Role of Uterine NK Cell Activation Markers NKp46 and NKG2D in Endometriosis Related Infertility

Abstract

Background: Endometriosis, affecting 10–40% of infertile women, is associated with endometrial immune dysregulation. Uterine natural killer (uNK) cells play pivotal roles in implantation and endometrial immune regulation. However, the differential expression of the activating receptors NKp46 and NKG2D between CD56^bright and CD56^dim uNK cell subsets in endometriosis-associated infertility remains poorly characterized. This study investigated these receptor profiles in infertile women with endometriosis.

Methods: Endometrial biopsies from 14 women with endometriosis and 21 controls were analyzed by flow cytometry. Disease severity was assessed using the revised American Society for Reproductive Medicine (rASRM) classification. Group comparisons and correlations were evaluated using appropriate statistical tests, with p<0.05 considered significant.

Results: NKp46⁺ NKG2D⁻ and NKp46⁻ NKG2D⁻ populations were significantly increased in both uNK cell subsets in women with endometriosis compared with controls. In the CD56^dim compartment, both populations increased significantly (p=0.012 and p=0.030, respectively), with comparable increases in CD56^bright cells (p=0.003 and p=0.023). In stage I–II endometriosis, NKp46⁻ NKG2D⁻ populations were significantly increased in both subsets, whereas no significant differences were observed in stage III–IV disease. Additionally, CD56⁺ NKp46⁺ NKG2D⁻ cells showed a significant inverse correlation with the rASRM score.

Conclusion: Altered uNK cell phenotypes, particularly those involving NKp46 expression, characterize the eutopic endometrium in endometriosis-associated infertility. Both CD56^bright and CD56^dim uNK cell subsets showed increased NKp46+ populations, particularly in early-stage endometriosis. These subset-specific changes suggest immune dysregulation that may affect NK-cell cytotoxicity and reproductive function. Larger cohorts with integrated functional assays are needed to clarify the biological and clinical significance of these receptor alterations.