Department of Metabolism, Digestion and Reproduction, Institute of Developmental Reproductive and Developmental Biology, Imperial College London, London, UK.
The Fertility Centre, Chelsea and Westminster Hospital, London, UK.
Hum Reprod Update. 2022 Jun 30;28(4):548-582. doi: 10.1093/humupd/dmac006.
Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focussed on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal-foetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared with controls.
The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared with controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared with controls.
MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger's test.
Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared with controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples (standardized mean difference (SMD) 0.49, CI 0.08, 0.90; P = 0.02; I2 88%; 1100 women). Meta-analysis of CD56+ uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women). There was no difference in pregnancy outcome in women with RM/RIF stratified by uNK level, and no significant correlation between pNK and uNK levels in women with RM/RIF. There was wide variation in studies conducted on uNK activity, which can be broadly divided into regulation and receptors, uNK cytotoxicity, cytokine secretion and effect of uNK on angiogenesis. These studies were largely equivocal in their results on cytokine secretion, but most studies found lower expression of inhibitory receptors and increased expression of angiogenic factors in women with RM.
The observation of significantly increased uNK level in endometrium of women with RM and RIF may point to an underlying disturbance of the immune milieu culminating in implantation and/or placentation failure. Further research is warranted to elucidate the underlying pathophysiology. The evidence for measuring pNK as an indicator of uNK behaviour is sparse, and of limited clinical use. Measurement of uNK level/activity may be more useful as a diagnostic tool, however, a standardized reference range must be established before this can be of clinical use.
在着床和妊娠早期，子宫内膜中的自然杀伤细胞（uNK）是最丰富的淋巴细胞。它们对早期胎盘发育很重要，尤其是滋养细胞浸润和螺旋动脉转化。然而，uNK 功能异常与生殖失败有关，如反复流产（RM）或反复着床失败（RIF）。尽管外周 NK 细胞（pNK）的表型和功能有明确的差异，但之前的研究主要集中在 pNK 上。近年来，对 uNK 的研究呈爆炸式增长，为母胎界面的免疫环境提供了更合适的代表性。在这里，我们总结了与对照组相比，在 RM/RIF 妇女中关于 uNK 的研究证据。
本系统评价和荟萃分析的目的是评估：与对照组相比，RM/RIF 妇女的 uNK 水平差异；根据 uNK 水平高低分层的 RM/RIF 妇女的妊娠结局；RM/RIF 妇女中 uNK 与 pNK 的相关性；与对照组相比，RM/RIF 妇女 uNK 活性的差异。
从成立到 2020 年 12 月，检索了 MEDLINE、EMBASE、Web of Science 和 Cochrane 临床试验注册中心，并按照 PRISMA 指南进行了研究选择。对 uNK 水平、妊娠结局和 uNK/pNK 相关性进行荟萃分析。对 uNK 活性进行叙述性综合。通过 ROBINS-I 评估偏倚风险，通过 Egger 检验评估发表偏倚。
我们最初的搜索产生了 4636 篇文章，其中 60 篇文章被纳入我们的系统评价。与对照组相比，RM 妇女子宫内膜中 CD56+uNK 水平的荟萃分析显示，RM 妇女的水平明显更高（亚组分析：标准化均数差（SMD）0.49，CI 0.08，0.90；P=0.02；I2 88%；1100 名妇女）。与对照组相比，RIF 妇女子宫内膜中 CD56+uNK 水平的荟萃分析显示，RIF 妇女的水平明显更高（SMD 0.49，CI 0.01，0.98；P=0.046；I2 84%；604 名妇女）。根据 uNK 水平分层的 RM/RIF 妇女的妊娠结局无差异，且 RM/RIF 妇女的 pNK 与 uNK 水平无显著相关性。uNK 活性的研究差异很大，大致可分为调节和受体、uNK 细胞毒性、细胞因子分泌和 uNK 对血管生成的影响。这些研究在细胞因子分泌方面的结果基本不一致，但大多数研究发现 RM 妇女的抑制性受体表达降低，血管生成因子表达增加。
在 RM 和 RIF 妇女的子宫内膜中观察到 uNK 水平明显升高，这可能表明免疫环境发生了潜在的紊乱，最终导致着床和/或胎盘形成失败。需要进一步的研究来阐明潜在的病理生理学。作为 uNK 行为的指标，测量 pNK 的证据很少，临床应用有限。测量 uNK 水平/活性可能更有用作为诊断工具，然而，在这可以用于临床之前，必须建立标准化的参考范围。
