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通讯作者:

陈欢欢,E-mail:drchenhuanhuan@njmu.edu.cn

中图分类号:R581.1

文献标识码:A

文章编号:1007-4368(2022)09-1335-06

DOI:10.7655/NYDXBNS20220921

参考文献 1
HIROMATSU Y,EGUCHI H,TANI J,et al.Graves’oph⁃ thalmopathy:epidemiology and natural history[J].Intern Med,2014,53(5):353-360
参考文献 2
BARTALENA L,TANDA M L.Clinical practice.Graves’ ophthalmopathy[J].N Engl J Med,2009,360(10):994-1001
参考文献 3
BARRIO⁃BARRIO J,SABATER A L,BONET⁃FARRIOL E,et al.Graves’ophthalmopathy:visa versus EUGOGO classification,assessment,and management[J].J Oph⁃ thalmol,2015,2015:249125
参考文献 4
TAKESHIMA K,INABA H,FURUKAWA Y,et al.Ele⁃ vated serum immunoglobulin G4 levels in patients with Graves’disease and their clinical implications[J].Thy⁃ roid,2014,24(4):736-743
参考文献 5
YU S H,KANG J G,KIM C S,et al.Clinical implications of immunoglobulin G4 to Graves’ophthalmopathy[J].Thyroid,2017,27(9):1185-1193
参考文献 6
BOZKIRLI E,BAKINER O S,ERSOZLU BOZKIRLI E D,et al.Serum immunoglobulin G4 levels are elevated in patients with Graves’ophthalmopathy[J].Clin Endocri⁃ nol(Oxf),2015,83(6):962-967
参考文献 7
MARTIN C S,SIRBU A E,BETIVOIU M A,et al.Serum immunoglobulin G4 levels and Graves’disease phenotype [J].Endocrine,2017,55(2):478-484
参考文献 8
LUO B,YUAN X,WANG W,et al.Ocular manifestations and clinical implications of serum immunoglobulin G4 levels in Graves’ophthalmopathy patients[J].Ocul Im⁃ munol Inflamm,2022,30(3):580-587
参考文献 9
DENG Y,WANG J,ZOU G,et al.The characteristics and clinical significance of elevated serum IgG4/IgG levels in patients with Graves’disease[J].Endocrine,2022,75(3):829-836
参考文献 10
吴联群,魏锐利,蔡季平,等.国人甲状腺相关眼病患者血清免疫球蛋白4水平的研究[J].中国实用眼科杂志,2016,34(1):36-40
参考文献 11
SY A,SILKISS R Z.Serum total IgG and IgG4 levels in thyroid eye disease[J].Int Med Case Rep J,2016,9:325-328
参考文献 12
YE H,XIAO W,CHEN R,et al.Elevated immunoglobu⁃ lin G4 levels in patients with thyroid eye disease and their clinical implications[J].Invest Ophthalmol Vis Sci,2020,61(5):57
参考文献 13
李亚玲.血清IgG4水平与Graves眼病的临床及实验室特征相关性研究[D].武汉:华中科技大学,2019
参考文献 14
BAHN R S.Graves’ophthalmopathy[J].N Engl J Med,2010,362(8):726-738
参考文献 15
SHAN S J,DOUGLAS R S.The pathophysiology of thy⁃ roid eye disease[J].J Neuroophthalmol,2014,34(2):177-185
参考文献 16
DOLMAN P J.Evaluating Graves’orbitopathy[J].Best Pract Res Clin Endocrinol Metab,2012,26(3):229-248
参考文献 17
BARTALENA L,KAHALY G J,BALDESCHI L,et al.The 2021 European Group on Graves ’ orbitopathy(EUGOGO)clinical practice guidelines for the medical management of Graves’orbitopathy[J].Eur J Endocri⁃ nol,2021,185(4):G43-G67
参考文献 18
刘春玲,罗清礼,吕红彬.甲状腺相关眼病眼眶组织病理学研究[J].四川大学学报(医学版),2005,36(3):436-437
参考文献 19
AALBERSE R C,STAPEL S O,SCHUURMAN J,et al.Immunoglobulin G4:an odd antibody[J].Clin Exp Aller⁃ gy,2009,39(4):469-477
参考文献 20
PETERSEN J G,DORRINGTON K J.An in vitro system for studying the kinetics of interchain disulfide bond for⁃ mation in immunoglobulin G[J].J Biol Chem,1974,249(17):5633-5641
参考文献 21
NIRULA A,GLASER S M,KALLED S L,et al.What is IgG4?A review of the biology of a unique immunoglobu⁃ lin subtype[J].Curr Opin Rheumatol,2011,23(1):119-124
参考文献 22
STONE J H,ZEN Y,DESHPANDE V.IgG4⁃ related dis⁃ ease[J].N Engl J Med,2012,366(6):539-551
参考文献 23
RISPENS T,OOIJEVAAR⁃DE HEER P,BENDE O,et al.Mechanism of immunoglobulin G4 Fab⁃arm exchange[J].J Am Chem Soc,2011,133(26):10302-10311
参考文献 24
KOIKE T.IgG4⁃related disease:why high IgG4 and fibro⁃ sis?[J].Arthritis Res Ther,2013,15(1):103
参考文献 25
DESHPANDE V,ZEN Y,CHAN J K,et al.Consensus statement on the pathology of IgG4 ⁃ related disease[J].Mod Pathol,2012,25(9):1181-1192
参考文献 26
UMEHARA H,OKAZAKI K,MASAKI Y,et al.A novel clinical entity,IgG4 ⁃ related disease(IgG4RD):general concept and details[J].Mod Rheumatol,2012,22(1):1-14
参考文献 27
UMEHARA H,OKAZAKI K,MASAKI Y,et al.Compre⁃ hensive diagnostic criteria for IgG4⁃related disease(IgG4⁃ RD),2011[J].Mod Rheumatol,2012,22(1):21-30
参考文献 28
GOTO H,TAKAHIRA M,AZUMI A,et al.Diagnostic cri⁃ teria for IgG4⁃related ophthalmic disease[J].Jpn J Oph⁃ thalmol,2015,59(1):1-7
参考文献 29
TOOLEY A A,SALOMAO D R,BRADLEY E A,et al.Distinguishing IgG4 ⁃ related ophthalmic disease from Graves orbitopathy[J].Ophthalmic Plast Reconstr Surg,2019,35(2):170-176
参考文献 30
SOUSSAN J B,DESCHAMPS R,SADIK J C,et al.Infra⁃ orbital nerve involvement on magnetic resonance imaging in European patients with IgG4 ⁃ related ophthalmic dis⁃ ease:a specific sign[J].Eur Radiol,2017,27(4):1335-1343
参考文献 31
MCLACHLAN S M,BAHN R,RAPOPORT B.Endocrine ophthalmopathy:a re ⁃ evaluation of the association with thyroid autoantibodies[J].Autoimmunity,1992,14(2):143-148
参考文献 32
CATUREGLI P,KUPPERS R C,MARIOTTI S,et al.IgG subclass distribution of thyroglobulin antibodies in pa⁃ tients with thyroid disease[J].Clin Exp Immunol,1994,98(3):464-469
参考文献 33
LATROFA F,CHAZENBALK G D,PICHURIN P,et al.Affinity⁃enrichment of thyrotropin receptor autoantibodies from Graves’patients and normal individuals provides in⁃ sight into their properties and possible origin from natural antibodies[J].J Clin Endocrinol Metab,2004,89(9):4734-4745
参考文献 34
高荣,王庆祝,吴丽娜,等.血清TRAb IgG 亚型在甲状腺相关性眼病患者中的特征及临床意义[J].中华内分泌代谢杂志,2020,36(4):315-320
参考文献 35
ECKSTEIN A K,PLICHT M,LAX H,et al.Thyrotropin receptor autoantibodies are independent risk factors for Graves’ophthalmopathy and help to predict severity and outcome of the disease[J].J Clin Endocrinol Metab,2006,91(9):3464-3470
参考文献 36
KAKUDO K,LI Y,TANIGUCHI E,et al.IgG4 ⁃ related disease of the thyroid glands[J].Endocr J,2012,59(4):273-281
参考文献 37
WIERSINGA W M,PRUMMEL M F.Pathogenesis of Graves’ophthalmopathy ⁃ current understanding[J].J Clin Endocrinol Metab,2001,86(2):501-503
参考文献 38
WAKELKAMP I M,BAKKER O,BALDESCHI L,et al.TSH⁃R expression and cytokine profile in orbital tissue of active vs.inactive Graves’ophthalmopathy patients[J].Clin Endocrinol(Oxf),2003,58(3):280-287
参考文献 39
HIROMATSU Y,KAKU H,MIYAKE I,et al.Role of cyto⁃ kines in the pathogenesis of thyroid ⁃ associated ophthal⁃ mopathy[J].Thyroid,2002,12(3):217-221
参考文献 40
BERGER A.Th1 and Th2 responses:what are they?[J].BMJ,2000,321(7258):424
参考文献 41
OLEJARZ M,SZCZEPANEK⁃PARULSKA E,DADEJ D,et al.IgG4 as a biomarker in Graves’orbitopathy[J].Me⁃ diators Inflamm,2021,2021:5590471
参考文献 42
LEE C G,HOMER R J,ZHU Z,et al.Interleukin⁃13 in⁃ duces tissue fibrosis by selectively stimulating and acti⁃ vating transforming growth factor beta(1)[J].J Exp Med,2001,194(6):809-821
参考文献 43
NAGATA K,NAKAYAMA Y,HIGAKI K,et al.Reactiva⁃ tion of persistent Epstein ⁃Barr virus(EBV)causes secre⁃ tion of thyrotropin receptor antibodies(TRAbs)in EBV ⁃ infected B lymphocytes with TRAbs on their surface[J].Autoimmunity,2015,48(5):328-335
参考文献 44
NAGATA K,FUKATA S,KANAI K,et al.The influence of Epstein⁃Barr virus reactivation in patients with Graves’ disease[J].Viral Immunol,2011,24(2):143-149
目录contents

