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   复旦学报(医学版)  2019, Vol. 46 Issue (1): 114-118, 142      DOI: 10.3969/j.issn.1672-8467.2019.01.020
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纪宗斐, 马玲瑛, 姜林娣. IgG4相关性疾病(IgG4-RD)发病机制的研究进展[J]. 复旦学报医学版, 2019, 46(1): 114-118, 142.
JI Zong-fei, MA Ling-ying, JIANG Lin-di. Research progress on the pathogenesis of IgG4-related disease (IgG4-RD)[J]. Fudan University Journal of Medical Sciences, 2019, 46(1): 114-118, 142.
IgG4相关性疾病(IgG4-RD)发病机制的研究进展
纪宗斐1,2  (综述), 马玲瑛1,2 , 姜林娣1,2  (审校)     
1. 复旦大学附属中山医院风湿免疫科 上海 200032;
2. 复旦大学风湿免疫过敏中心 上海 200032
收稿日期：2017-08-21
基金项目：复旦大学附属中山医院青年基金(2014ZSQN13)
摘要：IgG4相关性疾病(IgG4-related disease, IgG4-RD)是以多发脏器肿大、血清IgG4升高为特点的一类自身免疫性疾病, 发病机制仍不明确。病原体感染导致抗原呈递细胞表面模式识别受体激活, 通过抗原呈递促进CD4+T细胞激活, 分化为Th1、Th2、Treg和Tfh细胞, 产生一系列T细胞因子, 进一步促进B细胞活化并转化为浆细胞, 产生IgG4。而巨噬细胞和Treg细胞产生的转化生长因子β (transforming growth factor β, TGF-β)和血小板源性生长因子等进一步促进了纤维化的发生。以上细胞因子和免疫细胞参与IgG4-RD发病, 为今后的治疗策略提供了新的思路。
关键词：IgG4相关性疾病(IgG4-RD)    发病机制    浆细胞    
Research progress on the pathogenesis of IgG4-related disease (IgG4-RD)
JI Zong-fei1,2 , MA Ling-ying1,2 , JIANG Lin-di1,2     
1. Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China;
2. Institute of Rheumatology, Immunology and Allergy, Fudan University, Shanghai 200032, China
Foundation item: This work was supported by the Youth Fund of Zhongshan Hospital, Fudan University (2014ZSQN13)
Corresponding author: JIANG Lin-di, E-mail: zsh-rheum@hotmail.com.
Abstract: IgG4-related disease (IgG4-RD) is a kind of autoimmune disease which is characterized by multi-organomegaly and elevated serum IgG4.Till now, the pathogenesis of IgG4-RD is unknown.The pattern recognition receptor of antigen-presenting cell is activated by pathogen infection, then CD4+ T cell is activated by antigen presentation and transform into Th1, Th2, Treg and Tfh cell.The cytokines secreted by Th1, Th2, Treg and Tfh cell will promote the activation of B cells and transformation to plasma cells and production of IgG4.Futhermore, transforming growth factor β (TGF-β) and platelet-derived growth factor secreted by macrophage and Treg will promote the fibrosis.The above cytokines and immune cells play important roles in the pathogenesis of IgG4-RD, which provide new strategy for treatment in the future.
Key words: IgG4-related disease (IgG4-RD)    pathogenesis    plasma cell    

IgG4相关性疾病(IgG4-related disease, IgG4-RD)是以多发脏器肿大、血清IgG4升高为特点的一类自身免疫性疾病。IgG4-RD的组织病理特点为IgG4+浆细胞浸润、席纹状纤维化和闭塞性脉管炎, 可累及腺体、眼眶、鼻窦、腹膜后、胰腺、胆管、肺、肾、淋巴结, 甚至血管、脑垂体等。早在1995年Yoshida等[1]就提出了自身免疫性胰腺炎(autoimmune pancreatitis, AIP)的概念, 随后陆续报道了全身其他脏器发生的类似组织病理学表现, 并有部分患者以泪腺和涎腺炎为表现而被认为是米库利兹病, 实则为IgG4相关的自身免疫性疾病。Kamisawa等[2]于2003年首次引入IgG4系统性疾病概念, 并于2010年更名为IgG4-RD[3]。目前IgG4-RD的发病机制仍不明确, 相关研究涉及固有免疫和适应性免疫, 本文即从这两个方面进行阐述。

