[2-3]显示GD患者中大约有38%患有GO，且亚洲人发病率最高，一般女性高于男性。GO常见的临床表现为眼球向外突出、眼睑肿胀、自觉眼内异物感和畏光等。极少数患者病情严重，出现急性视神经病变并造成视力受损或失明^[4]。GO被广泛认为是一种自身免疫性疾病。糖胺聚糖特别是透明质酸(hyaluronic acid，HA)和脂肪的堆积、纤维化和免疫细胞的浸润是GO发病的主要病理特征。双抗原学说一直以来受到研究人员的认同，即GD和GO共用同一个抗原-促甲状腺激素受体(thyroid stimulating hormone receptor，TSHR)。然而，研究^[5]发现GO中TSHR与胰岛素样生长因子-1受体(insulin-likegrowthfactor-1 receptor，IGF-1R)组成的串扰信号也起着重要作用，如眼眶成纤维细胞(orbital fibroblasts，OFs)分泌HA就可由该信号激活。以往研究^[6-7]发现GO与Th1细胞及其相关因子有着密切的联系，但近年来研究^[8]表明Th17细胞及相关因子在GO中也占主导作用。本文将阐述Th17细胞及其相关因子在GO发生、发展中的作用，希望能为GO治疗及预后提供新的思路。

1. Th17细胞概述

1.1. Th17细胞的分化

研究人员^[9]在2005年首次发现一种特别的Th细胞可特异性产生IL-17，因此将这种特殊的Th细胞称为Th17细胞。Th17细胞的主要特征包括转录因子维甲酸相关孤独受体γt(retinoic acid receptor related orphan receptor γt，RORγt)及C-C基序趋化因子受体(C-C motif chemokine receptor，CCR)6呈阳性，并能特异性分泌IL-21、IL-17(主要包括IL-17A和IL-17F)、IL-22等炎性因子。转化生长因子-β(transforming growth factor-β，TGF-β)被认为是Th17细胞分化过程中必不可少的因素，IL-6、IL-1β、IL-21和IL-23在该过分化过程中也扮演着重要角色。

Tang等^[10]在体外观察到：Th0细胞在TGF-β1和IL-6的共同刺激下可向Th17细胞分化。IL-21也可作用于原始CD4⁺T细胞，主要通过下调叉头框蛋白P3(forkhead box P3，Foxp3)表达和上调RORγt表达而促进CD4⁺T细胞增殖和Th17细胞分化，与此同时抑制调节性T细胞(regulatory T cell，Treg)分化^[11]。上述过程使得Th17细胞与其分泌的IL-21形成循环，该循环可长久维持Th17细胞相关炎症因子的紊乱。去除TGF-β的刺激，在IL-1β、IL-6与IL-23共同作用下同样可驱动Th0细胞向Th17细胞分化，并且其分化过程离不开IL-1β的作用^[12]。最新研究^[13]表明致病性Th17细胞分化可由激活素A驱动，激活素A是TGF-β超家族的成员之一。有研究^[14]报道TGF-β不仅不是Th17细胞分化的必需成分，而且对于Th17的细胞分化有着抑制作用。在高浓度的TGF-β作用下，Th0细胞可拮抗RORγt的促分化作用，从而抑制其向Th17细胞分化，这是因为其表达了Foxp3。此外，研究^[15]发现Th17分化过程中需要转录因子参与调控，除开干扰素调节因子4(interferon regulatory factor-4，IRF-4)、信号转导与转录激活因子(signal transducer and activator of transcription，STAT)3与核受体视黄酸相关孤儿受体α(acid-related orphan receptor-α，RORα)外，还有4个转录因子起到关键作用，它们分别是缺氧诱导因子1(hypoxia inducible factor-1，HIF-1)、B细胞活化转录因子(B cell activating transcription factor，BATF)、芳香烃受体(aryl hydrocarbon receptor，AHR)和FOS相关抗原2(fos-related antigen 2，FOSL2)。