    摘要

    甲状腺相关性眼病(thyroid-associated ophthalmopathy,TAO)是一种威胁视力的自身免疫性疾病,患者通常出现突眼、复视或斜视,严重者可能会有视神经受压,造成视力受损甚或失明。血清免疫球蛋白G4(immunoglobulin G4,IgG4)是一种特异性抗体,与多种自身免疫性疾病有关。目前研究发现部分TAO患者血清IgG4水平升高,这些患者往往病情更加严重。在眼病的发生发展中,IgG4可能诱导眼眶成纤维细胞生成透明质酸,促进自身抗体产生,IgG4可能单独或联合促甲状腺激素受体抗体在TAO的发病机制中发挥作用。已有研究显示血清IgG4与眼病的临床活动性和严重程度相关,高IgG4可能预示TAO 处于炎症活动早期,及时干预可减缓其肌肉病变和眼眶纤维化的进程。因此,本文对相关文献进行综述,探讨血清IgG4与甲状腺相关性眼病的关系,以期对TAO患者进行更早期和更有效的临床管理。

    Abstract

    Thyroid - associated ophthalmopathy(TAO)is a vision - threatening autoimmune disease. Patients usually suffer from proptosis,diplopia or strabismus. In severe cases,the optic nerve may be compressed,resulting in visual impairment or even blindness. Serum immunoglobulin G4(IgG4)is a specific antibody that is associated with a variety of autoimmune diseases. Current studies have found that some TAO patients have elevated serum IgG4 levels,and these patients tend to have more severe symptoms. In the occurrence and development of ophthalmopathy,IgG4 may induce orbital fibroblasts to generate hyaluronic acid and promote the production of autoantibodies. IgG4 may play a role in the pathogenesis of TAO alone or in combination with thyrotropin receptor antibodies. Studies have shown that serum IgG4 is related to the clinical activity and severity of TAO. High IgG4 may indicate that TAO is in the early stage of inflammatory activity,and timely intervention can slow down the progression of muscle lesions and orbital fibrosis. Therefore,this article reviewed the relevant literature to explore the relationship between serum IgG4 and thyroid-associated ophthalmopathy,with a view to earlier and more effective clinical management of patients with TAO.

