BACKGROUND Peripheral and uterine natural killer cells (pNK and uNK cells) are key players in the establishment and maintenance of pregnancy and are disturbed in patients with recurrent miscarriage (RM). Different immunologic risk factors have been proposed between patients with primary RM (pRM, no previous live birth) and secondary RM (sRM, ≥ 1 previous live birth). However, so far, the study populations mainly consisted of small subgroups. Therefore, we aimed to analyse pNK and uNK cells in a large, well defined study population within a prospective study. METHODS In total, n = 575 RM patients (n = 393 pRM, n = 182 sRM) were screened according to a standard protocol for established risk factors as well as pNK and uNK cells. Peripheral blood levels of CD45+CD3-CD56+CD16+ NK cells were determined by flow cytometry and uterine CD56+ NK cells by immunohistochemistry in mid-luteal non-pregnant RM patients. Exclusion of patients with ≥1 established risk factor revealed n = 248 idiopathic RM patients (iRM, n = 167 primary iRM (ipRM), n = 81 secondary iRM (isRM)). RESULTS Patients with pRM and ipRM showed significant higher absolute numbers and percentages of pNK cells compared to sRM and isRM patients (pRM/ipRM vs sRM/isRM, mean ± SD /μl: 239.1 ± 118.7/244.9 ± 112.9 vs 205.1 ± 107.9/206.0 ± 105.6, p = 0.004/ p = 0.009; mean ± SD %: 12.4 ± 5.5/12.8 ± 5.4 vs 11.1 ± 4.6/11.1 ± 4.3, p = 0.001; p = 0.002). Only patients with isRM showed significantly higher uNK levels compared to patients with ipRM (mean ± SD /mm2 288.4 ± 239.3 vs 218.2 ± 184.5, p = 0.044). CONCLUSIONS The demonstrated differences in pNK and uNK cells in RM patients depending on previous live birth might indicate differences in NK cell recruitment and potentially different underlying immune disorders between pRM and sRM. As there is an overlap in the distribution of the NK cell results, further studies with focus on NK cell function are needed in order to clearly identify RM patients with distinct immune abnormalities. The clinical relevance of our findings should be interpreted cautiously until specificity and sensitivity are further evaluated.

中文翻译：

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反复流产患者先前的活产对外周和子宫自然杀伤细胞的影响。

背景技术外周和子宫自然杀伤细胞（pNK和uNK细胞）是妊娠建立和维持的关键因素，在反复流产（RM）的患者中会受到干扰。在原发性RM（pRM，无既往活产）和继发性RM（sRM，≥1活产）之间提出了不同的免疫危险因素。但是，到目前为止，研究人群主要由小的亚组组成。因此，我们旨在对前瞻性研究中定义明确的大量研究人群中的pNK和uNK细胞进行分析。方法根据标准方案，共筛查n = 575 RM患者（n = 393 pRM，n = 182 sRM）以及已确定的危险因素以及pNK和uNK细胞。黄体中期非妊娠RM患者通过流式细胞术测定外周血CD45 + CD3-CD56 + CD16 + NK细胞水平，通过免疫组织化学测定子宫CD56 + NK细胞水平。排除≥1个既定危险因素的患者后，发现n = 248名特发性RM患者（iRM，n = 167名主要iRM（ipRM），n = 81名继发性iRM（isRM））。结果与sRM和isRM患者相比，pRM和ipRM患者表现出明显更高的pNK细胞绝对数量和百分比（pRM / ipRM vs sRM / isRM，平均值±SD /μl：239.1±118.7 / 244.9±112.9与205.1±107.9 / 206.0 ±105.6，p = 0.004 / p = 0.009;平均值±SD％：12.4±5.5 / 12.8±5.4与11.1±4.6 / 11.1±4.3，p = 0.001; p = 0.002）。与ipRM患者相比，只有isRM患者显示出显着更高的uNK水平（平均值±SD / mm2 288.4±239.3 vs 218.2±184.5，p = 0.044）。结论在RM患者中pNK和uNK细胞的差异取决于以前的活产，这可能表明NK细胞募集的差异以及pRM和sRM之间潜在的潜在免疫紊乱。由于NK细胞结果的分布存在重叠，因此需要进一步研究以NK细胞功能为重点，以明确鉴定具有明显免疫异常的RM患者。在进一步评估特异性和敏感性之前，应谨慎解释我们发现的临床意义。为了清楚地鉴定具有明显免疫异常的RM患者，需要针对NK细胞功能的进一步研究。在进一步评估特异性和敏感性之前，应谨慎解释我们发现的临床意义。为了清楚地鉴定具有明显免疫异常的RM患者，需要针对NK细胞功能的进一步研究。在进一步评估特异性和敏感性之前，应谨慎解释我们发现的临床意义。