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Advances in Clinical Medicine
Vol. 12  No. 02 ( 2022 ), Article ID: 48829 , 7 pages
10.12677/ACM.2022.122177

母胎界面中HLA-G的调节作用

陈志锐，罗青清，邹丽*

华中科技大学同济医学院附属武汉协和医院妇产科，湖北 武汉

收稿日期：2022年1月17日；录用日期：2022年2月9日；发布日期：2022年2月21日

摘要

妊娠期间，随着胎儿组织植入子宫内膜，胎儿来源的滋养细胞和蜕膜细胞交互形成母胎界面。母胎界面中独特的局部免疫环境，在兼顾抵抗病原感染功能的同时，也实现了对胎儿这种半同源抗原的免疫赦免。作为一种非经典的MHC-I类分子，HLA-G在绒毛外滋养细胞(EVT)上大量特异性表达。HLA-G在母胎界面中发挥着调节螺旋动脉重塑、免疫耐受等作用；而滋养细胞HLA-G的表达异常与子痫前期(PE)、复发性自然流产(RSA)等不良妊娠结局有关。在此，我们总结了HLA-G对母胎界面中各种靶细胞的调节作用以阐明HLA-G发挥局部调节作用的内在机制。这些发现加深了我们对妊娠相关免疫机制的认识，也为妊娠相关疾病的治疗提供了线索。

关键词

人白细胞抗原G，妊娠，滋养细胞，自然杀伤细胞，螺旋动脉重塑

Regulatory Function of HLA-G in Maternal-Fetal Interface

Zhirui Chen, Qingqing Luo, Li Zou*

Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei

Received: Jan. 17th, 2022; accepted: Feb. 9th, 2022; published: Feb. 21st, 2022

ABSTRACT

During pregnancy, as fetal tissue implants into the endometrium, fetal trophoblast cells and decidua cells interact to form the maternal-fetal interface. The unique local immune environment in the maternal-fetal interface not only has the function of resistance to pathogen infection, but also achieves immunity to this semi-homologous antigen of the fetus. As a non-classical MHC-I molecule, HLA-G is highly specifically expressed in extravillous trophoblast cells (EVT). HLA-G plays a role in regulating spiral artery remodeling and immune tolerance at the maternal-fetal interface. The abnormal expression of HLA-G in trophoblast cells is associated with adverse pregnancy outcomes such as preeclampsia (PE) and recurrent spontaneous abortion (RSA). Here, we summarize the regulatory roles of HLA-G on various target cells in the maternal-fetal interface to clarify how HLA-G exerts the local regulatory function. These findings enhance our understanding of pregnancy-related immune mechanisms and provide clues for the treatment of pregnancy-related diseases.

Keywords:Human Leukocyte Antigen G, Pregnancy, Trophoblast Cell, Natural Killer Cells, Spiral Artery Remodeling