  • 甲状腺相关性眼病(thyroid⁃associated ophthal⁃mopathy,TAO)又称格雷夫斯眼病(Graves’ophthal⁃ mopathy,GO),是一种机制复杂的特异性自身免疫性疾病,发生于20%~50%的格雷夫斯病(Graves dis⁃ ease,GD)患者[1],少部分也可发生在桥本甲状腺炎伴甲状腺功能正常或减退的患者[2]。患者常有突眼、复视或斜视,3%~7%的TAO患者会因暴露性角膜炎或视神经受压而出现视力下降甚至失明[3],严重影响生活质量。

  • 血清免疫球蛋白G4(immunoglobulin G4,IgG4) 是一种特异性抗体,与多种自身免疫性疾病有关。多项研究表明,自身免疫性甲状腺疾病GD患者血清IgG4水平显著高于甲状腺功能正常的对照组, GD患者血清中IgG4阳性比例平均为10.3%,GD伴TAO患者的血清IgG4阳性比例平均为17.6%,显著高于GD不伴TAO患者[4-9]。近年来,研究发现部分TAO患者血清IgG4升高[4-69-13],且血清IgG4与TAO的临床活动性和严重程度可能存在相关性[5]。但迄今为止,血清IgG4与TAO的确切关系尚待研究,本文将对血清IgG4与TAO的关系作一综述。

  • 1 TAO概述

  • TAO是常见的眼眶炎症性疾病,患者常出现畏光、过度流泪、眼内异物感、眼球突出、复视、斜视、眼睑肿胀、眼睑挛缩等,损伤视力和外貌[14]。TAO发病机制复杂,眼眶成纤维细胞(orbital fibroblast, OF)是TAO自身免疫攻击的靶点,自身抗原和自身抗体相互作用激活OF,导致透明质酸生成、促炎细胞因子合成以及向肌成纤维细胞或脂肪细胞的分化增强,介导眼眶扩张和炎症浸润[15]

  • 临床上一般通过眼部症状和体征、血清甲状腺激素水平异常和/或甲状腺自身免疫性抗体及影像学检查以诊断TAO[16]。根据欧洲Graves眼眶病专家组 (European Group on Graves’Orbitopathy,EUGOGO) 标准[17],将TAO分为轻度、中度至重度、威胁视力 (非常严重)3级。根据临床活动性评分(clinical activity score,CAS)评估TAO的活动性,包括:①自发性球后疼痛;②眼球运动时疼痛;③眼睑发红;④ 结膜发红;⑤泪阜肿胀;⑥眼睑肿胀;⑦结膜肿胀。 CAS≥3分为活动期,CAS<3分为非活动期。活动期TAO眼眶组织病理检查结果通常表现为大小不等、形状不规则、梭形或圆形的肥大肌纤维,炎性细胞和免疫细胞大量浸润,糖胺聚糖聚积,成纤维细胞和血管增生;非活动期患者眼眶组织以眼外肌退行性变为主,出现纤维化[18]

  • 2 血清IgG4和IgG4相关眼病

  • 免疫球蛋白(immunoglobulin,Ig)分5种:IgG、 IgE、IgM、IgA和IgD,IgG是一种特异性的生物学抗体,在正常人体中有4个亚型,按照发现顺序和血清浓度的高低分别为IgG1、IgG2、IgG3和IgG4。其中IgG4水平最低,通常小于总IgG的5%[19]。4种IgG亚型之间最显著的序列差异在于铰链区,其富含脯氨酸的氨基酸序列长度不同,包含可参与两条重链形成共价二硫键的核心铰链。IgG4是一种结构动态的抗体,其中一个显著特征是两条核心铰链间的重链二硫键不稳定[20],形成链内环化二硫化物,出现“半抗体”[21]。IgG4在体内通过“半抗体交换”,产生双特异性重组抗体,具有两种不同抗原结合位点[22-23]。在机体中,血清IgG4主要是由Th2细胞和调节性T细胞(regulatory T cell,Treg)联合诱导及多种细胞因子相互作用促进生成[2124]

  • IgG4可参与自身免疫性疾病的发展,IgG4相关疾病(immunoglobulin G4⁃ related disease,IgG4⁃RD) 是一种与IgG4相关的慢性系统性自身免疫性疾病。其组织病理学特点是淋巴浆细胞浸润密集,以IgG4阳性浆细胞为主;席纹状纤维化;闭塞性静脉炎[25-27]。IgG4 ⁃RD累及眼部时称IgG4相关眼病 (IgG4⁃ related ophthalmic disease,IgG4⁃ROD),常有眼眶组织及眼附属器官肿大,IgG4阳性浆细胞浸润,可伴血清IgG4水平升高[28]。临床上常需与TAO相鉴别,TAO患者通常有促甲状腺激素受体抗体 (thyrotropin receptor antibody,TRAb)升高,出现眼睑收缩或眼睑迟滞和具有典型的肌腱保留形态的眼外肌扩大。而既往有哮喘和进行性眼眶疾病史,外直肌过大和眶下神经增粗,眼眶磁共振(magnetic resonance imaging,MRI)示眶下神经扩大是IgG4⁃ ROD的特异性标志,血清IgG4水平>135mg/dL及组织活检示每高倍镜视野>10个IgG4阳性浆细胞和IgG4/IgG>40%支持诊断IgG4⁃ROD[29-30]

  • 3 血清IgG4与TAO

  • 近年来,学者们陆续发现部分TAO患者血清IgG4和IgG4/IgG比值增高[4-68-13]。研究表明,在接受眼眶减压术的中至重度或威胁视力(非常严重) 的TAO患者中,血清IgG4阳性比例达20%,其中威胁视力的TAO患者血清IgG4阳性比例可高达25.3%[12]。因此,作为可参与多种自身免疫性疾病的特殊血清学标志物,血清IgG4与TAO的关系值得进一步研究和关注。

