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

Alfin Firasy Mufid, Fadhil Ahsan, Budi Santoso, Nanda Yuli Rahmawati, Fidyah Nanda Alditia
In: Journal of Reproduction & Infertility · 2026 · doi:10.18502/jri.v27i2.23147 · W7225065403
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Flow cytometry analysis of endometrial biopsies revealed that women with endometriosis-associated infertility exhibit increased NKp46-expressing uterine natural killer cell subsets, particularly in early-stage disease.

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This study investigated the expression of uterine natural killer cell activation markers NKp46 and NKG2D in infertile women with endometriosis compared to controls. Flow cytometry analysis of endometrial biopsies revealed that both CD56bright and CD56dim uNK cell subsets exhibited significantly increased proportions of NKp46-positive populations in patients with the disease. These alterations were most pronounced in early-stage (rASRM stage I–II) cases, where NKp46-negative NKG2D-negative cells also increased, while no significant differences were observed in advanced stages. The findings indicate that altered uNK cell phenotypes characterize the eutopic endometrium in endometriosis-associated infertility, although the authors note that larger cohorts are needed to clarify clinical significance. This paper is centrally about endometriosis — specifically examining immune dysregulation in the context of associated infertility.

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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 CD56bright and CD56dim 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 CD56dim compartment, both populations increased significantly (p=0.012 and p=0.030, respectively), with comparable increases in CD56bright 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 CD56bright and CD56dim 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.
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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 CD56bright and CD56dim 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 CD56dim compartment, both populations increased significantly (p=0.012 and p=0.030, respectively), with comparable increases in CD56bright 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 CD56bright and CD56dim 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.

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