固有免疫

模式识别受体  感染可能启动了IgG4-RD发病, 文献报道IgG4-RD的患者同时合并感染幽门螺杆菌[4-5]、分枝杆菌[6]和革兰氏阴性菌[7]。Toll样受体(Toll-like receptor, TLR)和NOD样受体(nucleotide-binding oligomerization domain-like receptor, NLR)是介导病原微生物免疫识别的重要受体, 广泛分布于免疫细胞表面。微生物抗原激活单核细胞表面的TLR和NLR后可通过B细胞激活因子(B cell activating factor, BAFF)信号通路促进IgG4的产生[8]。在IgG4相关的AIP患者中, TLR7在单核细胞表面的表达显著高于其他胰腺疾病患者, 而TLR8和TLR9的表达无明显差异, 提示TLR7是参与AIP发病的关键模式识别受体[9]。

在TLR介导的免疫反应中, 嗜碱性粒细胞起到了重要作用。嗜碱性粒细胞被认为是一种Th2效应细胞或者抗原呈递细胞(antigen-presenting cell, APC), 可启动Th2相关的免疫反应[10-11], 经过微生物抗原激活产生BAFF及Th2细胞因子, 从而促进免疫球蛋白产生[12-13]。体外研究证实, IgG4-RD患者的嗜碱性粒细胞表面TLR经配体激活后, 细胞液中BAFF和IgG4水平远远高于健康对照。因患者的嗜碱性粒细胞表面TLR活化后可产生BAFF和IL-13, BAFF通路的激活进一步促进了B细胞在非T细胞依赖途径下产生IgG4。同时, TLR2还能促进IL-10分泌, 从而激活Th2介导的免疫反应[14]。

NLR在细胞内细菌的识别中起到重要作用, 其中NOD2是NLRs家族成员之一。单核细胞表面NOD2激活后促进B细胞在非T细胞依赖途径下产生IgG4, 后者的产生同样依赖于BAFF通路, 而BAFF则是由NF-κb通路所激活的[15]。

补体  研究发现, 超过半数的IgG4-RD患者存在补体C3和C4下降, 提示补体系统激活可能参与了疾病的发生。然而, 目前补体系统在IgG4-RD疾病发生中的作用尚存在争议。有学者认为IgG4不能和C1q结合并形成免疫复合物并激活补体系统, 而IgG1却能通过经典途径导致补体激活[16]。然而, Sugimoto等[17]证实IgG4通过和C1q结合参与了IgG4-RD患者体内免疫复合物的形成, 在低补体血症的状态下, 可能通过多种途径促进了IgG4-RD患者补体系统的激活。有研究指出IgG4是通过抗铰链区抗体(anti-hinge antibodies, AHA)和AHA结合的。因慢性炎症状态可促进弹性蛋白酶和组织蛋白酶G的激活, 将IgG分解为Fab或F(ab’)2片段, AHA能和IgG4 F(ab’)2片段特异性结合形成免疫复合物, 从而导致补体系统激活[18]。

肥大细胞  嗜碱性细胞在结缔组织和黏膜上皮内时称为肥大细胞。肥大细胞能分泌多种细胞因子, 参与免疫调节, 同时可表达大量IgE Fc受体, 释放过敏介质。Takeuchi等[19]发现, IgG4-RD患者唾液腺组织中肥大细胞表达明显增多, 由肥大细胞产生细胞因子Th2和Treg而参与发病。IgG4-RD患者常合并过敏性疾病, 亦提示肥大细胞可能参与发病。病例报道显示该病可在使用抗组胺药物后缓解, 抗组胺药物可抑制肥大细胞释放介质及产生IL-10等细胞因子[20], 可能通过抑制肥大细胞的功能而改善疾病。