  • 3.1 血清IgG4与TAO的甲状腺自身免疫性抗体

  • Ye等[12] 对185例接受眼眶减压术的TAO患者进行血清学和眼眶组织病理评估,发现所有患者的血清IgG4水平与组织学IgG4和IgG4/IgG比值呈正相关,其中64例IgG4阳性(组织病理学或血清学阳性)患者血清TRAb水平和眼眶淋巴细胞浸润显著高于阴性组,抗甲状腺球蛋白抗体(antithyroglobu⁃ lin antibody,TgAb)和甲状腺过氧化物酶抗体(thy⁃ roid peroxidase antibody,TPOAb)水平也高于阴性组,但差异并不显著。McLachlan等[31] 曾观察到GD伴TAO和不伴TAO的患者血清中甲状腺自身抗体存在差异,包括TRAb水平和TgAb的IgG亚型均有不同。TAO组TgAb的IgG亚型表现出由IgG1向IgG4的转变,TgAb中IgG4亚型的比例明显高于非TAO组。随后,Caturegli等[32] 发现甲状腺疾病患者的血清TgAb不局限于某一特定的IgG亚型,其中IgG4是GD患者TgAb的主要亚型。Martin等[7] 的研究也发现TgAb阳性的GD患者血清IgG4更高,且血清IgG4水平与TgAb呈正相关。此外,Latrofa等[33] 研究认为GD患者的TRAb亚型主要是IgG1和IgG4,长期抗原刺激可能增加TRAb滴度,致抗体亚型从IgG1转变为IgG4。Yu等[5] 发现在GD伴TAO患者中,血清IgG4水平与TRAb水平呈正相关,刺激性促甲状腺激素受体抗体(thyrotropin receptor⁃stim⁃ ulating antibody,TSAb)表现为IgG4亚型。在此之前,Takeshima等[4] 也有相似发现,他们认为GD患者血清IgG4水平与TSAb正相关,TSAb的主要亚型是IgG4。高荣等[34] 对TAO患者血清TRAb的IgG亚型分布进行研究,认为TRAb不局限于单独某一种亚型,在TAO不同时期的不同类型Th细胞及细胞因子的刺激作用下,IgG亚型发生转变,他们观察到活动期TRAb亚型以IgG1为主,非活动期则以IgG4为主。产生IgG4的抗原刺激可能来源于甲状腺[35],鉴于IgG4包含两种不同抗原结合位点,具有双特异性特点[22-23],且有研究发现血清IgG4水平与TRAb、 TgAb均呈正相关[13],基于以上研究结果推测TAO患者血清中IgG4主要来源于TRAb和TgAb[4]

  • 3.2 血清IgG4与TAO的临床活动性和严重度

  • TRAb参与TAO的发病,与严重程度和活动性相关[35],多项研究表明血清IgG4与TRAb水平呈正相关[5813],基于此推测血清IgG4水平与TAO的临床活动性和严重度可能存在相关性。但有研究发现非活动期TAO的TRAb亚型以IgG4为主,而活动期以IgG1为主[34]。鉴于目前有关TAO自身抗体IgG亚型的研究有限,且研究可能因实验方法、样本例数、患者性别、眼病病程、活动性及严重程度等不同而出现差异[34]。因此,血清IgG4与TAO的活动性及严重度之间的关系值得关注。

  • Bozkirli等[6] 发现TAO患者的血清IgG4水平显著高于非TAO组,且血清IgG4与CAS之间有显著相关性。并且除CAS为3分组外,TAO患者血清IgG4水平均与CAS平行升高。但CAS为3分组只有4例患者,且均接受了甲状腺全切术。结合Kakudo等[36] 的研究,8例IgG4甲状腺炎患者的血清IgG4在切除甲状腺后显著降低,提示刺激产生IgG4的抗原来源于甲状腺。这就解释了Bozkirli等[6] 研究中CAS为3分组中4例切除甲状腺的患者IgG4水平较低的原因,所以仍考虑血清IgG4水平与CAS之间有相关性。但该研究纳入的活动期患者样本数过少,且缺乏CAS较高的TAO,无法得出TAO患者血清IgG4水平与临床活动性呈相关性的普遍结论。随后,吴联群等[10] 观察到活动期TAO患者的血清IgG4及IgG4/IgG均明显高于非活动期组,提出CAS是血清IgG4水平的独立影响因素,但血清IgG4与活动性和严重度之间均无线性相关,但该研究纳入的非活动期患者均为眼部体征稳定半年以上拟行眼部手术,患者的眼病病程相对较长,可能对研究结果造成干扰。

  • Yu等[5] 通过对比64例GD患者和64例性别及年龄匹配的甲状腺功能正常的对照组,首次指明血清IgG4水平与GD患者TAO的发展和分级有关,中重度眼病患者血清IgG4水平和IgG4/IgG比值均高于轻度患者,活动期患者均高于非活动期患者,且血清IgG4水平和IgG4/IgG比值随CAS的增加而升高。多变量分析调整年龄、性别、吸烟、甲状腺激素水平等重要因素后发现,GD患者的血清IgG4是TAO发展的独立影响因素,且IgG4水平与严重程度和活动性相关。但此研究GD伴活动期TAO只有6例,且CAS最高只有3分,故结论仍待验证。Ye等[12] 提出IgG4阳性(组织学或血清学)是TAO患者临床活动性的独立因素,IgG4阳性的TAO患者CAS比阴性患者更高,病情更严重,最佳矫正视力也更差。但该研究只包含接受眼眶减压术患者,多为中到重度甚至视力受威胁,缺少对轻度TAO患者的研究,因此仍需扩大研究范围进一步讨论。至此,已有多项研究表明,血清IgG4与TAO的严重程度存在相关性,但与临床活动性的关系尚存在争议。可能因为有些研究纳入的TAO患者未接受过治疗,而有些研究的部分患者接受过甲状腺切除术并接受了左旋甲状腺素替代治疗,或使用抗甲状腺药物后使甲状腺功能正常化,或不同研究纳入的眼病患者病程长短不一,这些可能都会影响血清IgG4水平及TAO的活动性或严重程度,造成研究结论出现分歧。

