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Advances in Clinical Medicine
Vol. 12  No. 03 ( 2022 ), Article ID: 49769 , 8 pages
10.12677/ACM.2022.123326

干燥综合征合并自身免疫性甲状腺疾病的研究进展

陈彦蓉，李钶*

重庆医科大学附属第二医院内分泌与代谢病科，重庆

收稿日期：2022年2月23日；录用日期：2022年3月15日；发布日期：2022年3月28日

摘要

干燥综合征(Sjögren’s syndrome, SS)是一种以外分泌腺受累为主的慢性全身性自身免疫性疾病，即唾液腺和泪腺存在淋巴细胞性和浆细胞性浸润，并伴有自身抗体的产生，其典型的临床表现为持续性的口干和眼干。自身免疫性甲状腺疾病(autoimmune thyroid diseases, AITD)是最常见的器官特异性自身免疫性疾病，主要包括弥漫性毒性甲状腺肿(Graves’ disease, GD)、原发性甲状腺功能减退症(简称甲减)和自身免疫性甲状腺炎(autoimmune thyroiditis, AIT)。临床上，SS和AITD经常共存于同一患者中，从而导致复杂的多自身免疫，这是自身免疫性疾病患者异质性表达的一个特殊例子。本文描述了近30年国内外文献中SS合并AITD的发病率，总结了SS合并AITD的发病机制和病因以了解这种令人着迷的自身免疫关联。

关键词

干燥综合征，自身免疫性甲状腺疾病，多自身免疫，发病率，发病机制

Research Progress of Autoimmune Thyroid Diseases in Sjögren’s Syndrome

Yanrong Chen, Ke Li*

Department of Endocrinology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing

Received: Feb. 23rd, 2022; accepted: Mar. 15th, 2022; published: Mar. 28th, 2022

ABSTRACT

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease dominated by exocrine gland involvement. SS is characterized by lymphocytic and plasma cell infiltration of salivary and lacrimal glands accompanied by the production of autoantibodies, and its typical clinical manifestations are persistent dry mouth and dry eyes. Autoimmune thyroid diseases (AITD) are the most common organ-specific autoimmune diseases, including Graves’ disease (GD), primary hypothyroidism and autoimmune thyroiditis (AIT). Clinically, SS and AITD often coexist in the same patient, resulting in complex polyautoimmunity, which is a special case of heterogeneous expression in patients with autoimmune diseases. This review describes the incidence of AITD in SS in the last 30 years of domestic and foreign literature, and summarizes the pathogenesis and etiology of AITD in SS to explore this fascinating autoimmune association.

Keywords:Sjögren’s Syndrome, Autoimmune Thyroid Diseases, Polyautoimmunity, Incidence, Pathogenesis

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 发病率

在自身免疫性疾病重叠现象中，SS和AITD共存最为常见。国内外文献显示，SS合并AITD的发病率为7.7%~45.0% [1] - [19]。其中，SS合并AIT为2.4%~30.0%，SS合并甲减的发病率为1.5%~36.6%，SS合并GD为0.7%~10.0%。甲状腺过氧化物酶抗体(thyroid peroxidaseantibody, TPOAb)阳性和甲状腺球蛋白抗体(thyroglobulin antibody, TgAb)阳性的SS患者分别为17.1%~45.0%和9.8%~21.4% (见表1)。由此可见，SS合并AIT、甲减最常见，SS合并GD则不多见；其中，TPOAb阳性较TgAb阳性在SS患者中更为常见。值得注意的是，在上述研究中观察到的疾病发病率可能因患者的年龄、性别、种族、入选及排除标准、实验室检测方法以及SS所采用的诊断标准差异而不同。

Table 1. The incidence of autoimmune thyroid diseases in Sjögren’s syndrome reported in the literature

