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Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis.
Human Reproduction Update ( IF 13.3 ) Pub Date : 2022-06-30 , DOI: 10.1093/humupd/dmac006
Ee Von Woon 1, 2 , Orene Greer 1 , Nishel Shah 1 , Dimitrios Nikolaou 2 , Mark Johnson 1 , Victoria Male 1
Affiliation  

BACKGROUND 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. OBJECTIVE AND RATIONALE 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. SEARCH METHODS 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. OUTCOMES 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. WIDER IMPLICATIONS 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.

中文翻译:

复发性流产和着床失败中子宫自然杀伤细胞的数量和功能:系统评价和荟萃分析。

背景技术子宫自然杀伤细胞(uNK)是在着床期间和妊娠早期在蜕膜中发现的最丰富的淋巴细胞。它们对于早期胎盘发育非常重要,尤其是滋养层侵袭和螺旋动脉的转化。然而,不适当的 uNK 功能与生殖失败有关,例如复发性流产 (RM) 或复发性着床失败 (RIF)。先前的研究主要集中在外周 NK 细胞 (pNK),尽管 pNK 和 uNK 表型和功能之间存在差异。近年来,针对 uNK 的研究激增,为母胎界面的免疫环境提供了更合适的表征。在这里,我们总结了在 uNK 上发表的关于 RM/RIF 女性与对照女性的研究证据。目的和基本原理 本系统评价和荟萃分析的目的是评估: RM/RIF 女性与对照组相比,unK 水平的差异;RM/RIF 女性的妊娠结局按高和正常的 UNK 水平进行分层;RM/RIF 女性中 uNK 和 pNK 之间的相关性;以及患有 RM/RIF 的女性与对照组相比,unK 活性的差异。检索方法 MEDLINE、EMBASE、Web of Science 和 Cochrane 试验注册中心的检索时间从开始到 2020 年 12 月,并根据 PRISMA 指南选择研究。对 uNK 水平、妊娠结局和 uNK/pNK 相关性进行荟萃分析。对 uNK 活动进行叙事合成。偏倚风险通过 ROBINS-I 评估,发表偏倚通过 Egger 测试评估。结果 我们的初步检索产生了 4636 篇文章,其中 60 篇文章包含在我们的系统评价中。与对照组相比,RM 女性 CD56+ uNK 水平的荟萃分析显示,在子宫内膜样本的亚组分析中,RM 女性的 CD56+ uNK 水平显着较高(标准化平均差 (SMD) 0.49,CI 0.08,0.90;P = 0.02;I2 88%; 1100 名女性)。与对照组相比,RIF 女性子宫内膜 CD56+ uNK 水平的荟萃分析显示,RIF 女性的 CD56+ uNK 水平显着较高(SMD 0.49,CI 0.01,0.98;P = 0.046;I2 84%;604 名女性)。按 uNK 水平分层的 RM/RIF 女性妊娠结局没有差异,RM/RIF 女性的 pNK 和 uNK 水平之间没有显着相关性。关于uNK活性的研究存在很大差异,大致可分为调节和受体、uNK细胞毒性、细胞因子分泌以及uNK对血管生成的影响。这些研究对于细胞因子分泌的结果在很大程度上是模棱两可的,但大多数研究发现患有 RM 的女性抑制性受体表达较低,血管生成因子表达增加。更广泛的影响 RM 和 RIF 女性子宫内膜中 uNK 水平显着升高的观察结果可能表明免疫环境存在潜在紊乱,最终导致着床和/或胎盘失败。需要进一步的研究来阐明潜在的病理生理学。将 pNK 测量作为 uNK 行为指标的证据很少,且临床用途有限。uNK 水平/活性的测量作为诊断工具可能更有用,但是,在临床使用之前必须建立标准化参考范围。
更新日期:2022-03-09
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