  • 3.3 血清IgG4与TAO的发病机制

  • TAO的病理生理机制十分复杂,OF作为关键效应细胞,对多种刺激易发生强烈的炎症反应[14],自身也能产生促炎信号,从而出现炎症并加重炎症损伤15]。这种激活机制可能涉及自身抗原促甲状腺激素受体(thyroid stimulating hormone receptor, TSHR)、1型胰岛素样生长因子受体(insulin ⁃like growth factor⁃1receptor,IGF⁃1R)和GD自身抗体(GD ⁃IgG),以及免疫细胞和促炎细胞因子之间的相互作用。机体对TSHR和IGF⁃1R的耐受性丧失,抗原提呈细胞内化TSHR和IGF⁃1R,Th细胞激活,诱导B细胞产生GD⁃IgG,或成为自身反应性T细胞。GD⁃IgG与TSHR在甲状腺滤泡上皮细胞上相互作用,造成甲状腺滤泡增生和肥大;此外,T细胞趋化因子诱导自身反应性CD4+ T细胞进入眼眶组织,与OF互相激活[15],刺激OF产生透明质酸,干扰素⁃γ(interferon, IFN⁃γ)、肿瘤坏死因子⁃α(tumor necrosis factor⁃α, TNF⁃α)和GD⁃IgG等均可以增强这一过程[37]。OF表面,IGF⁃1R和TSHR形成与GD⁃IgG相互作用的复合体[15]。而IgG4可能是诱导TAO眼眶OF合成透明质酸的IgG亚型[6],且有研究发现TAO患者血清IgG4水平与眼眶组织IgG4呈正相关[12]。活动期TSHR在眼眶组织中的表达明显高于非活动期[38], TRAb增高与TAO的发展及临床活动性和严重程度显著相关[35],有学者认为随访测定血清TRAb水平有助于评估约一半TAO患者的预后[35]。且研究发现TAO患者的血清IgG4与TRAb水平相关[4⁃5,12-13], IgG4可能单独或联合TRAb在眼病的发生发展中发挥作用[5],并且IgG4可能是眼眶组织中TRAb产生增加的标志物[6]。鉴于IgG4在TAO发病机制中可能发挥的作用,研究发现血清IgG4与TAO的临床活动性和严重程度存在相关性也是合理的。

  • 细胞因子在TAO发病过程中表达异常丰富。早期活动期主要以Th1型即促炎性细胞因子如IL⁃ 2、IFN⁃γ、TNF⁃α等为主,召集大量免疫细胞,增强眼眶内的免疫反应。眼病非活动期,Th2型即抗炎性细胞因子如IL⁃10、IL⁃4、IL⁃13等介导纤维化,还可通过促进浆细胞分化产生抗体[14153739-40]。活化的Th2细胞分泌的IL⁃4和IL⁃13,与Treg产生的IL⁃10和TGF⁃β是组织损伤的驱动因素[41],而IL⁃13和TGF⁃β 可促使胶原合成及成纤维细胞增殖,介导组织纤维化[42]。IgG4可能在TAO的早期发病中起重要作用,血清IgG4高水平可能意味着TAO正处于炎症活动早期,此时及时干预可能有助于减缓患者眼外肌病变和眼眶纤维化的进程[12]。从甲状腺破坏引起自身免疫性疾病的角度看,IgG4是一种不对称的双特异性抗体,与疾病的活动性相关[412]。机体受未知炎症激发的过度反应造成IgG4升高[22],血清IgG4升高可能意味着激活了机体的耐受诱导机制[19],也许此时免疫系统正在抑制某些不合适的炎症反应[13]。血清IgG4升高的GD患者甲状腺超声常表现出广泛的低回声,可能与IgG4释放和甲状腺破坏性收缩致密集的淋巴浆细胞浸润有关[4-57]

  • 研究表明,EB病毒主要存在于宿主的B淋巴细胞中,强烈的再激活可能会影响B细胞产生抗体,刺激宿主B淋巴细胞分化,使其倾向于产生TRAb,从而影响GD进展和恶化[43-44]。有学者认为血清IgG4可能是这种机制的促成因素之一[41],通过影响TRAb的产生导致TAO发展或恶化。

  • 3.4 血清IgG4对TAO的预测价值

  • Takeshima等[4] 观察到血清IgG4水平升高的GD患者对抗甲状腺药物治疗反应更敏感,更易发生甲减。血清IgG4水平升高的GD患者与更严重的自身免疫性慢性甲状腺炎过程相关,这可能与IgG4释放致密集的淋巴浆细胞浸润和更快的纤维化演变有关[7]。研究表明血清IgG4与TAO的发展有关,血清IgG4升高有助于早期筛选有TAO危险因素的GD患者[5-6]。众所周知,TRAb参与眼病的发展,TSAb与抗炎治疗的反应有关[6],在发生纤维化之前,IgG4⁃RD对类固醇治疗反应良好[27],血清IgG4水平可能是区分TAO急性炎症阶段的经济且简单的早期指标[6]。血清高IgG4水平可能表明TAO处于炎症活动早期,及时干预可减缓其肌肉病变和眼眶纤维化进程[12]。因此血清IgG4很可能成为眼病患者对糖皮质激素治疗反应良好的预测指标。研究发现激素治疗后的TAO患者血清IgG4、IgG4/IgG比值及TRAb水平均明显降低,伴有血清IgG4升高的TAO患者对激素的治疗效果要优于IgG4正常的患者,患者眼外肌肿胀明显好转,视力和临床活动性也明显改善,表明血清IgG4升高的TAO患者可能对激素治疗更加敏感[613]。但仍需大样本的临床研究及长期的随访观察加以佐证。

  • 4 小结与展望

  • 目前已有研究表明血清IgG4在TAO中具有一定临床意义。IgG4可能参与TAO的发病过程,并且与临床活动性及严重程度相关,提示IgG4有望成为评判眼病分期的血清生物标志物。测定血清IgG4水平有助于管理TAO以及选择合适的治疗方案,高IgG4水平可能有助于在GD患者中筛选出有TAO高危因素的患者。但由于TAO发病机制的复杂性, IgG4在其中的致病作用尚未完全清楚。目前为止,关于血清IgG4与TAO的研究有限,IgG4与TAO的临床活动性及严重程度的确切关系还存在部分争议,血清IgG4是否可以作为一个生物标志物来帮助临床医生早期有效管理TAO,这点值得关注和进一步验证。因此需要大样本前瞻性研究来阐明血清IgG4水平是否能够可靠地预测TAO的发展、评估病程分期、帮助判断预后和疗效预测。鉴于眼眶MRI在TAO中的诊断和分期价值,结合MRI检查有助于明确血清IgG4水平在TAO的预测、诊断和治疗中的价值,有助于提高临床诊治的可预期性,为临床诊治TAO提供新的思路。

  • 参考文献

    • [1] HIROMATSU Y,EGUCHI H,TANI J,et al.Graves’oph⁃ thalmopathy:epidemiology and natural history[J].Intern Med,2014,53(5):353-360

    • [2] BARTALENA L,TANDA M L.Clinical practice.Graves’ ophthalmopathy[J].N Engl J Med,2009,360(10):994-1001