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. 引言

母胎界面即蜕膜，由蜕膜基质细胞、蜕膜免疫细胞和滋养细胞组成 [1]。这里存在着复杂的母胎细胞交互调节以及庞大的分子调控网络，对妊娠结局有着至关重要的影响。人类白细胞抗原G (HLA-G)正是母胎界面中最重要的分子之一。HLA-G在30年前被S Kovats等在细胞滋养层中检测到表达，之后在产科领域一直广受关注 [2]。HLA-G虽然属于MHC家族，与经典HLA-I类基因在结构和序列上有86%的相似性 [3]，但其在多态性以及组织分布上与MHC家族格外不同。HLA-G的基因多态性较低，至今仅发现了51个HLA-G等位基因，而HLA-A已知等位基因为3356个 [4]。另一方面，HLA-G的生理表达仅局限于几种组织如：滋养细胞、羊膜细胞、前内皮细胞等 [5]。在母胎界面中，HLA-G主要表达于滋养细胞。尽管有研究指出在一些蜕膜免疫细胞亚群中能检测到HLA-G表达，如DC-10、SIGN+DCs、CD4+HLA-G+T细胞、CD8+HLA-G+T细胞 [6] [7] [8]。但从这些研究结果中我们仍不能得出HLA-G在其中自然表达的结论，因为蜕膜免疫细胞可以借助免疫突触通过胞啃(trogocytosis)的方式从滋养细胞中获取HLA-G [8]。HLA-G已发现有7种转录本，即HLA-G1-7。其中HLA-G2、3、4翻译为膜结合型HLA-G分子，HLA-G5、6、7编码游离型HLA-G分子，而HLA-G1可翻译为膜结合和可溶性两种HLA-G分子 [4]。而不同类型HLA-G在滋养细胞各亚群中的表达情况也不一样。绒毛外滋养细胞(extravillous trophoblast cells, EVT)可同时表达膜结合及游离型HLA-G，而绒毛滋养细胞则主要表达游离型HLA-G。大量研究表明，在子痫前期、复发性流产等妊娠期不良事件中，蜕膜HLA-G表达水平存在显著的下降 [9] [10] [11]。作为一个经典的免疫调节分子，HLA-G在母胎界面中起着重要的局部免疫调节作用。随着研究的深入，HLA-G的免疫调节机制得到了更加深入的阐明。而且更有研究发现蜕膜中非免疫细胞也表达有HLA-G的受体，继而HLA-G的免疫调节之外的作用开始得到关注。在本文中我们将从HLA-G靶细胞的角度系统阐述滋养细胞HLA-G在母胎界面中的调控功能。

2. 滋养细胞HLA-G的局部表达调控

众所周知，滋养细胞生活在一个相对缺氧的环境中。Anna K. Wakeland等发现，原代细胞滋养层细胞在低氧(2%)的培养条件下倾向于分化出HLA-G高表达的EVT表型，而在20% 氧气浓度的培养条件下则分化为HLA-G低表达、HCG高表达的STB表型 [12] [13]。此外，体外培养的人类细胞滋养层细胞的全基因组DNA甲基化谱显示，147个CpG位点中有70个在低氧条件下发生高甲基化，且与细胞滋养层细胞向合胞滋养层细胞分化时发生低甲基化的CpG位点重叠 [14]。这些证据反映了低氧环境对维持HLA-G高表达EVT表型的重要作用。有研究指出，黄体酮可通过促进黄体酮受体(PR)结合HLA-G初级启动子与孕酮反应元件(PRE)进而增强HLA-G的表达 [15]。此外许多炎症因子也对HLA-G的表达具有调控作用。无论是促炎症细胞因子如IFN-γ、IL-1β还是抗炎症细胞因子如TGF-β、IL-10均报道可诱导滋养层HLA-G表达。因而是高炎症状态还是低炎症状态促进滋养细胞的HLA-G的表达，还需要进一步的多因素研究来解答。

3. HLA-G的功能

因为可以抑制蜕膜免疫细胞对胎儿的细胞毒性，HLA-G最初多作为一个经典的免疫豁免诱导分子被人熟知。随着HLA-G受体在更多种类的蜕膜细胞如平滑肌细胞、内皮细胞中被检测到，HLA-G的各种其他功能逐渐被发掘出来。