适应性免疫

T细胞及其细胞因子  外周血CD4+Th细胞分类显示, IgG4-RD患者存在Th1/Th2不平衡和Th2细胞比例增加[21], 且Th2细胞介导的免疫反应参与IgG4的大量产生[22]。同时, IgG4-RD组织中的Th2细胞及Th2细胞因子包括IL-4、IL-5、IL-13表达明显增多[23-24], 其中IL-4、IL-13可促进B细胞转化为浆细胞并产生IgE和IgG4[25]。唾液腺组织免疫组化结果提示IgG4-RD患者IL-33表达明显增加。IL-33可促进Th2细胞表面ST-2(IL-33受体)激活, 诱导Th2细胞产生IL-4、IL-5和IL-13。研究证实, IL-33在IgG4-RD中主要由M2巨噬细胞分泌, 从而促进了后续Th2细胞介导的免疫反应[26]。合并过敏性疾病是导致IgG4-RD患者Th2细胞比例明显增加的原因[27]。与此结论相反, 有研究发现IgG4-RD中以Th1细胞表达增加为主, 同时伴有IFN-g水平升高[28-29]。

Treg细胞可通过与效应细胞相互作用或分泌IL-10和TGF-β来调节免疫耐受和免疫稳态。其中, IL-10能够协同IL-4促进B细胞产生IgG4, 并促进Ig的类别转换, 使IgE减少的同时IgG4增多。TGF-β具有促进纤维化的作用, 从而导致IgG4-RD组织中的纤维化改变。后续研究也证实Treg细胞、IL-10和TGF-β在IgG4-RD胰腺和胆管组织中表达增多[30-31], 可能参与了疾病的发生。

滤泡性辅助性T (Follicular helper T, Tfh)细胞是一种新型的Th细胞, 参与Ig类别转换和生发中心形成。Tfh细胞促进效应Th细胞的激活, 在IL-21作用下能协同Tfh细胞促进异位生发中心形成。Tfh细胞包括Tfh1、Tfh2和Tfh17细胞[32]。Tfh2和Tfh17能够促进Ig的类别转换。Tfh2细胞在IgG4-RD患者外周血中比例明显增加, 且与浆母细胞、IgG4、IL-4水平及疾病活动度存在相关性[33], 同时Tfh1细胞比例也增加, 与疾病活动度相关, 但与IgG4水平无相关性。体外实验显示, Tfh2细胞能促进B细胞转化为浆母细胞[34]。提示Tfh细胞可能是导致IgG4-RD疾病发生的一类T细胞。

有文献报道细胞毒CD4+T细胞在IgG4-RD患者外周血中比例明显升高, 在病变组织中大量浸润, 且组织中的数量与IgG4水平和累及的脏器数量成正比[35]。

除IL-4、IL-5、IL-10、IL-13和TGF-b之外, IL-21也参与IgG4-RD疾病的发生。IL-21是一种由CD4+T细胞和NK细胞分泌的细胞因子, 促进B细胞活化、增殖和Ig类别转换重组(class switch recombination, CSR), 诱导B细胞产生自身抗体及免疫球蛋白。IL-21在CD40L、BAFF和IL-4的协同作用下促进B细胞分化为浆细胞。IL-21在B细胞受体存在或T、B细胞交互作用时可促进B细胞的激活和分化, 缺乏以上刺激因素时IL-21反而能诱导B细胞凋亡, 因此IL-21在临床试验中还用于治疗B细胞淋巴瘤。在IgG4-RD患者的泪腺及唾液腺中, IL-21在mRNA和蛋白水平均表达增加, 且表达水平与病理组织中IgG4浆细胞比例和生发中心数量成正比[36], IL-21能促进Tfh细胞激活和异位生发中心形成, 故IL-21在IgG4-RD的发病中可能起到重要作用。

BAFF是TNF配体超家族的一员, 骨髓中的单核、巨噬细胞和外周血中的T细胞、活化B细胞和肥大细胞等均可产生BAFF。IL-10、TGF-β可促进BAFF的产生, 脂多糖(lipopolysaccharides, LPS)也可促进BAFF的产生。BAFF能调节B细胞存活、B细胞成熟, 促进B细胞转化为浆细胞, 并在IL-4的作用下诱导IgG4的类别转换。BAFF的同源物APRIL(A proliferation-inducing ligand), 对外周B细胞的稳态的维持也起重要的作用。和BAFF类似, APRIL在IL-4存在的情况下, 能促进浆细胞转换为产IgG4和IgE的浆细胞。在IgG4-RD患者血清中BAFF和APRIL水平较健康对照均明显升高[37]。因此, BAFF和APRIL可能促进了IgG4-RD患者体内IgG4的产生。