    • [3] BARRIO⁃BARRIO J,SABATER A L,BONET⁃FARRIOL E,et al.Graves’ophthalmopathy:visa versus EUGOGO classification,assessment,and management[J].J Oph⁃ thalmol,2015,2015:249125

    • [4] TAKESHIMA K,INABA H,FURUKAWA Y,et al.Ele⁃ vated serum immunoglobulin G4 levels in patients with Graves’disease and their clinical implications[J].Thy⁃ roid,2014,24(4):736-743

    • [5] YU S H,KANG J G,KIM C S,et al.Clinical implications of immunoglobulin G4 to Graves’ophthalmopathy[J].Thyroid,2017,27(9):1185-1193

    • [6] BOZKIRLI E,BAKINER O S,ERSOZLU BOZKIRLI E D,et al.Serum immunoglobulin G4 levels are elevated in patients with Graves’ophthalmopathy[J].Clin Endocri⁃ nol(Oxf),2015,83(6):962-967

    • [7] MARTIN C S,SIRBU A E,BETIVOIU M A,et al.Serum immunoglobulin G4 levels and Graves’disease phenotype [J].Endocrine,2017,55(2):478-484

    • [8] LUO B,YUAN X,WANG W,et al.Ocular manifestations and clinical implications of serum immunoglobulin G4 levels in Graves’ophthalmopathy patients[J].Ocul Im⁃ munol Inflamm,2022,30(3):580-587

    • [9] DENG Y,WANG J,ZOU G,et al.The characteristics and clinical significance of elevated serum IgG4/IgG levels in patients with Graves’disease[J].Endocrine,2022,75(3):829-836

    • [10] 吴联群,魏锐利,蔡季平,等.国人甲状腺相关眼病患者血清免疫球蛋白4水平的研究[J].中国实用眼科杂志,2016,34(1):36-40

    • [11] SY A,SILKISS R Z.Serum total IgG and IgG4 levels in thyroid eye disease[J].Int Med Case Rep J,2016,9:325-328

    • [12] YE H,XIAO W,CHEN R,et al.Elevated immunoglobu⁃ lin G4 levels in patients with thyroid eye disease and their clinical implications[J].Invest Ophthalmol Vis Sci,2020,61(5):57

    • [13] 李亚玲.血清IgG4水平与Graves眼病的临床及实验室特征相关性研究[D].武汉:华中科技大学,2019

    • [14] BAHN R S.Graves’ophthalmopathy[J].N Engl J Med,2010,362(8):726-738

    • [15] SHAN S J,DOUGLAS R S.The pathophysiology of thy⁃ roid eye disease[J].J Neuroophthalmol,2014,34(2):177-185

    • [16] DOLMAN P J.Evaluating Graves’orbitopathy[J].Best Pract Res Clin Endocrinol Metab,2012,26(3):229-248

    • [17] BARTALENA L,KAHALY G J,BALDESCHI L,et al.The 2021 European Group on Graves ’ orbitopathy(EUGOGO)clinical practice guidelines for the medical management of Graves’orbitopathy[J].Eur J Endocri⁃ nol,2021,185(4):G43-G67

    • [18] 刘春玲,罗清礼,吕红彬.甲状腺相关眼病眼眶组织病理学研究[J].四川大学学报(医学版),2005,36(3):436-437

    • [19] AALBERSE R C,STAPEL S O,SCHUURMAN J,et al.Immunoglobulin G4:an odd antibody[J].Clin Exp Aller⁃ gy,2009,39(4):469-477

    • [20] PETERSEN J G,DORRINGTON K J.An in vitro system for studying the kinetics of interchain disulfide bond for⁃ mation in immunoglobulin G[J].J Biol Chem,1974,249(17):5633-5641

    • [21] NIRULA A,GLASER S M,KALLED S L,et al.What is IgG4?A review of the biology of a unique immunoglobu⁃ lin subtype[J].Curr Opin Rheumatol,2011,23(1):119-124

    • [22] STONE J H,ZEN Y,DESHPANDE V.IgG4⁃ related dis⁃ ease[J].N Engl J Med,2012,366(6):539-551

    • [23] RISPENS T,OOIJEVAAR⁃DE HEER P,BENDE O,et al.Mechanism of immunoglobulin G4 Fab⁃arm exchange[J].J Am Chem Soc,2011,133(26):10302-10311

    • [24] KOIKE T.IgG4⁃related disease:why high IgG4 and fibro⁃ sis?[J].Arthritis Res Ther,2013,15(1):103

    • [25] DESHPANDE V,ZEN Y,CHAN J K,et al.Consensus statement on the pathology of IgG4 ⁃ related disease[J].Mod Pathol,2012,25(9):1181-1192

    • [26] UMEHARA H,OKAZAKI K,MASAKI Y,et al.A novel clinical entity,IgG4 ⁃ related disease(IgG4RD):general concept and details[J].Mod Rheumatol,2012,22(1):1-14

    • [27] UMEHARA H,OKAZAKI K,MASAKI Y,et al.Compre⁃ hensive diagnostic criteria for IgG4⁃related disease(IgG4⁃ RD),2011[J].Mod Rheumatol,2012,22(1):21-30

    • [28] GOTO H,TAKAHIRA M,AZUMI A,et al.Diagnostic cri⁃ teria for IgG4⁃related ophthalmic disease[J].Jpn J Oph⁃ thalmol,2015,59(1):1-7

    • [29] TOOLEY A A,SALOMAO D R,BRADLEY E A,et al.Distinguishing IgG4 ⁃ related ophthalmic disease from Graves orbitopathy[J].Ophthalmic Plast Reconstr Surg,2019,35(2):170-176

    • [30] SOUSSAN J B,DESCHAMPS R,SADIK J C,et al.Infra⁃ orbital nerve involvement on magnetic resonance imaging in European patients with IgG4 ⁃ related ophthalmic dis⁃ ease:a specific sign[J].Eur Radiol,2017,27(4):1335-1343

    • [31] MCLACHLAN S M,BAHN R,RAPOPORT B.Endocrine ophthalmopathy:a re ⁃ evaluation of the association with thyroid autoantibodies[J].Autoimmunity,1992,14(2):143-148

    • [32] CATUREGLI P,KUPPERS R C,MARIOTTI S,et al.IgG subclass distribution of thyroglobulin antibodies in pa⁃ tients with thyroid disease[J].Clin Exp Immunol,1994,98(3):464-469

