Functional NK surrogate biomarkers for inflammatory recurrent pregnancy loss and recurrent implantation failure

Abstract

Problem: Expansion of circulating NK cells has been related to pregnancy complications. This study aims at investigating several surface NK cell markers to identify a baseline inflammatory profile in women with recurrent pregnancy loss (iRPL) and recurrent implantation failure (iRIF).

Method of study: Expression of NKp30, TIGIT, NKp46, and DNAM-1 on total peripheral blood NK subsets, regulatory (CD56^bright CD16^neg ), and cytotoxic (CD56^dim CD16^pos/neg ) NK cells was measured.

Results: Eighty-three women were recruited and classified into two groups, 58 women with RPL and 25 with RIF. A control group of 31 fertile women was included. Expression of NKp30 on cytNK was significantly higher in RPL (p = .019) and RIF (p < .001) than HC. TIGIT on cytNK cells was also higher in both RPL (p < .001) and RIF (p < .01). An optimal cutoff of 70% for NKp30⁺ cytNK disclosed a sensitivity of 82%, a specificity of 55%, and 83% PPV for RPL diagnosis. A cutoff level of 83% for TIGIT⁺ cytNK was chosen to discriminate between healthy controls and RPL women, with PPV of 84%.

Conclusion: Our preliminary data on this RPL and RIF cohorts suggest a simple diagnostic tool by combining NKp30 and TIGIT on cytNK cells to better identify a subgroup of RPL and RIF patients with a baseline inflammatory profile. A more rigorous selection of these patients through phenotyping peripheral cytNK cells may better define patients that could benefit from an immunomodulatory treatment to prevent further pregnancy losses. The performance of these biomarkers requires further investigation and validation in independent cohorts.

Keywords: NKp30; T-cell immunoglobulin and ITIM domain; cytotoxic NK cells; inflammation; recurrent implantation failure; recurrent pregnancy loss.