The State of Peripheral Blood Natural Killer Cells and Cytotoxicity in Women with Recurrent Pregnancy Loss and Unexplained Infertility (original) (raw)
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Human Reproduction, 2005
BACKGROUND: To evaluate the association between the absolute counts of the peripheral natural killer (NK) cells (including total CD56 1 NK cells, CD56 dim NK cells and CD56 bright NK cells), B cells and T cells on the implantation rate and miscarriage rate after IVF treatment. METHODS: This was a prospective observation study. A total of 138 patients who underwent IVF treatment from December 2002 to July 2003 were recruited to the study. Blood samples were obtained on the day of vaginal oocyte retrieval prior to the procedure. The absolute counts of lymphocytes, NK cells, B cells and T cells were identified by flow cytometry. These absolute counts and their relationships to IVF treatment outcome and miscarriage rate were analysed. RESULTS: There were no significant differences with regard the mean values of absolute lymphocyte count, T cell count, B cell count and NK cell count (including total CD56 1 NK, CD56 dim NK and CD56 bright NK cells) between the pregnant and non-pregnant groups and also between the ongoing pregnancy and miscarriage groups. The cause of infertility, duration of infertility, basal FSH levels, number of previous failed IVF treatments, number of previous miscarriages and stimulation characteristics were not significantly different between the pregnant and non-pregnant groups. Previous studies have suggested that women with a history of recurrent miscarriage and those with infertility accompanied by recurrent failed IVF treatments are associated with a peripheral blood NK cell percentage > 12%, therefore further analysis of peripheral CD56 1 NK cell levels <12% (group A) and >12% (group B) was performed. There was no significant difference in implantation rate (group A: 17.0%; group B: 23.2%), pregnancy rate (group A: 36.6%; group B: 47.7%) or miscarriage rate (group A: 23.3%; group B: 28.6%). CONCLUSION: There were no significant differences between simple enumerations of peripheral blood NK cells (including total CD56 1 NK, CD56 dim NK and CD56 bright NK cells), B cells and T cells with IVF treatment outcome and pregnancy outcome. Women who had a peripheral NK cell level > 12% did not have higher number of previous pregnancy losses. Importantly their pregnancy rate was not reduced and their miscarriages were not increased compared to women who had a peripheral NK cells level <12%.
Reproductive Medicine and Biology, 2015
The regulation of uterine and peripheral blood natural killer (NK) cells has been associated with problems related to reproductive immunology such as recurrent pregnancy loss (RPL), implantation failure or preeclampsia. NKp46, one of the natural cytotoxicity receptors (NCRs), is a unique marker that functions in NK cell cytotoxicity and cytokine production. Expression of NKp46 on NK cells is lower in women with recurrent pregnancy loss and pregnancy-induced hypertension. Moreover, expression of NKp46 on peritoneal fluid NK cells is lower in women with pelvic endometriosis. Therefore, evaluation of NKp46 on peripheral blood NK cells may provide a means of screening for reproductive abnormalities. Recently, a new type of NK cell, the NK22 cell, has been reported. This cell may be a regulator not only of the mucosal barrier but also of reproduction.For women with RPL showing abnormal uterine and/or peripheral blood NK cells, both intravenous immunoglobulin treatment and intralipid treatment have been reported. The effects of these treatments are still controversial, and further studies are needed in order to clarify their true impact. The present review examines variations in the expression of NCRs on NK cells, the participation of NK22 cells in reproduction, and the possible use of intravenous immunoglobulin or intralipid treatment for women with recurrent pregnancy loss and NK cell abnormality.