浆母细胞  浆母细胞是未成熟的浆细胞前体, 是介于激活的B细胞和浆细胞的中间状态。健康人外周血的浆母细胞是极少的。然而, IgG4-RD患者体内的B细胞大量地活化并转化为浆细胞。因此, 活动和复发的IgG4-RD患者血液中均发现CD19lowCD38+CD20-CD27+循环浆母细胞数量明显升高。浆母细胞的增多还与患者累及脏器数量有关。在利妥昔单抗治疗后, 浆母细胞数量明显减少。研究显示, 即使活动期IgG4-RD患者血清IgG4水平正常, 浆母细胞仍增多。以上均提示浆母细胞数量可作为疾病活动的预测标志, 可用于疾病的诊断、监测和随访, 该标志物甚至优于IgG4[38]。CD19+CD24-CD38hi浆母细胞和浆细胞在疾病活动期明显增加, 经糖皮质激素治疗后减少[39]。除了和IgG4-RD存在相关性以外, 浆母细胞的数量在RA、SLE和溃疡性结肠炎中均发现有异常升高。

抗原递呈细胞  APC在免疫应答中起重要作用。病原体激活APC表面的TLR和NLR, APC进行抗原递呈, 激活CD4+T细胞, 促进其分化, 并产生一系列T细胞因子, APC还能通过产生BAFF和APRIL来促进Ig类别转换[40]。树突细胞和单核-巨噬细胞是最常见的APC。M2巨噬细胞分泌IL-33, 能促进Th2细胞因子的分泌。巨噬细胞还能产生TGF-β1和血小板源性生长因子, 直接激活成纤维细胞, 导致纤维化的发生。

浆细胞样树突状细胞(plasmacytoid dendritic cell, pDC), 又称淋巴样树突细胞, 也被证实和IgG4-RD的发病相关。IgG4相关AIP小鼠模型和患者的胰腺组织中均发现存在较多产IFN-α的pDC和中性粒细胞胞外陷阱(neutrophil extracellular trap, NET)。通过外周血pDC细胞培养提示, 在NETs的作用下, 患者的pDC细胞较对照组产生更多IFN-α和BAFF并能促进B细胞产生IgG4而非IgG1。因此推测pDC在IgG4相关AIP的发病中起到一定的作用[41]。NET是一种网状结构, 由染色体和颗粒蛋白组成, 在炎症部位大量产生, 捕获并杀死各种病原体, 并能促进pDC的活化[42]。乳铁蛋白(lactoferrin, LF)是存在于NET结构中的一种蛋白, 其抗体能促进pDC产生IFN-α, 而在AIP患者也发现血清中LF抗体显著升高[22], 再次提示了NET参与疾病的发生。

免疫球蛋白G4(IgG4)  IgG4是IgG的4个亚型之一, 正常人血液中IgG4仅占IgG的1%~7%, 多数IgG4-RD患者的血清IgG4水平明显升高。据文献报道, AIP患者IgG4水平是对照组的10倍, 90%AIP患者的IgG4水平明显升高, 而其他疾病如慢性硬化性胆管炎、胰腺癌、干燥综合征和非IgG4相关的慢性胰腺炎极少升高。因此推测IgG4在IgG4-RD的发病中起重要作用。IgG4能够封闭抗体、减轻过敏反应, 还参与一些疾病(如寻常性天疱疮、血小板减少性紫癜等)的发病。IgG4通过结合循环过敏物质, 抑制IgE与其结合, 从而减少肥大细胞的激活, 同时还能抑制Th2细胞相关的免疫反应。除了以上作用, Fab臂交换[43-44]和类风湿因子样作用[42]可能也是其致病的关键。IgG4和H链有一个不稳定的二硫化物连接, 可导致半个分子脱落后与其他IgG4分子的一半进行重组, 妨碍了IgG4与抗原的交联反应, 抑制了免疫复合物沉积和中性粒细胞产生IL-8, 最终抑制固有免疫反应。研究发现, AIP患者血清中提取的IgG4能通过Fc-Fc相互作用和IgG的Fc段结合, 提示具有类风湿因子样作用, 称为新型RF(novel RF, NRF), 能作为一种自身抗体和体内抗原进行反应, 导致疾病的发生[45]。

