The Association of NKp۴۶-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 NKp۴۶ (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 ۴۸ participants, including ۱۶ healthy controls, ۲۷ cases with RM, and ۵ 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 NKp۴۶ antibody expressed by uNK cells.Results: A significantly higher number of cells positive for NKp۴۶ was obtained among two groups of cases versus healthy subjects (patients: ۱.۴۶±۰.۷۸, controls: ۰.۸۲±۶۲, P=۰.۰۰۶), and the number of CD۵۶+cells was significantly higher in patients than in controls (patients: ۱۸.۱۴±۷.۱۴, controls: ۱۱.۷۱±۶.۱۷, P=۰.۰۰۳). Additionally, there was not a significant difference in the frequency ratio of NKp۴۶+NK cell subset to CD۵۶+uNK cells between the patients (P=۰.۵۹) 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.

Keywords:

Natural killer cells , NCR۱ , Abortion , Recurrent implantation failure , Immunohistochemistry