1.2. Th17细胞的可塑性

现已经证实Th17细胞具有可塑性，可在某些特定的条件下同时具有Th1和Th17细胞的特征，即分泌Th1细胞特有的细胞因子IFN-γ和IL-17，这种特殊的细胞被称为Th1样Th17细胞或Th17.1细胞，其分化途径可以体现于以下几种：1)Th17细胞无法自分泌TGF-β1时，其更易分化成Th1样Th17细胞，与此同时IL-12受体β2和IL-27受体α表达水平也升高了^[16]；2)IL-23促进T细胞表达的T-bet诱导是导致Th1样Th17细胞表达IFN-γ的重要一步^[17]；3)IL-12可直接诱导Th17细胞的细胞因子分泌谱改变，并成为Th1样Th17细胞^[18]。Th17细胞与Th1样Th17细胞主要通过其表达的趋化因子受体区分，表达CCR6和CCR4的细胞是Th17细胞，表达CCR6和C-X-C基序趋化因子受体(C-X-C motif chemokine receptor，CXCR)3的细胞则是Th1样Th17细胞^[19]。研究^[20]表明Th1样Th17细胞具有强烈的致病性。与Th17细胞和Th1细胞相比，Th17.1细胞的存活和增殖能力更强，可分泌更多功能性的细胞因子。而且Th17.1细胞可对抗Treg介导的细胞增殖和细胞因子生成的作用^[21]。

2. Th17细胞与GO

Th17细胞及其相关因子可导致GO。Th17细胞分泌的IFN-γ、IL-21、IL-17(主要包括IL-17A、IL-17F)和IL-22等促炎因子可激活内皮细胞、巨噬细胞、中性粒细胞和成纤维细胞，还可产生单核细胞趋化蛋白(monocyte chernotactic protein，MCP)-1、巨噬细胞炎症蛋白(macrophage inflammatory protein，MIP)-1α、IL-8、IL-6、肿瘤坏死因子(tumor necrosis factor，TNF)-α以及活性氧中间物，并能释放溶酶体等炎性因子。Th17细胞也可表达不同的转录因子(如RORγt、RORα和STAT3)而参与炎症损伤。无论是GO患者血液中，还是组织中，都发现存在高频率的Th17细胞及其相关因子，说明Th17细胞失衡参与了GO的发生、发展。如在GO患者的外周血样本中发现有比GD患者更高频率的Th17细胞^[22]。与健康人相比，Th17细胞特异性分泌的IL-17高度表达于GO患者的泪液和眼眶组织中^[23]。此外，研究^[24]表明IL-17受体基因家族之一的IL17RE基因的甲基化水平与临床活性评分(clinical activity score，CAS)呈正相关。Fang等^[25]的实验表明：来源于GO眼眶组织的CD34^-OFs可产生前列腺素E2(prostaglandin E2，PGE2)、促进PGE2-前列腺素E受体(prostaglandin E receptor，EP)2/EP4-环磷酸腺苷(cyclic adenosine monophosphate，cAMP)途径，并上调IL-23受体和IL-1受体表达，从而进一步促进Th17细胞分化。最新的研究^[26]发现：GO患者中Th17细胞占优势，且中度至重度GO患者中存在一种特殊的Th17细胞，该细胞可独立表达RORγt而产生最高水平的IL-17A，而在非常严重的GO中，这种特殊的细胞(Th1样Th17细胞)可共表达RORγt和Th1细胞特征型转录因子T-bet，并能产生最高水平的IFN-γ。Th17细胞能促进GO患者纤维细胞的抗原呈递功能，也能促进其释放IL-6、IL-8、MCP-1、MIP-3、TNF-α等炎症因子，体外纤维细胞能反作用增强Th17细胞功能，并以MIP-3/CCR6依赖性方式招募Th17细胞^[27]。研究^[28]表明对于GO患者起治疗作用的药物参与调节了Th17细胞的稳态，如甲基强的松龙可通过降低Th17/Treg细胞的比例而达到对GO患者的治疗作用。随机临床试验^[29]显示：托珠单抗治疗难治性中度或重度 GO患者1个月后，GO患者的临床症状都得到明显改善且维持时间长达1年。其可能是因为托珠单抗可作为一种针对IL-6受体的重组人源化单克隆抗体，可抑制Th17细胞分化的关键信号IL-6/IL-6受体，从而可达到治疗GO的目的。