结语  病原体感染导致APC表面TLR和NLR的激活可能是导致IgG4-RD发生的启动因素。APC表面的模式识别受体激活后, 分泌BAFF、APRIL等细胞因子促进B细胞活化和IgG4产生, 同时进行抗原呈递, 促进CD4+T细胞激活, 分化为Th1、Th2、Treg和Tfh细胞, 产生IL-4、IL-10、IL-13和IL-21等细胞因子, 能促进B细胞活化、转化为浆细胞, 进一步产生IgG4并能促进Ig类别转换。在B细胞转化过程中产生了大量浆母细胞。其中, IgG4大量产生抑制了固有免疫反应并激活了补体系统, 并可能作为一种自身抗体和体内抗原进行反应。IL-21促进了Tfh细胞产生和异位生发中心的形成。最终导致组织器官内IgG4+的浆细胞浸润。而巨噬细胞和Treg细胞产生的TGF-β、血小板源性生长因子等进一步促进了纤维化的发生。目前临床上发现的IgG4-RD表现不一。在血清学改变上, 43%的患者血清IgG4水平仍处于正常水平[46]。同时, 还有些患者对糖皮质激素和CD20单抗治疗均不敏感。因此, 需要进一步研究IgG4-RD的发病机制, 以期使临床诊治获益。

