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Chinese Journal of Hepatology logoLink to Chinese Journal of Hepatology
. 2018 Jun 20;26(6):472–475. [Article in Chinese] doi: 10.3760/cma.j.issn.1007-3418.2018.06.019

免疫球蛋白G4相关肝胆疾病的发病机制

Pathogenesis ofimmunoglobulin G4-related hepatobiliary disease

Huang Bingyuan 1, Wang Qixia 1, Ma Xiong 1,通信作者：
Editor: 朱 红梅
PMCID: PMC12770721  PMID: 30317766

Abstract

IgG4-relaed hepatobiliary diseases (IgG4-HBD) are the hepatobiliary manifestations of IgG4-related disease, a multisystem fibro-inflammatory disorder. Previous studies on the pathogenesis of genetics and immunology have provided significant assistance in understanding the disease, rational diagnosis and treatment, but there are stillmany unknowns and challenges. The current research progress summarizes several factors influencing fibrosis and inflammation in the pathogenesis of disease.

Keywords: Hepatitis, autoimmune; Immunoglobulin G4-related sclerosing cholangitis; Genetics; B lymphocytes; T lymphocytes; Pathogenesis

免疫球蛋白G4相关疾病（immunoglobulin G4-related disease，IgG4-RD）是一种好发于中老年男性的多系统纤维炎性疾病，特征为受累器官肿胀硬化，病灶中IgG4＋浆细胞浸润增加，血清IgG4浓度升高。IgG4相关肝胆疾病（immunoglobulin G4-related hepatobiliary disease，IgG4-HBD）包括IgG4相关硬化性胆管炎（immunoglobulin G4-related sclerosing cholangitis，IgG4-SC）和IgG4相关肝病，后者最初用于描述自身免疫性胰腺炎（autoimmune pancreatitis，AIP）患者肝脏中存在IgG4＋浆细胞的情形，还包括累及肝内小胆管的IgG4-SC，目前，此概念已涵盖IgG4-RD的所有肝脏受累。IgG4-SC通常与AIP相关，流行病学研究结果表明仅1.5%的IgG4-SC患者不伴有AIP。现有的IgG4-HBD发病机制研究主要与IgG4-SC的遗传学和免疫学特征相关，而较少提及IgG4相关肝病，明确疾病中纤维变性过程的始动因素和促进因素是研究人员面临的重大挑战。

1.遗传学机制：人类白细胞抗原（human leukocyte antigen，HLA）分子和其他免疫调节基因是自身免疫性胰腺疾病易感性、类固醇治疗后复发和胰腺外受累的决定因素[1，2，3]。HLA与疾病关联研究报道称日本AIP患者HLA-DRB1*0405-HLA-DQB1*0401单体型的频率显著高于健康人和慢性钙化性胰腺炎患者[3]。一项韩国研究结果表明，位于HLA-DQB1*57处的非天冬氨酸氨基酸与AIP患者的治疗后复发相关，但该结论在日本队列研究中未被证实[1]。有报道IgG4-SC或AIP患者的HLA-DRB1*0301-HLA-DQB1* 0201频率高于健康人[4]。目前已报道的与AIP疾病易感性或复发相关的单核苷酸多态性存在于编码多种蛋白质如细胞毒性T淋巴细胞抗原-4、肿瘤坏死因子α和Fc受体样蛋白3等[5，6，7]的基因中。