3. Th17细胞相关因子与GO

3.1. IL-17A与GO

IL-17A主要由Th17细胞产生，在GO的病程中扮演着重要角色。目前普遍的观点是IL-17A是致炎性细胞因子。研究^[25]表明高度表达的IL-17A存在于GO患者的眼眶组织中，且CAS以及视力降低水平与IL-17A表达水平呈正相关。来自于GO患者的纤维细胞和OFs都高度表达IL-17受体A^{[27, 30]}，这表明从外周循环到局部眼眶结缔组织均受到IL-17A的连续刺激。IL-17A在GO中表达明显上升。IL-17A可激活核因子κB(nuclear factor kappa-B，NF-κB)通路和丝裂原活化蛋白激酶(mitogen-activated protein kinase，MAPK)通路并促进纤维细胞和OFs表达多种炎症因子，包括IL-6、TNF-α、IL-1β、趋化因子[如MCP-1、C-X-C基序趋化因子配体(C-X-C motif chemokine ligand，CXCL)1、CXCL2、CXCL9、CXCL10、C-C基序趋化因子配体(C-C motif chemokine ligand，CCL)7、CCL20]、粒细胞-巨噬细胞刺激因子(granulocyte-macrophage colony-stimulating factor，GM-CSF)、细胞间黏附分子(intercellular cell adhesion molecule，ICAM)、PGE₂、一氧化氮合酶、共刺激分子[CD40和主要组织相容性复合体(major histocompatibility complex，MHC)II]等^[31]。IL-17A也可起到招募、促进炎症细胞增殖并迁移到靶细胞的黏膜表面的作用^[31]。另外，IL-6参与Th17细胞分泌IL-17A的过程，这使得IL-6与IL-17A在GO患者中形成一个正反馈环路。这个正反馈环路维持了Th17细胞的活性及相关免疫异常应答和炎症反应。研究^{[30, 32]}发现IL-17A可促进TGF-β所诱导的GO-OFs向肌纤维细胞分化的过程，该过程依赖c-Jun-N末端激酶(c-Jun-N-terminal kinase，JNK)信号通路，并可上调α-平滑肌肌动蛋白(alpha-smooth muscle actin，α-SMA)等纤维化标志物和相关蛋白，表明在GO患者中IL-17A能加速纤维化进程。IL-17A对于脂肪生成有着调节作用。有研究^[30]报道IL-17A减弱环戍烯酮类前列腺素(15-deoxy-Δ-12,14-Prostaglandin J2，15d-PGJ2)触发的CD90^-OFs中脂肪生成，并且下调与脂肪生成相关的过氧化物酶体增殖物激活受体-γ(peroxisome proliferator-activated receptor-γ，PPAR-γ)等蛋白水平。然而最新研究^[33]却发现IL-17A可促进15d-PGJ2所触发的CD34⁺泪液成纤维细胞(lacrimal fibroblasts，LFS)和OFs中脂肪的生成，且IL-17A可激活CD34⁺ OFs中的成脂通路，如PPAR-γ和胰岛素信号通路等。

