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.

AIM: 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). METHODS: Lymphocytes were extracted from PB and UE, derived from women with uI or uRPL. Expression of RORγt and NCRs in NK cells and NK cell-produced cytokines were analyzed by flow cytometry. RESULTS: CD56+ /NKp46+ /RORγt+ cells were positively correlated with CD56+ /IL-22+ cells in both PB and UE. CD56bright /NKp46bright /RORγt+ cells were significantly higher in uRPL than in uI, and endometrial CD56bright /NKp46bright /RORγt+ cells were positively correlated with PB. In UE, CD56bright /RORγt+ cells were negatively correlated with CD56bright /interferon-γ+ and CD56bright /tumor necrosis factor-α+ cells of uRPL. CONCLUSION: RORγt may be associated with NK22 cells in reproduction. Particularly, higher expression of RORγt may be associated with elevated NK22 cells in uRPL.

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

PROBLEM: 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). METHOD OF STUDY: Peripheral blood and endometrial samples were collected from women with URPL (n = 43) and UI (n = 38). Intracellular cytokine production, such as IL-22, IFN-γ and TNF-α, and the expression of NKp46 on NK cells were analyzed by three-color flow cytometry. RESULTS: The percentages of endometrial CD56(+) /IL-22(+) and CD56(dim) /IL-22(+) cells in women with URPL were significantly higher than those of UI (P < 0.05, respectively). In addition, the percentage of CD56(bright) /IL-22(+) cells in women with RPL was negatively correlated with those of CD56(bright) /IFN-γ(+) and CD56(bright) /TNF-α(+) in both peripheral blood and endometrial NK cells. This was not seen in women with UI. The percentage of CD56(bright) /IL-22(+) cells was negatively correlated with CD56(bright) /NKp46 expressing NK cells in peripheral blood. CONCLUSION: Endometrial NK22 cells are differently regulated in women with URPL and UI. Women with URPL have higher level of NK22 cells with a potential to induce NK2 shift than women with UI.

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.

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

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)-ß1] were measured using multicolor flow cytometry. RESULTS: The percentages of CD56(+)/NKp46(+) cells and CD56(dim) /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.

Role of NKp46 expression in cytokine production by CD56-positive NK cells in the peripheral blood and the uterine endometrium.

PROBLEM: To investigate the role of natural cytotoxicity receptor, NKp46 expression in cytokine-producing NK cells. METHOD OF STUDY: CD56(+) /NKp46(+) NK cells from the peripheral blood and the uterine endometrium were magnetically separated. IFN-γ, TNF-α, IL-4, IL-10, and TGF-ß(1) expressions on NK cells were investigated using multicolor flow cytometry. RESULTS: Peripheral blood and uterine endometrial NK cells were grouped into 4 subpopulations based upon the degree of CD56 and NKp46 expressions. NKp46 expression was associated with higher frequency of cytokine-producing NK cells, including CD56(dim) NK cells. The percentage of TNF-α(+) and IL-10(+) NK cells per total CD56(+) /NKp46(+) NK cells in the uterine endometrium showed a significant correlation with those of the peripheral blood in all subpopulations, but that of IFN-γ(+) , IL-4(+,) and TGF-ß(1) (+) NK cells showed partial correlation. CONCLUSION: Expression of NKp46 is involved in cytokine production of CD56(+) NK cells in the peripheral blood and the uterine endometrium.

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.