2.先天免疫：既往研究结果已经证明IgG4相关疾病患者存在天然免疫的异常。尽管特定的病原体仍然不清楚，但已确定IgG4-SC患者的单核细胞和嗜碱性粒细胞上NOD样受体和Toll样受体被激活，通过产生B淋巴细胞激活因子（B cell activating factor，BAFF）和白细胞介素（interleukin，IL）-13诱导B淋巴细胞产生更多IgG4，增强相关免疫应答[8]。在动物模型中，TLR3（polyinosinic: polycytidylic acid）或TLR4（脂多糖）的激活也可诱导类似于人类IgG4-RD表现的免疫介导的胆管炎、胰腺炎和唾液腺炎[9]。巨噬细胞、嗜酸性粒细胞和嗜碱性粒细胞也常在IgG4-RD受累组织中检测到，如在IgG4相关的泪腺炎和唾液腺炎中，受累部位的M2型巨噬细胞数量与组织纤维化程度呈显著正相关，其分泌的IL-10与趋化因子C-C基序配体（cemokine C-C motif ligand，CCL）18在发病过程中可能起到关键作用[8，10]。多种固有免疫细胞在IgG4-HBD中的作用还有待进一步研究。

3.抗原与抗体：IgG4-SC患者的外周血和组织中存在的寡克隆B淋巴细胞提示发病机制中包括一个抗原-抗体介导过程[11，12]。部分IgG4-RD患者中检测到非特异性自身抗体阳性，如我们所熟知的抗核抗体。然而目前并无证据表明IgG4-RD与干燥综合征、系统性红斑狼疮有直接关联。一系列的候选抗原在既往研究中被提出，包括乳铁蛋白（lactoferrin，LF）、碳酸酐酶（carbonic anhydrase，CA）2和4、胰分泌胰蛋白酶抑制剂、胰蛋白酶原、胰α-淀粉酶和热休克蛋白等[13，14，15]。在动物模型中，用CA-2或LF免疫实验小鼠可引起系统性损伤，包括胰腺炎、涎腺炎、胆管炎和间质性肾炎等，类似于人类的多器官受累的IgG4-RD。然而，这些抗原及对应抗体在疾病中并非是稳定出现的，并且大多是IgG1而不是IgG4亚类。蛋白质组学研究曾将一个大小为1.31×104的蛋白质鉴定为候选自身抗原，但具体序列尚未阐明[16]。

亦有研究者提出，胃幽门螺杆菌感染可能通过分子模拟或抗体交叉反应过程在遗传易感个体中引发AIP和IgG4-SC[17]。幽门螺杆菌生存和增殖所必需的α-CA和人类的CA-2具有高度同源性，同源区段含有DRB1*0405的结合基序，因此，可增加AIP和IgG4-SC发病的风险。94%的意大利AIP患者检测到针对幽门螺杆菌纤溶酶原结合蛋白的抗体，但不具有疾病特异性[18]。而相关研究并未检测到AIP患者的组织或胰液中存在幽门螺杆菌DNA[19]。有报道IgG4-SC患者的幽门螺杆菌感染率并未显著增加，也未发现与幽门螺杆菌纤溶酶原结合蛋白相关的免疫记忆[20]。

IgG4-SC或AIP患者偶尔会出现补体C3、C4减少，伴随循环免疫复合物水平升高及IgG4亚类免疫复合物水平升高。然而，最近的一项研究结果表明，IgG4-SC疾病进程中补体系统激活可能并非通过IgG4的替代激活途径或凝集素途径，而是通过IgG1的经典途径激活[21]。

4. IgG4特点及其在IgG4-SC中的作用：健康人血清中IgG4仅占IgG的3%～6%，但在长期抗原暴露后可以占到IgG的80%以上[22]。IgG4的产生需要Th2型细胞的辅助，与Ig E类似，诱导Ig E产生的过敏原也可诱导产生IgG4。

机体内IgG4处于动态且活跃的“Fab臂交换”过程中，这种半分子（一条重链和附着于其上的一条轻链）交换虽然使得IgG4具有两个不对称的抗原结合位点，但IgG4常表现为单价抗体，不易形成大的免疫复合物。此外，IgG4与补体C1q和Fcγ受体的亲和力较低。这些特点都使得IgG4被认为是一种非致病性抗体[23]。此外，在IgG抗体的过敏及其免疫治疗作用的相关研究中，有人提出IgG4的主要作用可能是结合循环过敏性物质，这有助于减轻Th2型细胞的炎症效应。

