The Association of NKp46-Positive uNK Cells With a Higher Risk of Recurrent Miscarriage and IVF Failure

Background: Uterine natural killer (uNK) cells have a significant impact on pregnancy and related complications. Given the importance of receptors in the activity of uNK cells, the present study aimed to determine the number of uNK cells and NKp46 (one of the most important NK cell-activating receptors) expression in the endometrium of women with recurrent miscarriage (RM) or a history of in vitro fertilization (IVF) failure. Materials and Methods: This case-control study was performed on 48 participants, including 16 healthy controls, 27 cases with RM, and 5 cases with repeated implantation failure (RIF) during the mid-luteal phase according to a standardized diagnostic protocol. All participants were assessed using transvaginal ultrasound to determine embryo survival rate and confirm gestational age. Endometrial specimens were collected and subjected to immunohistochemistry (IHC) staining using an anti-human NKp46 antibody expressed by uNK cells. Results: A significantly higher number of cells positive for NKp46 was obtained among two groups of cases versus healthy subjects (patients: 1.46±0.78, controls: 0.82±62, P=0.006), and the number of CD56+cells was significantly higher in patients than in controls (patients: 18.14±7.14, controls: 11.71±6.17, P=0.003). Additionally, there was not a significant difference in the frequency ratio of NKp46+NK cell subset to CD56+uNK cells between the patients (P=0.59) and control healthy group. Conclusion: The increase in the number of uterine NK cells and their cytotoxic activity during implantation and early pregnancy, possibly resulting from an excessive expression of inflammatory cytokines, confirms a significant association between uNK cell activity and a higher risk of RM and RIF. Therefore, immunomodulatory treatments may benefit these patients.