    • [33] LATROFA F,CHAZENBALK G D,PICHURIN P,et al.Affinity⁃enrichment of thyrotropin receptor autoantibodies from Graves’patients and normal individuals provides in⁃ sight into their properties and possible origin from natural antibodies[J].J Clin Endocrinol Metab,2004,89(9):4734-4745

    • [34] 高荣,王庆祝,吴丽娜,等.血清TRAb IgG 亚型在甲状腺相关性眼病患者中的特征及临床意义[J].中华内分泌代谢杂志,2020,36(4):315-320

    • [35] ECKSTEIN A K,PLICHT M,LAX H,et al.Thyrotropin receptor autoantibodies are independent risk factors for Graves’ophthalmopathy and help to predict severity and outcome of the disease[J].J Clin Endocrinol Metab,2006,91(9):3464-3470

    • [36] KAKUDO K,LI Y,TANIGUCHI E,et al.IgG4 ⁃ related disease of the thyroid glands[J].Endocr J,2012,59(4):273-281

    • [37] WIERSINGA W M,PRUMMEL M F.Pathogenesis of Graves’ophthalmopathy ⁃ current understanding[J].J Clin Endocrinol Metab,2001,86(2):501-503

    • [38] WAKELKAMP I M,BAKKER O,BALDESCHI L,et al.TSH⁃R expression and cytokine profile in orbital tissue of active vs.inactive Graves’ophthalmopathy patients[J].Clin Endocrinol(Oxf),2003,58(3):280-287

    • [39] HIROMATSU Y,KAKU H,MIYAKE I,et al.Role of cyto⁃ kines in the pathogenesis of thyroid ⁃ associated ophthal⁃ mopathy[J].Thyroid,2002,12(3):217-221

    • [40] BERGER A.Th1 and Th2 responses:what are they?[J].BMJ,2000,321(7258):424

    • [41] OLEJARZ M,SZCZEPANEK⁃PARULSKA E,DADEJ D,et al.IgG4 as a biomarker in Graves’orbitopathy[J].Me⁃ diators Inflamm,2021,2021:5590471

    • [42] LEE C G,HOMER R J,ZHU Z,et al.Interleukin⁃13 in⁃ duces tissue fibrosis by selectively stimulating and acti⁃ vating transforming growth factor beta(1)[J].J Exp Med,2001,194(6):809-821

    • [43] NAGATA K,NAKAYAMA Y,HIGAKI K,et al.Reactiva⁃ tion of persistent Epstein ⁃Barr virus(EBV)causes secre⁃ tion of thyrotropin receptor antibodies(TRAbs)in EBV ⁃ infected B lymphocytes with TRAbs on their surface[J].Autoimmunity,2015,48(5):328-335

    • [44] NAGATA K,FUKATA S,KANAI K,et al.The influence of Epstein⁃Barr virus reactivation in patients with Graves’ disease[J].Viral Immunol,2011,24(2):143-149

  • 参考文献

    • [1] HIROMATSU Y,EGUCHI H,TANI J,et al.Graves’oph⁃ thalmopathy:epidemiology and natural history[J].Intern Med,2014,53(5):353-360

    • [2] BARTALENA L,TANDA M L.Clinical practice.Graves’ ophthalmopathy[J].N Engl J Med,2009,360(10):994-1001

    • [3] BARRIO⁃BARRIO J,SABATER A L,BONET⁃FARRIOL E,et al.Graves’ophthalmopathy:visa versus EUGOGO classification,assessment,and management[J].J Oph⁃ thalmol,2015,2015:249125

    • [4] TAKESHIMA K,INABA H,FURUKAWA Y,et al.Ele⁃ vated serum immunoglobulin G4 levels in patients with Graves’disease and their clinical implications[J].Thy⁃ roid,2014,24(4):736-743

    • [5] YU S H,KANG J G,KIM C S,et al.Clinical implications of immunoglobulin G4 to Graves’ophthalmopathy[J].Thyroid,2017,27(9):1185-1193

    • [6] BOZKIRLI E,BAKINER O S,ERSOZLU BOZKIRLI E D,et al.Serum immunoglobulin G4 levels are elevated in patients with Graves’ophthalmopathy[J].Clin Endocri⁃ nol(Oxf),2015,83(6):962-967

    • [7] MARTIN C S,SIRBU A E,BETIVOIU M A,et al.Serum immunoglobulin G4 levels and Graves’disease phenotype [J].Endocrine,2017,55(2):478-484

    • [8] LUO B,YUAN X,WANG W,et al.Ocular manifestations and clinical implications of serum immunoglobulin G4 levels in Graves’ophthalmopathy patients[J].Ocul Im⁃ munol Inflamm,2022,30(3):580-587

    • [9] DENG Y,WANG J,ZOU G,et al.The characteristics and clinical significance of elevated serum IgG4/IgG levels in patients with Graves’disease[J].Endocrine,2022,75(3):829-836

    • [10] 吴联群,魏锐利,蔡季平,等.国人甲状腺相关眼病患者血清免疫球蛋白4水平的研究[J].中国实用眼科杂志,2016,34(1):36-40

    • [11] SY A,SILKISS R Z.Serum total IgG and IgG4 levels in thyroid eye disease[J].Int Med Case Rep J,2016,9:325-328

    • [12] YE H,XIAO W,CHEN R,et al.Elevated immunoglobu⁃ lin G4 levels in patients with thyroid eye disease and their clinical implications[J].Invest Ophthalmol Vis Sci,2020,61(5):57

    • [13] 李亚玲.血清IgG4水平与Graves眼病的临床及实验室特征相关性研究[D].武汉:华中科技大学,2019

    • [14] BAHN R S.Graves’ophthalmopathy[J].N Engl J Med,2010,362(8):726-738

    • [15] SHAN S J,DOUGLAS R S.The pathophysiology of thy⁃ roid eye disease[J].J Neuroophthalmol,2014,34(2):177-185

    • [16] DOLMAN P J.Evaluating Graves’orbitopathy[J].Best Pract Res Clin Endocrinol Metab,2012,26(3):229-248

    • [17] BARTALENA L,KAHALY G J,BALDESCHI L,et al.The 2021 European Group on Graves ’ orbitopathy(EUGOGO)clinical practice guidelines for the medical management of Graves’orbitopathy[J].Eur J Endocri⁃ nol,2021,185(4):G43-G67