但值得一提的是，IgG4自身抗体在一些免疫介导的与AIP或IgG4-SC无关的疾病如寻常天疱疮、大疱性类天疱疮、重症肌无力、边缘性脑炎、肺出血肾炎综合征等的发病过程中亦具有重要致病作用。在天疱疮中，疾病起始阶段IgG4就识别皮肤自身抗原桥粒芯蛋白发挥致病性效应[23]。

虽然特异性尚未明确定义，但AIP患者血清的IgG4自身抗体对健康人正常胰腺导管、胆管、胆囊及唾液腺导管的上皮细胞具有一定结合活性，所以并不能排除IgG4在IgG4-RD中可能起到致病性作用[24]。与之相反的是，在IgG4-SC患者外周血和肝组织中，诱导型调节性T淋巴细胞（Treg）数量与血清IgG4水平呈正相关[25]。IgG4-SC患者的肝脏中显着浸润的Treg上调了IL-10的表达[26]。这些结果表明IgG4过多产生也可能是由增多的Treg引起的下游效应；类似的，异常先天免疫细胞如单核细胞或嗜碱性粒细胞的BAFF诱导产生的过量IgG4可能与IgG4-SC的发展有关。总而言之，IgG4在IgG4-RD中的具体作用仍需要更完整和更明确的阐释。

5. T淋巴细胞：在IgG4-SC或AIP患者的外周血和组织中存在着Th2型免疫应答。在IgG4-SC或AIP患者的血液以及患有胆汁淤积患者的胆汁中，从m RNA水平检测到多种Th2型细胞因子，如IL-4、IL-5和IL-13等[26，27]。

调节性免疫反应在AIP或IgG4-SC中被激活，而不是像诸多自身免疫性疾病那样被抑制。诱导型记忆Treg在IgG4-SC或AIP患者的血液及受累组织中的浸润与IL-10和转化生长因子（transforming growth factor，TGF）β的上调相关，IL-10与Ig E向IgG4的类别转换有关，而TGFβ则可能参与了纤维组织形成[26，28]。IgG4-SC患者胆道组织中Treg数量与IgG4＋浆细胞浸润呈正相关，而AIP患者循环中的Treg数量与血清IgG4水平正相关[25，29]。根据其他多种免疫相关疾病的研究经验，以Th2和调节性T淋巴细胞为主的免疫反应与过敏性疾病密切相关，提示该疾病的发病机制也可能牵涉过敏反应，此时IgG4在其中的角色是一种抑制性抗体。

可参与Ig类别转换、体细胞超突变和生发中心形成的滤泡辅助性T淋巴（Tfh）细胞也在IgG4-SC的发病过程中起到重要作用[30]。对IgG4-RD患者外周血浆母细胞的免疫球蛋白重链库的高通量测序结果提示，存在着广泛的体细胞超突变，而在这一过程中Tfh细胞是不可或缺的[12]。IgG4-RD患者循环中的Tfh细胞扩增并倾向于分泌Th2型细胞因子，这可能会驱动B淋巴细胞分化为IgG4＋浆母细胞或浆细胞[30，31]。在IgG4-SC和AIP患者受累组织器官中存在明显的C-X-C趋化因子受体5型（CXCR5）阳性Tfh细胞浸润[32]。

此外，CD4＋效应T淋巴细胞的一个细胞毒性表型的克隆扩增群存在于IgG4-RD患者的外围血和受累组织中。这类CD4＋细胞毒性T淋巴细胞（cytotoxic T lymphocyte，CTL）表达SLAMF7、穿孔素、颗粒酶A和B、IL-1β、TGFβ1和干扰素γ，这些细胞因子可能是导致IgG4-RD中慢性炎症和席纹状纤维化的原因。在采取利妥昔单克隆抗体介导的B淋巴细胞耗竭治疗后观察到CD4＋CTL数量减少，而CTL本身并不表达CD20，对这种现象的一个推测性解释是CD4＋CTL通过主要组织相容性复合物Ⅱ类分子与T淋巴细胞受体之间的相互作用而被B淋巴细胞所维持，因此才受到利妥昔单克隆抗体的影响。这一点充分体现了IgG4-RD发病机制中T淋巴细胞与B淋巴细胞密切的相互作用。

