Department of Gynecological Endocrinology and Reproductive Medicine, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria.
Department of Gynecological Endocrinology and Fertility Disorders, Ruprecht-Karls University Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.
Reprod Biol Endocrinol. 2019 Aug 31;17(1):72. doi: 10.1186/s12958-019-0514-7.
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.
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 CD45CD3CD56CD16 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)).
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 /mm 288.4 ± 239.3 vs 218.2 ± 184.5, p = 0.044).
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.
外周血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，在复发性流产（RM）患者中受到干扰。已经提出了原发性 RM（pRM，无既往活产）和继发性 RM（sRM，≥1 次既往活产）患者之间存在不同的免疫危险因素。然而，到目前为止，研究人群主要由小亚组组成。因此，我们旨在通过一项前瞻性研究中的大型、明确的研究人群来分析 pNK 和 uNK 细胞。
根据既定风险因素以及 pNK 和 uNK 细胞的标准方案，对 575 名 RM 患者（n=393 例 pRM，n=182 例 sRM）进行筛查。通过流式细胞术测定外周血 CD45CD3CD56CD16NK 细胞水平，在 RM 患者的黄体中期非妊娠状态下通过免疫组化测定子宫 CD56NK 细胞。排除≥1 个既定危险因素的患者后，发现 248 例特发性 RM 患者（iRM，n=167 例原发性 iRM（ipRM），n=81 例继发性 iRM（isRM））。
与 sRM 和 isRM 患者相比，pRM 和 ipRM 患者的 pNK 细胞绝对值和百分比明显更高（pRM/ipRM 与 sRM/isRM，平均±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±SD/%：12.4±5.5/12.8±5.4 与 11.1±4.6/11.1±4.3，p=0.001;p=0.002）。仅 isRM 患者的 uNK 水平明显高于 ipRM 患者（平均±SD/mm288.4±239.3 与 218.2±184.5，p=0.044）。
RM 患者根据既往活产情况出现的 pNK 和 uNK 细胞差异可能表明 NK 细胞募集存在差异，pRM 和 sRM 之间潜在的免疫紊乱不同。由于 NK 细胞结果存在重叠，因此需要进一步研究 NK 细胞功能，以明确识别具有不同免疫异常的 RM 患者。在进一步评估特异性和敏感性之前，应谨慎解释我们研究结果的临床相关性。