表1. 文献报道干燥综合征合并自身免疫性甲状腺疾病的发病率

注：1) 包括临床型甲状腺功能减退症和亚临床型甲状腺功能减退症；AITD：自身免疫性甲状腺疾病；AIT：自身免疫性甲状腺炎；GD：弥漫性毒性甲状腺肿；TPOAb：甲状腺过氧化酶抗体；TgAb：甲状腺球蛋白抗体。

2. 发病机制

2.1. 功能学和组织学

在胚胎发育过程中，唾液腺和甲状腺共同起源于内胚层上皮细胞，具有相似的功能，其中包括碘的摄取和浓缩 [20]。在组织学上，唾液腺、泪腺和甲状腺中的淋巴细胞被激活，尤其是CD4+ T淋巴细胞和B淋巴细胞，导致局灶性或弥漫性浸润。通过组织学方法检测SS和AITD患者的甲状腺和唾液腺时，发现两者的腺体上皮细胞表面表达相似的人类白细胞抗原(human leukocyte antigen, HLA)分子，提示甲状腺上皮细胞和唾液腺上皮细胞(salivary gland epithelial cells, SGEC)具有相似的自身抗原，即它们在免疫反应和免疫表达上有着相似性 [21]。

2.2. 细胞因子

细胞因子是一种可溶性小蛋白，具有调节细胞增殖、细胞分化、免疫反应和炎症反应的功能。多自身免疫是指在同一个患者中可以发生一种以上的自身免疫性疾病。一项纳入1083例患者的队列研究中发现，多自身免疫的发生率为34.4% (373/1083例)，其中，SS和AITD是最常见的自身免疫性疾病 [22]。这提示SS和AITD可能存在相似的发病机制。在SS和AITD患者中检测到相同的细胞因子表达，可能与异常的免疫应答和炎症反应密切相关。

SS的发病起源于SGEC，它在自身免疫和炎症反应中起着积极作用。在炎症过程中，SS的上皮细胞作为非专职抗原呈递细胞(antigen presenting cells, APC)，其主要组织相容性复合物II类分子(major histocompatibility complex class II molecules, MHC II)的表达增加，具有一定的抗原处理和提呈功能，进而通过产生细胞因子和募集大量免疫细胞来参与炎症反应 [23]。在SS的淋巴细胞浸润过程中，Th1/Th2细胞因子的平衡会转向以促炎因子为特征的Th1反应，同时Th17淋巴细胞(IL-17的主要来源，在SS的炎症反应、自身免疫和腺组织损伤中起关键作用)的扩增，均有促进局部炎症的作用 [24]。Th1淋巴细胞分泌γ-干扰素(IFN-γ)和α-干扰素(IFN-α)，它们能诱导CXCL9和CXCL10的分泌，这些趋化因子介导B细胞和T细胞浸润唾液腺，激活淋巴细胞，诱导MHC表达并促进自身抗体的产生，而自身抗体在SS的发病机制中起着重要的作用 [25]。

在AITD中，T细胞向甲状腺迁移在桥本甲状腺炎(Hashimoto’s thyroiditis, HT)和GD的发病机理中起着重要作用。甲状腺具有特征性的Th1和Th17细胞浸润，尤其是CD8+ T细胞，导致慢性炎症和细胞凋亡 [26]。甲状腺滤泡细胞(thyroid follicular cells, TFC)作为非专职APC，通过MHC II将甲状腺球蛋白的抗原表位呈递给T细胞。当HT患者受到免疫原性刺激后，则影响T调节细胞(T regulatory cells, T-reg)与自身反应性T细胞之间的正常平衡，免疫耐受性遭到破坏，从而启动自身免疫过程 [27]。其中，CXCL10通过与趋化因子受体3 (CXCR3)结合发挥其功能，它们似乎参与了许多自身免疫性疾病(autoimmune diseases, ADs)的发病机制，包括器官特异性(如AIT、GD和Graves眼病)或全身性(如SS、类风湿关节炎和系统性红斑狼疮)自身免疫性疾病 [28]。在外周血中检测到高水平CXCL10是宿主免疫反应的标志物，特别是Th1淋巴细胞。在组织中，募集的Th1淋巴细胞分泌IFN-γ和肿瘤坏死因子-α (TNF-α)，刺激多种细胞(如内皮细胞、甲状腺细胞、成纤维细胞、前脂肪细胞等)分泌CXCL10，从而形成放大反馈回路，来启动和维持自身免疫过程 [29]。研究发现，IFN-γ诱导产生的促炎因子CXCL10在甲状腺炎的早期阶段起着重要作用。AIT患者的循环CXCL10水平升高，并与甲减有关，因此CXCL10被认为是一种更具侵袭性的甲状腺炎的标志物 [30]。另一项研究表明，在HT患者的甲状腺组织中，TFC表达了CXCL10，这提示TFC合成的CXCL10能将炎症细胞募集到腺体中发挥作用，同时也提示CXCL10可能参与HT的发病机制 [31]。

