Expression of natural cytotoxicity receptors and cytokine production on endometrial natural killer cells in women with recurrent pregnancy loss or implantation failure, and the expression of natural cytotoxicity receptors on peripheral blood natural killer cells in pregnant women with a history of recurrent pregnancy loss

Abstract

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.

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss

“…Accumulating evidence supports this hypothesis. For instance, it has been shown that women with uRPL have increased endometrial populations of cytotoxic CD16 + uNK [92] and of uNK expressing the natural cytotoxicity receptors NKp46, NKp44, and NKp30 at higher levels than those detected in control women and in women with unexplained infertility or recurrent implantation failure [28,92,134,135]. This suggests that the cytotoxic activity of uNK is higher in RPL than in control women.…”

Interleukin-1/-33 Signaling Pathways as Therapeutic Targets for Endometriosis

“…However, because the reflux of menstrual blood is observed in most women, endometriosis cannot be explained by reflux alone. In addition, inflammatory cytokines, such as tumor necrosis factor α (5, 6), interleukin (IL)-1β (7, 8), and IL-33 (9), and immune cells, such as macrophages (10) and natural killer cells (11, 12), were reported to be involved in the pathogenesis of endometriosis. However, limited studies have investigated the mechanism of their actions in endometriosis.…”

Immune regulation at the foetal-maternal interface; implications for healthy and complicated pregnancies

“…Aberrations in the innate immune system have also been associated with RPL. For instance, lower proportions of the dNK CD56 bright CD16phenotype have been found in the endometrium of RPL patients, and with this, an increase in the more cytotoxic CD16+ NK cell population (152), showing abnormal receptor expression and cytokine profile compared to pregnancies in control women (153). Similar observations have been made for peripheral blood NK-cells in women with a history of RPL (154).…”