Ayano Funamizu

Uterine and circulating natural killer cells and their roles in women with recurrent pregnancy loss, implantation failure and preeclampsia

The regulation of uterine and circulating peripheral blood natural killer (NK) cells has been associated with reproductive conditions including recurrent pregnancy loss (RPL), implantation failure and preeclampsia. Natural cytotoxicity receptors (NCRs) are unique markers that regulate NK cell cytotoxicity and cytokine production. The role of NCRs in reproductive events has not yet been fully characterized. There is an NK1 (Type 1) shift in peripheral blood NK cells in non-pregnant women prone to RPL and implantation failure. The different profile of NCR expression in endometrial or aborted decidual NK cells suggests the presence of abnormal regulation of NK cells in women with reproductive failure. Women with a history of RPL and preeclampsia carry immunological abnormalities of NCRs on peripheral blood NK cells during pregnancy. Evaluation of NKp46 on peripheral blood NK cells may be applicable for the prediction of preeclampsia. The lower expression of NKp46(+) NK cells in women with preeclampsia may account for the higher production of NK1 cytokines - known as the NK1 shift - in pregnant women with preeclampsia. In this review, the expression of NCRs in peripheral blood NK cells and endometrial or decidual NK cells is discussed in relation to reproductive failure.

Expression of natural cytotoxicity receptors on peritoneal fluid natural killer cell and cytokine production by peritoneal fluid natural killer cell in women with endometriosis.

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.

Changes of NK Cells in Preeclampsia

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.

Role of NKp46 Expression in Cytokine Production by CD56-Positive NK Cells in the Peripheral Blood and the Uterine Endometrium

To investigate the role of natural cytotoxicity receptor, NKp46 expression in cytokine‐producing NK cells.

NK22 Cells in the Uterine Mid-Secretory Endometrium and Peripheral Blood of Women with Recurrent Pregnancy Loss and Unexplained Infertility

We aimed to investigate natural killer 22 (NK22) cells in the peripheral blood and the uterine endometrium of women with unexplained recurrent pregnancy loss (URPL) and unexplained infertility (UI).

Expression of Natural Cytotoxicity Receptors on and Intracellular Cytokine Production by NK Cells in Women with Gestational Diabetes Mellitus.

To determine the role of peripheral blood NK (pNK) cells in putative etiology of gestational diabetes, the expression of surface markers on pNK cells and the percentage of cytokine‐producing pNK cells in women at 12 weeks of pregnancy with gestational diabetes mellitus (GDM) were studied.

Laparoscopically assisted cervical canalization and neovaginoplasty in a woman with cervical atresia and vaginal aplasia

Cervical atresia is a Müllerian duct system anomaly, and it is often associated with vaginal aplasia. We report the case of a 17-year-old girl who presented with primary amenorrhea and cyclical abdominal pain, and was diagnosed with cervical atresia and vaginal aplasia that were treated laparoscopically. Laparoscopically assisted cervical canalization and neovaginoplasty were performed to relieve dysmenorrhea and allow for sexual intercourse and fertility. We did not use a bowel segment, skin, or peritoneum as a graft for the neovaginoplasty. To prevent adhesions and promote epithelialization, we used an estrogen-containing cream. Moreover, we did not use a vaginal mold. The patient is free of cervical stenosis and able to have intercourse. Long-term follow-up is necessary to ensure a future pregnancy and childbirth.

Expression of retinoid‐related orphan receptor (ROR)γt on NK22 cells in the peripheral blood and uterine endometrium of women with unexplained recurrent pregnancy loss and unexplained infertility

Recently, NK22 cells, a subset of interleukin (IL)‐22‐producing natural killer (NK) cells, were identified. We have previously reported the higher percentage of NK22 cells in women suffering recurrent pregnancy loss (RPL). Moreover, we have also reported lower expression of NKp46, a kind of natural cytotoxicity receptor (NCR), on NK cells and the changes of NK cell producing cytokines in women who experience RPL. NK22 cells express NCRs, such as NKp44 or NKp46. Retinoid‐related orphan receptor γt (RORγt) is known as a regulator of NK22 cells; however, in NK22 cells of peripheral blood (PB) and the uterine endometrium (UE), the relationship between NCRs and RORγt is unclear. We investigate RORγt expression NK22 cells in the PB and UE of women with unexplained infertility (uI) or unexplained RPL (uRPL).

Functional Role of Uterine Natural Killer Cells

The most abundant cells in the uterine endometrium (from the secretory phase to the stage of early-pregnancy decidua) are natural killer (NK) cells. Endometrial (uterine) NK cells and decidual NK cells are phenotypically and functionally different from peripheral blood NK cells.

NK cell abnormality and its treatment in women with reproductive failures such as recurrent pregnancy loss, implantation failures, preeclampsia, and pelvic endometriosis

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.