参考文献
[1]
YOSHIDA K, TOKI F, TAKEUCHI T, et al. Chronic pancreatitis caused by an autoimmune abnormality.Proposal of the concept of autoimmune pancreatitis[J]. Dig Dis Sci, 1995, 40(7): 1561-1568. [DOI]
[2]
KAMISAWA T, FUNATA N, HAYASHI Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease[J]. J Gastroenterol, 2003, 38(10): 982-984. [DOI]
[3]
TAKAHASHI H, YAMAMOTO M, SUZUKI C, et al. The birthday of a new syndrome:IgG4-related diseases constitute a clinical entity[J]. Autoimmun Rev, 2010, 9(9): 591-594. [DOI]
[4]
GUARNERI F, GUARNERI C, BENVENGA S. Helicobacter pylori and autoimmune pancreatitis:role of carbonic anhydrase via molecular mimicry?[J]. J Cell Mol Med, 2005, 9(3): 741-744. [DOI]
[5]
FRULLONI L, LUNARDI C, SIMONE R, et al. Identification of a novel antibody associated with autoimmune pancreatitis[J]. N Engl J Med, 2009, 361(22): 2135-2142. [DOI]
[6]
SIDDIQUEE Z, ZANE NA, SMITH RN, et al. Dense IgG4 plasma cell infiltrates associated with chronic infectious aortitis:implications for the diagnosis of IgG4-related disease[J]. Cardiovasc Pathol, 2012, 21(6): 470-475. [DOI]
[7]
KAWANO M, YAMADA K, KAKUCHI Y, et al. A case of immunoglobulin G4-related chronic sclerosing sialadenitis and dacryoadenitis associated with tuberculosis[J]. Mod Rheumatol, 2009, 19(1): 87-90. [DOI]
[8]
WATANABE T, YAMASHITA K, FUJIKAWA S, et al. Activation of Toll-like receptors and NOD-like receptors is involved in enhanced IgG4 responses in autoimmune pancreatitis[J]. Arthritis Rheum, 2012, 64: 914-924. [DOI]
[9]
FUKUI Y, UCHIDA K, SAKAGUCHI Y, et al. Possible involvement of Toll-like receptor 7 in the development of type 1 autoimmune pancreatitis[J]. J Gastroenterol, 2015, 50(4): 435-444. [DOI]
[10]
SOKOL CL, MEDZHITOV R. Role of basophils in the initiation of Th2 responses[J]. Curr Opin Immunol, 2010, 22(1): 73-77. [DOI]
[11]
PAUL WE, ZHU J. How are T(H)2-type immune responses initiated and amplified?[J]. Nat Rev Immunol, 2010, 10(4): 225-235. [DOI]
[12]
CHEN K, XU W, WILSON M, et al. Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils[J]. Nat Immunol, 2009, 10(8): 889-898. [DOI]
[13]
PHILLIPS C, COWARD WR, PRITCHARD DI, et al. Basophils express a type 2 cytokine profile on exposure to proteases from helminths and house dust mites[J]. J Leukoc Biol, 2003, 73(1): 165-171. [DOI]
[14]
WATANABE T, YAMASHITA K, SAKURAI T, et al. Toll-like receptor activation in basophils contributes to the development of IgG4-related disease[J]. J Gastroenterol, 2013, 48(2): 247-253. [DOI]
[15]
FRITZ JH, GIRARDIN SE. How Toll-like receptors and Nod-like receptors contribute to innate immunity in mammals[J]. J Endotoxin Res, 2005, 11(6): 390-394. [DOI]
[16]
MURAKI T, HAMANO H, OCHI Y, et al. Autoimmune pancreatitis and complement activation system[J]. Pancreas, 2006, 32(1): 16-21. [DOI]
[17]
SUGIMOTO M, WATANABE H, ASANO T, et al. Possible participation of IgG4 in the activation of complement in IgG4-related disease with hypocomplementemia[J]. Mod Rheumatol, 2016, 26(2): 251-258. [DOI]
[18]
TERNESS P, KOHL I, HUBENER G, et al. The natural human IgG anti-F(ab')2 antibody recognizes a conformational IgG1 hinge epitope[J]. J Immunol, 1995, 154(12): 6446-6452. [URI]
[19]
TAKEUCHI M, SATO Y, OHNO K, et al. T helper 2 and regulatory T-cell cytokine production by mast cells:a key factor in the pathogenesis of IgG4-related disease[J]. Mod Pathol, 2014, 27(8): 1126-1136. [DOI]
[20]
GALATOWICZ G, AJAYI Y, STERN ME, et al. Ocular anti-allergic compounds selectively inhibit human mast cell cytokines in vitro and conjunctival cell infiltration in vivo[J]. Clin Exp Allergy, 2007, 37(11): 1648-1656. [DOI]
[21]
MIYAKE K, MORIYAMA M, AIZAWA K, et al. Peripheral CD4+ T cells showing a Th2 phenotype in a patient with Mikulicz's disease associated with lymphadenopathy and pleural effusion[J]. Mod Rheumatol, 2008, 18(1): 86-90. [DOI]
[22]
TANAKA A, MORIYAMA M, NAKASHIMA H, et al. Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease[J]. Arthritis Rheum, 2012, 64(1): 254-263. [DOI]
[23]
AKITAKE R, WATANABE T, ZAIMA C, et al. Possible involvement of T helper type 2 responses to Toll-like receptor ligands in IgG4-related sclerosing disease[J]. Gut, 2010, 59(4): 542-545. [DOI]
[24]