3.2. IFN-γ与GO

免疫调控是IFN-γ的主要生理功能，IFN-γ可诱导多种抗原提呈细胞表达 MHCI/II分子并活化自然杀伤细胞(natural killer cell，NK)、巨噬细胞而产生成纤维细胞生长因子(fibroblast growth factor，FGF)、TNF-α、IL-6等炎性细胞因子，导致急性炎症反应而出现红、肿、热、痛等典型的炎症症状。IFN-γ有促进细胞毒性T细胞(cytotoxic tlymphocyte，CTL)增殖及分化的作用，活化后的CTL可释放穿孔素、颗粒酶、颗粒溶素而促进眼部组织的损伤。IFN-γ可通过促进IL-1β、IL-6等促炎因子的产生，同时减少IL-10、IL-11、TGF-β等抗炎介质的产生而加重炎症反应，继而促进眼部组织损伤。另外，IFN-γ可通过增强IL-1β诱导的透明质酸合成酶-2(hyaluronan synthase 2，HAS2)mRNA的表达而促进透明质酸的合成^[34]。在体外细胞实验中，IFN-γ可刺激GO患者的OFs和前脂肪细胞分泌趋化因子CXCL10而招募淋巴细胞，同时抑制CXCL8的生成^[35]。IFN-γ本就可活化Th1细胞而促进IFN-γ、TNF-α等细胞因子分泌，这些促炎因子又可抑制Th2细胞的活化。上述过程确保了GO患者眼眶组织的Th1细胞相关免疫应答的持续发生。研究^[36]显示每种浓度的IFN-γ都可以在体外细胞培养实验中促进GO患者和正常人的OFs增殖，且夏枯草多糖抑制IFN-γ是在OFs增殖及透明质酸分泌的抑制过程中不可或缺的条件。多项研究^[32-33]证实IFN-γ可在体外抑制TGF-β诱导GO-OFs所产生的纤维化标志物和相关蛋白而抑制纤维化。Huang等^[33]报道了IFN-γ对15d-PGJ2处理的CD34⁺泪液成纤维细胞和OFs的脂肪生成的抑制作用。GO患者中IFN-γ表达水平明显高于健康人，且IFN-γ表达水平与GO的活动性成正相关，提示IFN-γ表达越高，其临床症状也就越严重。

3.3. Th17细胞其他因子与GO

研究^[37]表明IL-23在GO患者外周血中高度表达，且与CAS呈正相关。IL-23主要通过调控Th17细胞及炎症因子参与GO的发病过程。IL-23主要激活转录因子STAT3，并且可通过Janus激酶(Janus kinase，JAK)-STAT途径促进Th17细胞分化及相关因子IL-17A的分泌。研究^[38]表明IL-23能诱导来源于GO患者的外周血单核细胞(peripheral blood mononuclear cells，PBMCs)产生PGE₂，并通过PGE₂/EP2+EP4，上调IL-23受体，促进Th17分化和IL-17A分泌，加剧GO的炎症反应。

与IL-23一样，IL-21在GO患者外周血中呈高度表达，IL-21表达水平越高，患者的CAS也越高^[39]。IL-21可激活JAK/STAT、MAPK和磷脂酰肌醇3-激酶(phosphatidylinositide 3-kinases，PI3K)途径，促进滤泡Th和Th17细胞的发育，平衡Th亚群，诱导B细胞生成并分化成浆细胞，且可促进免疫球蛋白的产生而参与免疫紊乱^[40]。此外，有研究^[41]曾报道IL-21基因多态性rs13143866与GO显著有关。

4. 结语

Th17细胞及其相关因子稳态被破坏后，过度表达的Th17细胞及相关因子可相互作用、共同协调，从而参与GO的发生、发展过程，调节Th17细胞及其相关因子的稳态或将成为治疗GO的有效手段。值得指出的是，IFN-γ和Th1样Th17细胞的表达水平似乎可以作为GO患者的预后因素之一。由于Th17细胞与GO的关系研究尚在起步阶段，其相互的作用机制尚未完全明了，有待未来研究人员进一步探索。

基金资助

河南省中医药传承与创新人才工程(仲景工程)中医药拔尖人才(CZ0237-02)；河南省中医药科学研究专项课题(20-21ZY1016)。

This work was supported by Henan Traditional Chinese Medicine Inheritance and Innovation Talent Project (Zhongjing Project) Top-Notch Talents of Traditional Chinese Medicine (CZ0237-02) and the Special Project of Scientific Research on Traditional Chinese Medicine in Henan Province (20-21ZY1016), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

蒋敏敏论文构想，撰写；赵静晓、王萍论文修订；燕树勋、王颖论文修改。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2022121748.pdf

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