Human Reproduction, 2001
The aim of this study was to investigate the functional status and immunophenotypic characteristics of natural killer (NK) cells in women who suffer recurrent spontaneous abortions (RSA) or have infertility of unknown aetiology. Peripheral blood mononuclear cells (PBMC) were obtained from 40 study patients and 13 normal healthy multiparous controls. NK cells were identified using anti-CD56 and anti-CD16 monoclonal antibodies (mAb). The expression of CD69, CD25, CD122, CD30, CD154, CD128 and CD94 on NK cells was detected using specific mAb and analysed by flow cytometry. CD69 expression on NK cells after ED 27 human trophoblast cell line co-culture with PBMC was also investigated. A significant increase in CD69 expression on CD56 ⍣ NK cells was demonstrated in women with RSA (P < 0.005) and infertility (P < 0.05) as compared with that of normal controls. Conversely, CD94 expression was significantly decreased in women with RSA (P < 0.005) and infertility (P < 0.05) in comparison with that of controls. Increased CD69 expression on NK cells was induced after 24 h co-culture with ED 27 . In conclusion, peripheral blood NK cells of women with RSA and infertility of unknown aetiology have higher proportions of activated NK cells in vivo. Unbalanced CD69 and CD94 expression may explain the underlying pathology.
Human Reproduction, 2004
BACKGROUND: Our aim was to evaluate the effect of the absolute count of the activation marker (CD69), IgG Fc receptor (CD16) and inhibitor marker (CD94) expression on peripheral blood natural killer (NK) cells on implantation and miscarriage rates after IVF treatment. METHODS: Prospective observational study of 138 randomly selected women who underwent IVF treatment from December 2002 to September 2003. NK cells were identified as CD56 1 (dim 1 bright) and CD3by flow cytometry. The absolute counts of the CD69 1 , CD16 1 and CD94 1 expressing NK cells were recorded and their relation to IVF treatment outcome and miscarriage rate was analysed. RESULTS: The mean (6SD) absolute count of the CD56 dim CD16 1 CD69 1 NK cells for women who had a successful ongoing pregnancy was 0.61 3 10 6 /l (60.31). For those women who failed to achieve a pregnancy, the mean value of the absolute count of CD56 dim CD16 1 D69 1 NK cells was significantly (P 5 0.003) higher at 1.66 3 10 6 /l (60.52). The absolute count of CD56 dim CD16 1 CD94 1 and CD56 dim CD16 1 NK cells did not show any statistically significant differences between those women with successful and failed IVF treatment. Receiver operating characteristic (ROC) curve analysis was performed to select a CD69 threshold for further statistical analysis. The implantation rate (IR) was significantly lower (13.1%) and miscarriage rate (MR) was significantly higher (66.7%) for women with an absolute CD56 dim CD16 1 CD69 1 NK cell count of > 1.0 3 10 6 /l compared to women with count below this value (IR 28.2% and MR 16.7%). Further analysis of the absolute count of CD56 bright CD69 1 and CD56 bright CD94 1 NK cells did not show any significant difference between those women with successful and failed IVF treatment. CONCLUSIONS: An increase in the absolute count of activated NK cells (CD56 dim CD16 1 CD69 1 ) in the peripheral blood is associated with a reduced rate of embryo implantation in IVF treatment. Furthermore, women with high CD56 dim CD16 1 CD69 1 peripheral blood NK cell absolute count, who are able to achieve pregnancy, have a significantly higher miscarriage rate.
Diagnostics
Changes in the number and cytotoxic potential of uterine Natural Killer (uNK) cells have been associated with reduced fertility. To provide a better characterization of immunophenotypes in the endometrium of women with uRPL (unexplained recurrent pregnancy loss), we examined the applicability of a set of five immune cell markers. The concentration (cells/mm2) of CD45+ leukocytes, CD56+ uNK cells, and CD138+ plasma cells as well as of CD16+ and CD57+ cells, which indicate high cytotoxic uNK cells, were assessed by immunohistochemistry in endometrial biopsies from 61 uRPL patients and 10 controls. Control fertile endometria presented 90–300 CD56+ uNK cells/mm2. uRPL cases were classified in subgroups of low (uRPL-CD56low < 90 cells/mm2), normal (uRPL-CD56normal 90–300 cells/mm2), and high uNK cell counts (uRPL-CD56high > 300 cells/mm2). Some cases from the uRPL-CD56low and uRPL-CD56normal subgroups showed elevated proportions of cytotoxic CD16+ and CD57+ cells in relation to CD5...