SUZUKI K, TAMARU J, OKUYAMA A, et al. IgG4-positive multi-organ lymphoproliferative syndrome manifesting as chronic symmetrical sclerosing dacryo-sialadenitis with subsequent secondary portal hypertension and remarkable IgG4-linked IL-4 elevation[J]. Rheumatology (Oxford), 2010, 49(9): 1789-1791. [DOI]
[25]
MEILER F, KLUNKER S, ZIMMERMANN M, et al. Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors[J]. Allergy, 2008, 63(11): 1455-1463. [DOI]
[26]
SCHMITZ J, OWYANG A, OLDHAM E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines[J]. Immunity, 2005, 23(5): 479-490. [DOI]
[27]
MATTOO H, MAHAJAN VS, DELLA-TORRE E, et al. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease[J]. J Allergy Clin Immunol, 2014, 134(3): 679-687. [DOI]
[28]
OKAZAKI K, UCHIDA K, OHANA M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response[J]. Gastroenterology, 2000, 118(3): 573-581. [DOI]
[29]
OHTA N, MAKIHARA S, OKANO M, et al. Roles of IL-17, Th1, and Tc1 cells in patients with IgG4-related sclerosing sialadenitis[J]. Laryngoscope, 2012, 122(10): 2169-2174. [DOI]
[30]
MAIZELS RM, YAZDANBAKHSH M. Immune regulation by helminth parasites:cellular and molecular mechanisms[J]. Nat Rev Immunol, 2003, 3(9): 733-744. [DOI]
[31]
ZEN Y, FUJⅡ T, HARADA K, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis[J]. Hepatology, 2007, 45(6): 1538-1546. [DOI]
[32]
MORITA R, SCHMITT N, BENTEBIBEL SE, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion[J]. Immunity, 2011, 34(1): 108-121. [DOI]
[33]
AKIYAMA M, SUZUKI K, YAMAOKA K, et al. Number of circulating follicular helper 2 T cells correlates with IgG4 and interleukin-4 levels and plasmablast numbers in IgG4-related disease[J]. Arthritis Rheumatol, 2015, 67(9): 2476-2481. [DOI]
[34]
AKIYAMA M, YASUOKA H, YAMAOKA K, et al. Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease[J]. Arthritis Res Ther, 2016, 18: 167. [DOI]
[35]
MATTOO H, MAHAJAN VS, MAEHARA T, et al. Clonal expansion of CD4(+) cytotoxic T lymphocytes in patients with IgG4-related disease[J]. J Allergy Clin Immunol, 2016, 138(3): 825-838. [DOI]
[36]
MAEHARA T, MORIYAMA M, NAKASHIMA H, et al. Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz's disease[J]. Ann Rheum Dis, 2012, 71(12): 2011-2019. [DOI]
[37]
KIYAMA K, KAWABATA D, HOSONO Y, et al. Serum BAFF and APRIL levels in patients with IgG4-related disease and their clinical significance[J]. Arthritis Res Ther, 2012, 14(2): R86. [DOI]
[38]
WALLACE ZS, MATTOO H, CARRUTHERS M, et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations[J]. Ann Rheum Dis, 2015, 74(1): 190-195. [DOI]
[39]
LIN W, ZHANG P, CHEN H, et al. Circulating plasmablasts/plasma cells:a potential biomarker for IgG4-related disease[J]. Arthritis Res Ther, 2017, 19(1): 25. [DOI]
[40]
LITINSKIY MB, NARDELLI B, HILBERT DM, et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL[J]. Nat Immunol, 2002, 3(9): 822-829. [DOI]
[41]
ARAI Y, YAMASHITA K, KURIYAMA K, et al. Plasmacytoid dendritic cell activation and IFN-alpha production are prominent features of murine autoimmune pancreatitis and human IgG4-related autoimmune pancreatitis[J]. J Immunol, 2015, 195(7): 3033-3044. [DOI]
[42]
LANDE R, GANGULY D, FACCHINETTI V, et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus[J]. Sci Transl Med, 2011, 3(73): 73r. [URI]
[43]
VAN DER NEUT KOLFSCHOTEN M, SCHUURMAN J, LOSEN M, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange[J]. Science, 2007, 317(5844): 1554-1557. [DOI]
[44]
RISPENS T, OOIEVAAR-DE HEER P, VERMEULEN E, et al. Human IgG4 binds to IgG4 and conformationally altered IgG1 via Fc-Fc interactions[J]. J Immunol, 2009, 182(7): 4275-4281. [DOI]
[45]
KAWA S, KITAHARA K, HAMANO H, et al. A novel immunoglobulin-immunoglobulin interaction in auto-immunity[J]. PLoS One, 2008, 3(2): e1637. [DOI]
[46]
马玲瑛, 马莉莉, 纪宗斐. IgG4相关性疾病49例分析[J]. 中华风湿病学杂志, 2005, 19(2): 119-121. [URI]

文章信息

纪宗斐, 马玲瑛, 姜林娣
JI Zong-fei, MA Ling-ying, JIANG Lin-di
IgG4相关性疾病(IgG4-RD)发病机制的研究进展
Research progress on the pathogenesis of IgG4-related disease (IgG4-RD)
复旦学报医学版, 2019, 46(1): 114-118, 142.
Fudan University Journal of Medical Sciences, 2019, 46(1): 114-118, 142.
Corresponding author
JIANG Lin-di, E-mail: zsh-rheum@hotmail.com.
基金项目
复旦大学附属中山医院青年基金(2014ZSQN13)
Foundation item
This work was supported by the Youth Fund of Zhongshan Hospital, Fudan University (2014ZSQN13)

工作空间

IgG4相关性疾病(IgG4-RD)发病机制的研究进展
纪宗斐 (综述), 马玲瑛 , 姜林娣 (审校)