BACKGROUND Although the immune system intuitively must have an important role in embryo implantation and in the achievement of a pregnancy, the molecular details have for long been controversial. The role of the human leukocyte antigen (HLA) system has been debated. The unique HLA expression profile of the HLA Class Ia molecule HLA-C and the HLA Class Ib molecules HLA-E, HLA-F and HLA-G at the feto–maternal interface is now recognized. However, HLA Class Ib molecules may also have a role in embryo implantation and pregnancy success. OBJECTIVE AND RATIONALE The aim of this review was to evaluate the literature and recent discoveries on the role of the non-polymorphic HLA Class Ib molecules with a focus on HLA-F and HLA-G molecules at the time of implantation, including the interaction with uterine immune cells through the specific receptors immunoglobulin-like transcript 2 (ILT2), ILT4 and a number of killer cell immunoglobulin-like receptors (KIRs), and the importance of HLA-F and HLA-G genetic variation that influences fertility and time-to-pregnancy. SEARCH METHODS Drawing on recent advances in basic and clinical studies, we performed a narrative review of the scientific literature to provide a timely update on the role of HLA Class Ib in embryo implantation, fertility and infertility. Pertinent studies were searched in PubMed/Medline using relevant key words. OUTCOMES Both HLA-F and HLA-G interact with inhibitory or activating ILT2 or ILT4 receptors and KIRs on uterine immune cells, especially uterine natural killer (NK) cells that are highly abundant in the mid-secretory endometrium and in early pregnancy. The binding of HLA-G to ILT2 stimulates the secretion of growth-promoting factors from decidual NK cells. However, functional aspects of a HLA-F–receptor interaction remain to be clarified. Recent studies indicate that HLA-F and HLA-G are expressed in mid-secretory endometrium and HLA-G is expressed in the blastocyst. HLA-F fluctuates during the menstrual cycle with high levels during the implantation window. The level of HLA-F protein expression correlates with the number of CD56-positive NK cells in the mid-secretory endometrium. HLA-F and HLA-G gene polymorphisms, including a single nucleotide polymorphism (SNP) in a progesterone-responsive element, are associated with time-to-pregnancy. Depending on the SNP genotype, the effect of progesterone varies resulting in differences in HLA-F expression and thereby the interaction with receptors on the uterine NK cells. Studies suggest that the expression of HLA-G and HLA-F, both by the embryonic-derived trophoblast cells and by cells in the endometrium and decidua, and the interaction between HLA-G and HLA-F with specific receptors on uterine immune cells, stimulate and facilitate embryo implantation and placentation by secretion of growth factors, cytokines and angiogenic factors. WIDER IMPLICATIONS A detailed understanding of the molecular mechanisms controlling the expression of HLA-F and HLA-G periconceptionally and in early pregnancy may improve the success of ART and holds promise for further insight into pathophysiological aspects of certain pregnancy complications.

中文翻译：

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胚胎植入和妊娠早期 HLA Ib 类受体相互作用

背景虽然从直觉上看，免疫系统在胚胎植入和妊娠成功中必然具有重要作用，但其分子细节长期以来一直存在争议。人类白细胞抗原 (HLA) 系统的作用一直存在争议。HLA Ia 类分子 HLA-C 和 HLA Ib 类分子 HLA-E、HLA-F 和 HLA-G 在胎儿-母体界面处的独特 HLA 表达谱现已被识别。然而，HLA Ib 类分子也可能在胚胎植入和妊娠成功中发挥作用。目的和基本原理 本综述的目的是评估关于非多态性 HLA Ib 类分子作用的文献和近期发现，重点关注 HLA-F 和 HLA-G 分子在植入时的作用，包括通过特异性受体免疫球蛋白样转录物 2 (ILT2)、ILT4 和许多杀伤细胞免疫球蛋白样受体 (KIR) 与子宫免疫细胞的相互作用，以及影响 HLA-F 和 HLA-G 遗传变异的重要性生育能力和怀孕时间。检索方法 根据基础和临床研究的最新进展，我们对科学文献进行了叙述性回顾，以及时更新 HLA Ib 类在胚胎植入、生育力和不孕症中的作用。使用相关关键词在 PubMed/Medline 中搜索相关研究。结果 HLA-F 和 HLA-G 均与抑制或激活子宫免疫细胞上的 ILT2 或 ILT4 受体和 KIR 相互作用，尤其是在分泌中期的子宫内膜和妊娠早期高度丰富的子宫自然杀伤 (NK) 细胞。HLA-G 与 ILT2 的结合刺激蜕膜 NK 细胞分泌生长促进因子。然而，HLA-F-受体相互作用的功能方面仍有待澄清。最近的研究表明，HLA-F 和 HLA-G 在分泌中期的子宫内膜中表达，而 HLA-G 在胚泡中表达。HLA-F 在月经周期中波动，在植入窗口期间水平较高。HLA-F 蛋白表达水平与分泌中期子宫内膜中 CD56 阳性 NK 细胞的数量相关。HLA-F 和 HLA-G 基因多态性，包括孕酮反应元件中的单核苷酸多态性 (SNP)，与怀孕时间有关。根据 SNP 基因型，孕酮的作用各不相同，导致 HLA-F 表达的差异，从而与子宫 NK 细胞上的受体相互作用。研究表明，HLA-G 和 HLA-F 在胚胎来源的滋养层细胞和子宫内膜和蜕膜细胞中的表达，以及 HLA-G 和 HLA-F 与子宫免疫细胞上的特定受体之间的相互作用，通过分泌生长因子、细胞因子和血管生成因子来刺激和促进胚胎着床和胎盘。更广泛的意义 详细了解围孕期和妊娠早期控制 HLA-F 和 HLA-G 表达的分子机制可能会提高 ART 的成功率，并有望进一步深入了解某些妊娠并发症的病理生理学方面。