6. B淋巴细胞：IgG4＋浆细胞在病灶中的浸润和患者的血清IgG4水平升高表明B淋巴细胞发育、激活和抗体产生在IgG4-HBD发病机制中十分关键[33]。与健康人相比，IgG4-SC患者IgG1和IgG4 B淋巴细胞的频率和表型有明显差异。如前文所述，它们对补体和Fc受体激活反应的潜力差异可能有助于解释IgG4抗体应答的差异性调节[34]。

多种因子可诱导B淋巴细胞增殖，促进IgG4类别转换并驱动重组、体细胞高频突变和抗体亲和力成熟，这些因子包括IL-21、IL-10、IL-4、活化诱导的胞苷脱氨酶和B淋巴细胞诱导的成熟蛋白1等[28]。

表征为CD19＋CD20-CD27＋CD38hi的浆母细胞从活化的幼稚/记忆B淋巴细胞发育而来，是抗体分泌浆细胞的直接前体。活动期IgG4-SC患者外周血中存在IgG4记忆B淋巴细胞和浆母细胞的扩增水平高于正常人及其他炎症性疾病对照[35，36，37]；且循环中浆母细胞计数与血清IgG4水平、疾病受累器官数量及国际IgG4相关疾病研究委员会裁定的IgG4-RD应答者指数显著相关。因此，和血清IgG4水平相比，IgG4＋浆母细胞计数可能是灵敏度和特异度更高的用于疾病诊断和评估的因子。浆母细胞表面主要组织相容性复合物Ⅱ类分子表达水平较高，提示其亦可能充当了CD4＋T淋巴细胞的重要抗原呈递细胞。最近，我们课题组发现IgG4-SC患者的成熟B淋巴细胞可分泌高水平RANKL，它通过激活核因子-κB信号通路诱导髓系源性抑制细胞扩增活化，并高表达一氧化氮，从而调控IgG4-SC肝内Th1/Th2型免疫平衡[38]。

7.免疫细胞的募集：有报道称胰胆系统局部组织特异性的因子与IgG4-SC患者病灶中胆道周围胰腺腺泡的炎症相关[39]。IgG4-SC患者的胰管上皮细胞、胆道周围腺细胞和血管内皮细胞大量表达CCL1，表达部位存在大量CCR8＋淋巴细胞（主要为Th2型细胞和Treg细胞）的浸润，提示CCL1-CCR8的相互作用在淋巴细胞募集中具有重要作用[40]。在IgG4-SC或AIP患者受累组织器官中表达上调的其他趋化因子及其配体包括CXCL13、CCL17、CCL19和CCL21，但它们在疾病中的具体作用尚不明确[41]。此外，IgG4-SC或AIP患者血液中的基因表达分析涉及CCL23和CCL25，这两者在免疫细胞向“肠-肝轴”的归巢过程中至关重要，且是其他自身免疫性疾病的重要生物标志物。

利益冲突

无

作者贡献声明

黄冰源、王绮夏：收集文献，撰写文章；马雄：审阅

Funding Statement

基金项目：国家自然科学基金（81620108002，81771732，81570511，81770564）；上海市卫生计生系统优秀青年医学人才培养计划（2017YQ037）；上海市青年科技启明星计划（18QA1402700）

Fund program: National Natural Science Foundation of China (81620108002, 81771732, 81570511, 81770564);the Municipal Human Resources Development Program for Outstanding Young Talents in Medical and Health Sciences in Shanghai (2017YQ037);Shanghai Rising-Star Program (18QA1402700)

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