除了上述提及的细胞因子外，在SS和AITD中还存在一些相同的细胞因子表达，比如白细胞介素2 (IL-2)、IL-4、IL-8、血管内皮生长因子(VEGF)、B淋巴细胞刺激因子(BAFF)等，这些细胞因子在抗原提呈、局部组织炎症和损伤、细胞凋亡等方面有着密切联系 [32]。

3. 病因

3.1. 遗传因素

遗传因素在ADs的发展中起着重要作用。SS和AITD有家族性聚集现象，在受累对象的家庭成员(尤其是一级亲属)中发现了SS和AITD遗传易感性的流行病学的证据 [33] [34]。由此可见，SS和AITD发病是具有遗传倾向性。

在近十几年的全基因组关联分析(Genome-Wide Association Studies, GWAS)中已经发现与ADs相关的基因变异，其中大部分集中在HLA区域。尽管目前SS和AITD的具体致病机制尚不确切，但可以推断其与HLA基因及其相关产物有关。从遗传学角度看，SS和AITD有相似的表达背景，甲状腺和上皮细胞表达相同的II类HLA分子：HLA-B8和HLA-DR3 [35] [36] [37] [38]。Anaya等人通过GWAS总结了导致SS和AITD发生的遗传易感基因，包括HLA-DPB1、HLA-DQA1、HLA-DRB1和HLA-DQB1 [26]。上述结果表明，在基因层面上SS和AITD具有共同的免疫遗传基础。同时，有研究指出，虽然国内外研究识别出的SS和AITD易感基因的数量正在增加，但这不足以解释它们10%的遗传力 [38]。因此，期待未来有更多的科学研究来识别SS和AITD中新的遗传易感基因，进一步证明遗传因素在二者发病机制中的重要作用。

3.2. 非遗传因素

3.2.1. 内源性因素

SS和AITD的发生发展与年龄、性别、性激素等内源性因素有关。随着年龄的增长，SS和AITD 的发病率也逐年增加。Amador-Patarroyo等人提出年龄是SS合并AITD的危险因素之一 [39]。女性，尤其是围绝经期的妇女，在SS和AITD中占比更高。在一项纳入超过14,000名SS患者的研究中，女性与男性的比例接近10:1 [40]。Antonelli等人根据HT流行病学研究发现，女性比男性的发病风险更高(男女比例1:4~10) [34]。雌激素和雄激素通过与免疫细胞上的特定受体结合后，它们能在表型和作用方面影响免疫系统，这使得女性和男性在免疫反应上有着深刻的差异；此外，这也有助于发展特定的性别相关性疾病，例如ADs [41]。雌激素被认为是细胞免疫活性的增强剂，而孕酮和雄激素是免疫抑制剂。与男性相比，女性有更高的抗原呈递活性，也能产生更高滴度的自身抗体 [42]。这也解释了女性在ADs中发病率高于男性。