American journal of reproductive immunology (New York, N.Y. : 1989), 2014
Uterine natural killer cells (uNK) have been thought to play a key role in endometriosis and infertility. We investigated the expression of CD56, CD16, and NKp46 in endometrial tissues from 61 women with unexplained recurrent pregnancy loss (uRPL) or infertility (UI) and correlated this with the presence or absence of endometriosis. The results from the patients with subfertility were compared with those from 10 fertile patients. Mid-secretory phase endometrial biopsies were obtained, and the endometrial expression of CD56, CD16, or NKp46 was identified by immunohistochemistry and quantified (ImageJ Software). The percentage of CD16(+) cells was higher in women with uRPL (7.9 ± 3.2) and UI (9.0 ± 5.5), even when these conditions were associated with endometriosis (8.9 ± 5.3), compared with fertile patients (5.6 ± 2.4, P < 0.05). Likewise, the ratio of NKp46(+) :CD56(+) cells was higher in women with uRPL (0.28 ± 0.25) and UI (0.21 ± 0.2), even when these conditions were associate...
Background: Recurrent spontaneous abortion (RSA) and in vitro fertilization (IVF) failure with unknown causes are the controversial issues that are probably related to the immune system. Objective: To compare circulating NK cells expressing activation and inhibition surface markers between patients with RSA and IVF failure with those of healthy multiparous and successful IVF control women, respectively. Methods: In this case-control study peripheral blood samples were collected from 43 patients who included 23 women with RSA and 20 with IVF failure, plus 43 healthy control women comprising of 36 normal multiparous women and seven women with successful IVF. The expression of CD69, CD94 and CD161 surface markers on CD56+NK cells were assessed using specific monoclonal antibodies by flowcytometry. Results: The percentage of NK cells increased significantly in patients with RSA and in women with IVF failure in comparison to healthy multiparous and successful IVF control groups (p<0.001). The overall expression of CD69, CD94, CD161 were also increased significantly on NK cells in both patient groups compared to control groups (p<0.001). Conclusion: Elevated expression of CD69 and CD161 on NK cells can be considered as immunological risk markers in RSA and IVF failure. However, it is not clear if high expression of CD94 on peripheral blood NK cells is related to abnormal activity of endometrial NK cells.
Journal of Reproductive Immunology, 2014
Natural killer (NK) cells play fundamental function in maintaining pregnancy. Based on the availability and non-invasive method of collection of menstrual blood (MB), here we investigated for the first time comparative analysis of NK cell subsets in MB and peripheral blood (PB) of recurrent spontaneous abortion (RSA) and fertile women. PB and MB of healthy fertile (n=15) and RSA women (n=15) were sampled simultaneously in the second day of menstrual cycle. Frequency of CD56+CD3-CD16+/-, CD56+CD3-CCR7+/-, and CD56+CD3-CD45RO+/-cells was analyzed by flow cytometry. In MB of both groups, CD16+ and CD45RO-NK cells were significantly lower compared to PB. In parallel, CD56+CD16+CCR7-and CCR7+ cells were present at significantly lower frequencies in MB than PB. However, the frequencies of CD56+CD16-CCR7-and CCR7+ cells were higher in MB. In comparison to fertile group, percentage of MB CD45RO+ NK cells was significantly lower and frequencies of PB CD16-, CD45RO-and CD56+CD16+CCR7+ subsets were significantly higher in RSA patients. Different subsets of NK cells are differentially distributed in MB in comparison with PB in RSA and fertile subjects. Population differences of NK cell subsets in RSA patients and normal controls were more reflected at the systemic level.