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The regulation of uterine and circulating peripheral blood natural killer (NK) cells has been associated with reproductive immunology such as recurrent pregnancy losses, implantation failures, or preeclampsia. Preeclampsia is a hypertensive disorder of pregnancy characterized by increased blood pressure accompanied by proteinuria and is a major cause of maternal and fetal mortality. Natural cytotoxicity receptors (NCRs) are unique markers, which regulate NK cell cytotoxicity and cytokine production. The relation of NCRs to reproduction is not fully characterized yet. The different profile of NCRs expression may suggest presence of abnormal regulation of NK cell in women with reproductive failures. Pregnant women with preeclampsia carry immunological abnormalities of NCRs on peripheral blood NK cells during pregnancy. The lower expression of NKp46 + NK cells in women with preeclampsia may account for the higher production of NK1 cytokine that is known as NK1 shift in pregnant women with preeclampsia. Evaluation of NKp46 on peripheral blood NK cells may be applicable to find the onset of preeclampsia. In this review, various expressions of NK cell surface markers including NCRs on NK cells, NK cell cytotoxicity, and production of cytokines and angiogenic factors by NK cells were reviewed in relation to preeclampsia.

Problem To investigate the relationship between the expression of natural cytotoxicity receptors (NCRs) on peritoneal fluid (PF) natural killer (NK) (pfNK) cells and cytokine production by pfNK cells in women with endometriosis. Method of study Peritoneal fluid was collected from women with endometriosis undergoing laparoscopic surgery (n = 21) and controls without endometriosis (n = 28). The expression of NK cell surface antigens such as CD16 and NCRs (NKp46, NKp44 and NKp30) on pfNK cells, and cytokines production by pfNK cells [tumor necrosis factor (TNF)‐α, IFN‐γ, IL‐4, IL‐10, GM‐CSF and transforming growth factor (TGF)‐β1] were measured using multicolor flow cytometry. Results The percentages of CD56+/NKp46+ cells and CD56dim/NKp46+ cells in severe endometriosis group were significantly lower than that in controls. TNF‐α and IFN‐γ production by pfNK cells in severe endometriosis group was significantly higher than those in controls. Conclusion The differential expression of NKp46, TNF‐α, and IFN‐γ on pfNK cells in women with severe endometriosis may allow the proliferation and angiogenesis of endometriotic cells.

Aim: Natural cytotoxicity receptors (NCR) are unique markers that regulate natural killer (NK) cell cytotoxicity and cytokine production. In this study, we investigated the expression of NCR (NKp46, NKp44, and NKp30) and cytokine production in NK cells derived from the uterine endometrium of women with recurrent pregnancy loss (RPL). We also investigated the expression of NCR in peripheral blood NK cells in pregnant women with and without a history of RPL. Methods: The expression of NCR (NKp46, NKp44, and NKp30) in NK cells (CD56 dim and CD56 bright ) in the uterine endometrium was analyzed using 3-color flow cytometry. Cytokine (tumor necrosis factor-α and interferon-γ) production was also analyzed. NK cells from the mid-secretory endometrium of 28 women with RPL, 34 women with implantation failure, and 74 controls were collected and mechanically dispersed using a tissue grinder. The expression of NCR in peripheral blood NK cells from pregnant women with (n = 17) and without (n = 91) a history of RPL was analyzed. Results: The percentages of NKp46 + NK cells were significantly lower in both women with RPL and pregnant women with a history of RPL. The percentages of tumor necrosis factor-α-and/or interferon-γ-producing uterine endometrial NK cells were significantly lower in women with RPL compared with controls. Conclusion: The changes in NCR expression and cytokine production, especially decreased NKp46 expression in endometrial NK cells, suggests the presence of abnormal NK cell regulation in women with reproductive failures.

Gestational diabetes mellitus (GDM) is characterized by glucose intolerance that is caused by metabolic changes during pregnancy, and is considered a risk factor for the occurrence of DM in future. There are studies that reported changes in the cytokine in women with GDM. The concentration of serum IFN-γ and adiponectin decreased, while serum leptin, IL-6, IL-10, and TNF-α increased in GDM women when compared to that in healthy pregnant women. 16 17 Placenta and adipose tissues from patients with GDM released higher amounts of TNF-α in response to high glucose than that from normal pregnant women.18 Plasma TNF-α were reported to be low during the first and second trimester, but it increased during late pregnancy, and was inversely correlated with the insulin sensitivity. 19, 20 However, the relationship between GDM and the functions of NK cells in pregnant women has not been clarified so far. The purpose of this study was to evaluate the expression of peripheral blood NK (pNK) cell surface markers (CD16, NKp46, and NKp30) and the percentage of cytokine (IFN-γ, TNF-α, TGF-β, and VEGF) producing pNK cells in women with / without GDM at 12 weeks of pregnancy. 2 Materials and Methods Study SubjectsWe designed a prospective study and patients from Hirosaki University Hospital were recruited for this study between July 2014 and March 2015. This study was approved by the local ethics committee, and signed informed consent forms were obtained from all study subjects. Blood samples were collected during routine blood tests for prenatal check-up at 12weeks of gestation.Thirty-four Japanese women (GDM (n=7), non-GDM (n=27)) with singleton pregnancy were included. All GDM patients were diagnosed at 12 to 16 weeks of gestation. Pregnant women with multi-fetal gestations, pre-gestational diabetes, and overt diabetes were excluded, while pregnant women with impaired glucose tolerance before the onset of pregnancy were included in this study. Maternal and neonatal characteristics are shown in Table 1. Two-hour-glucose level of 75-g OGTT in GDM group was significantly higher than that in the non-GDM group.There were no complications reported in the newborn infants (such as macrosomia, shoulder dystocia, and hypoglycemia) in both the GDM and non-GDM groups and there were no pregnant women suffering from PE in both the GDM and non-GDM groups. Screening of GDMAll pregnant women were subjected to a two-step screening method for GDM. This screening method is based on the Guideline for Obstetrical Practice in Japan 2014. 21 Briefly, women who had a random plasma glucose level of ≥95mg/dl at 12 weeks of gestation were subjected to 75-g OGTT after fasting overnight. Diagnosis of GDM was based on the criteria of one or more abnormal values [fasting ≥92mg/dl (5.1mmol/l), such as 1 hour ≥180mg/dl (10.0mmol/l) or 2 hour ≥153mg / dl (8.5mmol/l)] reported for the subjects. Pregnant women, not diagnosed as GDM at 12 weeks of screening, were again subjected to random blood glucose measurement at 3 28 weeks of gestation. Women with random...