3.2.2. 环境因素

在SS和AITD中，环境因素也是导致免疫耐受性下降和疾病发展的关键因素之一，包括吸烟、咖啡摄入量、血清维生素D水平。从病理生理机制上，吸烟对淋巴细胞和浆细胞功能、细胞因子和激素失衡以及细胞凋亡有影响。在AITD中，吸烟与罹患GD和Graves眼病的风险升高相关 [43]。相反地，在一项病例对照研究中发现，吸烟能降低TPOAb和TgAb阳性率，也能降低甲减的发病率。但这种关联具有剂量依赖性，且在戒烟后3年内消失 [44]。关于吸烟对SS的影响是有争议的。有研究证实，吸烟通过减少唾液腺中的淋巴细胞浸润从而降低抗Ro抗体和抗La抗体的阳性率。因此，当前正在吸烟与不吸烟的SS患者相比，前者存在抗Ro抗体和抗La抗体的风险较低 [45]。但是，鉴于吸烟对心脑血管和肺部的负面影响，应该鼓励SS和AITD患者远离香烟。

咖啡是生物活性化合物的复杂混合物，包括咖啡因、抗突变蛋白、抗氧化剂多酚等。目前，越来越多的科学证据支持咖啡在免疫调节方面起着重要作用。咖啡因具有免疫抑制作用。当Th1和Th2细胞以不可控制的方式激活时，它们可能释放细胞因子并诱导其损害自身组织。然而，咖啡因能抑制Th1和Th2细胞增殖。同时，咖啡因可以改变B细胞功能并抑制抗体产生 [46]。此外，咖啡因还有抗炎作用，通过抑制机体mRNA的表达水平来下调血清炎性细胞因子水平 [47]。咖啡还能降低HT患者左旋甲状腺激素(L-T4)药物的肠道吸收率以及使血浆中L-T4的峰值水平延迟 [48]。然而，关于咖啡是否与SS和AITD有明确的相关性，需要进一步的研究来验证。

在AITD中，最具有代表性的病毒是丙型肝炎病毒(hepatitis C virus, HCV)和人细小病毒B19 (human parvovirus B19, EVB19) [49] [50]。在西班牙的SS患者中HCV感染率高于健康个体 [51]。然而，最近研究发现，HCV 感染会改变唾液腺组织学和唾液成分，表明HCV感染能通过不同于SS的致病机制来导致口干症 [52]。关于病毒感染如何触发自身免疫以及是在疾病发生之前还是发生之后触发自身免疫的问题，有待进一步去探索和解决。

维生素D在SS和AITD中的作用，目前仍存在争议。维生素D受体基因(vitamin D receptor gene, VDRG)的多态性和维生素D缺乏可能与SS的发生有关 [53]。Ramagopalan等人发现SS患者发生维生素D缺乏症、骨软化症和佝偻病的风险增加 [54]。然而，有研究表明，SS与低水平的维生素D无关 [55]。2017年的一项回顾性研究发现，低水平的维生素D与GD复发率升高相关 [56]。最近的研究表明，维生素D缺乏与甲状腺自身抗体(TPOAb和TgAb)阳性有相关性 [57]。此外，饮酒、药物、心理应激、社会经济地位和教育水平等环境因素对SS、AITD的发生发展也有着不可忽视的作用。

综上所述，SS和AITD是两种不同的自身免疫性疾病，但在临床上两者常共存于同一患者中，可能是具有相似的发病机制、相同的遗传背景和致病因素。细胞因子、免疫应答、炎症反应、吸烟、咖啡摄入量、维生素D水平都可能参与其致病过程。

文章引用

陈彦蓉,李 钶. 干燥综合征合并自身免疫性甲状腺疾病的研究进展
Research Progress of Autoimmune Thyroid Diseases in Sj?gren’s Syndrome[J]. 临床医学进展, 2022, 12(03): 2266-2273. https://doi.org/10.12677/ACM.2022.123326

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    58. NOTES

    *通讯作者。

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