    • [18] 刘春玲,罗清礼,吕红彬.甲状腺相关眼病眼眶组织病理学研究[J].四川大学学报(医学版),2005,36(3):436-437

    • [19] AALBERSE R C,STAPEL S O,SCHUURMAN J,et al.Immunoglobulin G4:an odd antibody[J].Clin Exp Aller⁃ gy,2009,39(4):469-477

    • [20] PETERSEN J G,DORRINGTON K J.An in vitro system for studying the kinetics of interchain disulfide bond for⁃ mation in immunoglobulin G[J].J Biol Chem,1974,249(17):5633-5641

    • [21] NIRULA A,GLASER S M,KALLED S L,et al.What is IgG4?A review of the biology of a unique immunoglobu⁃ lin subtype[J].Curr Opin Rheumatol,2011,23(1):119-124

    • [22] STONE J H,ZEN Y,DESHPANDE V.IgG4⁃ related dis⁃ ease[J].N Engl J Med,2012,366(6):539-551

    • [23] RISPENS T,OOIJEVAAR⁃DE HEER P,BENDE O,et al.Mechanism of immunoglobulin G4 Fab⁃arm exchange[J].J Am Chem Soc,2011,133(26):10302-10311

    • [24] KOIKE T.IgG4⁃related disease:why high IgG4 and fibro⁃ sis?[J].Arthritis Res Ther,2013,15(1):103

    • [25] DESHPANDE V,ZEN Y,CHAN J K,et al.Consensus statement on the pathology of IgG4 ⁃ related disease[J].Mod Pathol,2012,25(9):1181-1192

    • [26] UMEHARA H,OKAZAKI K,MASAKI Y,et al.A novel clinical entity,IgG4 ⁃ related disease(IgG4RD):general concept and details[J].Mod Rheumatol,2012,22(1):1-14

    • [27] UMEHARA H,OKAZAKI K,MASAKI Y,et al.Compre⁃ hensive diagnostic criteria for IgG4⁃related disease(IgG4⁃ RD),2011[J].Mod Rheumatol,2012,22(1):21-30

    • [28] GOTO H,TAKAHIRA M,AZUMI A,et al.Diagnostic cri⁃ teria for IgG4⁃related ophthalmic disease[J].Jpn J Oph⁃ thalmol,2015,59(1):1-7

    • [29] TOOLEY A A,SALOMAO D R,BRADLEY E A,et al.Distinguishing IgG4 ⁃ related ophthalmic disease from Graves orbitopathy[J].Ophthalmic Plast Reconstr Surg,2019,35(2):170-176

    • [30] SOUSSAN J B,DESCHAMPS R,SADIK J C,et al.Infra⁃ orbital nerve involvement on magnetic resonance imaging in European patients with IgG4 ⁃ related ophthalmic dis⁃ ease:a specific sign[J].Eur Radiol,2017,27(4):1335-1343

    • [31] MCLACHLAN S M,BAHN R,RAPOPORT B.Endocrine ophthalmopathy:a re ⁃ evaluation of the association with thyroid autoantibodies[J].Autoimmunity,1992,14(2):143-148

    • [32] CATUREGLI P,KUPPERS R C,MARIOTTI S,et al.IgG subclass distribution of thyroglobulin antibodies in pa⁃ tients with thyroid disease[J].Clin Exp Immunol,1994,98(3):464-469

    • [33] LATROFA F,CHAZENBALK G D,PICHURIN P,et al.Affinity⁃enrichment of thyrotropin receptor autoantibodies from Graves’patients and normal individuals provides in⁃ sight into their properties and possible origin from natural antibodies[J].J Clin Endocrinol Metab,2004,89(9):4734-4745

    • [34] 高荣,王庆祝,吴丽娜,等.血清TRAb IgG 亚型在甲状腺相关性眼病患者中的特征及临床意义[J].中华内分泌代谢杂志,2020,36(4):315-320

    • [35] ECKSTEIN A K,PLICHT M,LAX H,et al.Thyrotropin receptor autoantibodies are independent risk factors for Graves’ophthalmopathy and help to predict severity and outcome of the disease[J].J Clin Endocrinol Metab,2006,91(9):3464-3470

    • [36] KAKUDO K,LI Y,TANIGUCHI E,et al.IgG4 ⁃ related disease of the thyroid glands[J].Endocr J,2012,59(4):273-281

    • [37] WIERSINGA W M,PRUMMEL M F.Pathogenesis of Graves’ophthalmopathy ⁃ current understanding[J].J Clin Endocrinol Metab,2001,86(2):501-503

    • [38] WAKELKAMP I M,BAKKER O,BALDESCHI L,et al.TSH⁃R expression and cytokine profile in orbital tissue of active vs.inactive Graves’ophthalmopathy patients[J].Clin Endocrinol(Oxf),2003,58(3):280-287

    • [39] HIROMATSU Y,KAKU H,MIYAKE I,et al.Role of cyto⁃ kines in the pathogenesis of thyroid ⁃ associated ophthal⁃ mopathy[J].Thyroid,2002,12(3):217-221

    • [40] BERGER A.Th1 and Th2 responses:what are they?[J].BMJ,2000,321(7258):424

    • [41] OLEJARZ M,SZCZEPANEK⁃PARULSKA E,DADEJ D,et al.IgG4 as a biomarker in Graves’orbitopathy[J].Me⁃ diators Inflamm,2021,2021:5590471

    • [42] LEE C G,HOMER R J,ZHU Z,et al.Interleukin⁃13 in⁃ duces tissue fibrosis by selectively stimulating and acti⁃ vating transforming growth factor beta(1)[J].J Exp Med,2001,194(6):809-821

    • [43] NAGATA K,NAKAYAMA Y,HIGAKI K,et al.Reactiva⁃ tion of persistent Epstein ⁃Barr virus(EBV)causes secre⁃ tion of thyrotropin receptor antibodies(TRAbs)in EBV ⁃ infected B lymphocytes with TRAbs on their surface[J].Autoimmunity,2015,48(5):328-335

    • [44] NAGATA K,FUKATA S,KANAI K,et al.The influence of Epstein⁃Barr virus reactivation in patients with Graves’ disease[J].Viral Immunol,2011,24(2):143-149

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