3.1. NK细胞

NK细胞是一种经典的天然免疫细胞，在人体中发挥这对肿瘤、外来移植物和受感染细胞等异常情况的免疫监视作用。蜕膜NK细胞(dNK)也是母胎界面中含量最高的免疫细胞之一。大量证据表明，无论是原代滋养细胞还是HLA-G+滋养细胞系，HLA-G都能有效保护滋养细胞免受NK细胞的攻击 [16] [17] [18] [19]。ILT2和KIR2DL4是两种可表达于dNK细胞的HLA-G受体。Benoit Favier等报道HLA-G 与NK细胞上的受体ILT2结合可阻碍F-actin的聚集和微管形成中心(MTOC)的极化，进而削弱细胞毒性颗粒向免疫突触的极化与释放 [19]。在该研究中，他们还发现用选择性抗体阻断ILT2几乎完全恢复了NK细胞的细胞毒性。而KIR2DL4的作用方式则更加复杂。一方面，KIR2DL4属弱活化抗体，HLA-G与之结合可以激活NK细胞较弱的细胞毒性 [20]。但是可溶性HLA-G结合dNK细胞表面的KIR2DL4可触发HLA-G/KIR2DL4复合体的内吞，内吞小体中的KIR2DL4进而促进NK细胞分泌IFN-γ、TNF-α、IL-1β、IL-6、IL-8、IL-10、IL-23、MIP-1-α、MIP-3-α等活性因子，可调节局部免疫以及促进滋养细胞侵袭 [21] [22]。此外，KIR2DL4和HLA-G的相互作用可诱导NK细胞衰老，并表现出衰老相关的分泌表型(SASP)，对滋养细胞迁移和子宫动脉重塑具有积极意义 [23] [24]。因此，这种HLA-G/ILT2/KIR2DL4的调节系统赋予了dNK功能的灵活性，这或许在一定程度上解释了dNK在实现对胎儿成分表现出免疫豁免的同时，也具备一定的病原反应能力。

3.2. 巨噬细胞

蜕膜巨噬细胞(dMac)约占蜕膜细胞的20%，参与了蜕膜局部的免疫调节和组织重塑。蜕膜巨噬细胞多表达CD206、 DC-SIGN和CD163，表现出强吞噬能力以及抑炎表型。ILT2和ILT4是dMac上检测到的两个HLA-G受体。与ILT2相比，ILT4对HLA-G的亲和力稍弱，但专一性更强 [25]。Cheuk等人报道HLA-G可以促进外周血单个核细胞分化为类似蜕膜巨噬细胞的表型，表现为高CD163低CD86表达特征以及较强的吞噬能力 [26]。而且这种被HLA-G极化的巨噬细胞可以通过分泌高水平CXCL-1促进滋养细胞的侵袭。此外，HLA-G可刺激蜕膜基质细胞分泌IL-6、IL-8、IFN-γ、TNF-α等促炎因子，进而促进滋养细胞侵袭 [22]。因此，我们推测HLA-G一方面可促进蜕膜巨噬细胞获得较强的吞噬能力，以适应蜕膜局部的组织重铸需求；另一方面促进巨噬细胞分泌促炎因子以促进滋养细胞的迁移侵袭能力。

3.3. 树突状细胞

人类树突状细胞(DC)属于抗原呈递细胞(APCs)，可分为：浆细胞样树突状细胞、髓系树突状细胞、单核细胞来源树突状细胞等等 [27]。蜕膜DC细胞(dDC)为髓系来源，占蜕膜总细胞数的1%，表现为CD11c+、D1a−、CD123− [28]。dDC可以同时表达两种HLA-G受体：ILT2和ILT4。当HLA-G与dDC细胞上的ILT2和ILT4受体结合，会激活下游信号下调CD80、CD86和MHC II类分子的表达，从而损害DCs的抗原呈递功能 [29] [30] [31]。此外，HLA-G修饰的DC细胞可有效抑制CD4+CD25+T细胞的活化，增加负调节性受体CTLA4+T细胞的比例，导致CD4+T细胞的IL-2合成分泌减少且IL-10的产生增加 [30] [32]。DC-10是蜕膜树突状细胞的一个亚群，它以合成分泌IL-10及表达HLA-G为特征，这些细胞也可以通过与IL-4、GM-CSF和IL-10培养单核细胞来分化 [33]。DC-10能有效诱导I型Treg细胞的分化，后者则能产生高水平的抗炎细胞因子IL-10和TGF-β [34]。因此，在母胎界面中HLA-G一方面可以通过受体ILT2和ILT4抑制dDC的抗原提呈能力，弱化T细胞介导的细胞毒性。同时，以HLA-G+为特征的DC-10细胞可以诱导T细胞分化为I型Treg细胞，进而抑制T细胞介导的细胞毒性，保证了胎儿的正常生长发育。

3.4. T淋巴细胞

蜕膜T淋巴细胞是蜕膜淋巴细胞的一个主要亚群，其独特的异质性使其具有灵活而复杂的功能。HLA-G除了通过与dDC和dMac的相互作用间接调节蜕膜T细胞外，还可以通过结合T细胞表面受体ILT2、ILT4、KIR2DL4和CD8直接调节T细胞的功能 [25]。在CD8+T细胞中，HLA-G结合CD8分子可促进Fas配体的分泌并诱导活化的T细胞进入凋亡程序 [35] [36]。另外HLA-G可以抑制CD4+T细胞增殖并驱使其向Th2型细胞分化，而这种偏Th2型细胞分化的现象恰好也在正常妊娠被观察到 [37] [38] [39] [40]。值得一提的是，K. Kapasi等的研究发现HLA-G对CD8+T细胞的细胞毒性以及Th1/Th2分化的影响是依浓度而定的，即相对高浓度的HLA-G可抑制CD8+T细胞的细胞毒性并促进Th2分化，而较低浓度的HLA-G的作用则相反 [40]。因而蜕膜T细胞对HLA-G的这种特殊的浓度依赖性反应可能是由弱免疫激活性受体KIR2DL4和免疫抑制受体ILT2/ILT4在数量和亲和力的特定模式所致。同时，这也提示蜕膜中HLA-G表达水平的改变可能会导致局部免疫微环境的偏离，导致子痫前期、流产等不良妊娠事件的发生。

3.5. 非免疫细胞

在对蜕膜HLA-G功能的研究中，免疫细胞始终是最受关注的，而蜕膜非免疫细胞如血管细胞、蜕膜间质细胞则少有提及。事实上，蜕膜基质细胞和血管细胞均检测到HLA-G受体的表达 [41]。Pierre Fons等研究发现，sHLA-G1可通过与内皮细胞膜上的CD160结合进而诱导内皮细胞凋亡、抑制内皮细胞增殖和迁移，这可能是螺旋动脉重铸过程中绒毛外滋养细胞取代内皮细胞的一种途径 [42]。而且该研究发现sHLA-G1在体内的抗血管生成作用，有助于在抗血管生成和促血管生成之间取得平衡 [42]。这也提示，母胎界面中HLA-G或许参与了局部血管的生产以及重铸。研究指出，HLA-G抑制NK细胞的滚动粘附和跨内皮迁移，因此HLA-G阳性的血管内滋养细胞可能作为一种屏障，阻碍外周血NK细胞的大量进入母胎界面，有助于维持蜕膜局部特有的免疫环境 [43] [44]。血管平滑肌细胞(VSMC)表面表达可表达ILT4受体。Amelia G等发现可溶性HLA-G可以抑制平滑肌细胞的增殖，这可能对子宫螺旋动脉重塑的进展有意义 [45]。

4. 讨论

在本文中，我们主要讨论了非经典MHCI类分子HLA-G在母胎界面中的表达调控以及HLA-G对蜕膜局部各种细胞的调控作用。我们认识到，局部氧气浓度、孕激素以及IFN-γ、IL-1β、TGF-β、IL-10等细胞因子参与了HLA-G的表达。而母胎界面中HLA-G具有抑制NK细胞、T细胞的细胞毒性，促进巨噬细胞、Th细胞免疫耐受，抑制抗原提呈细胞的抗原提呈能力，进而保护胎儿在母体环境中免受免疫攻击，促进滋养细胞侵袭。此外HLA-G还被发现可以调节内皮凋亡、平滑肌细胞增殖，提示HLA或可通过调节内皮细胞、平滑肌细胞进而调节妊娠期血管重铸的过程。

文章引用

陈志锐,罗青清,邹 丽. 母胎界面中HLA-G的调节作用
Regulatory Function of HLA-G in Maternal-Fetal Interface[J]. 临床医学进展, 2022, 12(02): 1222-1228. https://doi.org/10.12677/ACM.2022.122177

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    46. NOTES

    *通讯作者。

期刊菜单