Peripheral blood natural killer cell cytotoxicity in recurrent miscarriage: a systematic review and meta-analysis

Historically, recurrent miscarriage (RM) was defined as the occurrence of three or more spontaneous abortions, preceded (secondary RM) or not (primary RM) by any pregnancy that has progressed for more than 20 weeks gestation (WHO, 1977). In 2009, the American Society for Reproductive Medicine (ASRM) updated the definition of RM as the occurrence of two or more miscarriages (Zegers-Hochschild et al., 2009). RM can affect 0.5–2.5 % of reproductive-age couples (Ford and Schust, 2009, Christiansen, 2021). Yet, the causes of RM have not been fully determined; the majority of international societies in the field of reproductive medicine recommend the investigation of genetic, hormonal, anatomical factors and antiphospholipid antibody syndrome (APS) as an initial workup for RM (ASRM, 2012; Bender Atik et al., 2018; Vomstein et al., 2021). Following this guideline, about half of the patients may identify underlying causes of RM (RCOG, 2011; ASRM, 2012; Bender Atik et al., 2018; Toth et al., 2018; Vomstein et al., 2021). Although autoimmune and alloimmune abnormalities are often associated with RM, the investigation of these immunological conditions, except APS, has not been recommended by international medical societies (Vomstein et al., 2021).

Natural killer (NK) cells belong to the innate immune system and are responsible for recognizing virus-infected, cancerous, or foreign cells (Cooper et al., 2001). In women, uterine NK (uNK) cells and peripheral blood NK (pNK) cells are crucial in the process of embryo implantation and placenta formation by regulating trophoblast invasion, angiogenesis, and remodeling of uterine spiral arteries, while protecting the fetus against infectious pathogens (Guerrero et al., 2020, Díaz-Hernández et al., 2021).

Studies have suggested that uNK cells may originate from three sources: (1) resident CD34 + hematopoietic progenitor cells (HPC) in the endometrium, (2) peripheral blood HPC, and (3) mature pNK cells or immature pNK precursors (Díaz-Hernández et al., 2021, Strunz et al., 2021, Xie et al., 2022). Peripheral blood HPC-derived NK cells and pNK precursors migrate into the endometrium in response to cytokines and chemokines produced by endometrial cells during the luteal phase and by trophoblasts in early pregnancy and modify their phenotypes by various uterine factors (King et al., 1991, Strunz et al., 2021).

The uNK cells preferentially produce cytokines (e.g., IFN-γ and TNF-α), but they are poorly cytotoxic, despite their abundant intracellular granules that contain granzyme, granulysin, and perforin (Lash et al., 2010, Xie et al., 2022). Considering these characteristics, the frequency of uNK cells at the maternal-fetal interface, specific phenotype, and ability to identify trophoblastic cells, uNK cells seem to play a key role in pregnancy success (Guerrero et al., 2020, Díaz-Hernández et al., 2021, Xie et al., 2022). Immature uNK cells or elevated cytotoxic activity appears to increase the risk of reproductive failure (Chao et al., 1995, Manaster et al., 2008, Bao et al., 2012, Li et al., 2019, Lédée et al., 2020). Additionally, women with a history of reproductive failure show abnormal expression of endometrial markers associated with uNK cells, such as granzyme, IL-15, and NKp46 (Lédée et al., 2020; Dambaeva et al., 2020; Yamamoto et al., 2022).

pNK cells originate from hematopoietic stem cells. Mature pNK cells account for 5–10 % of peripheral blood lymphocytes (Cooper et al., 2001). The majority (over 90 %) of pNK cells express low-density CD56 and CD16 (CD56dimCD16+), while approximately 10 % of pNK cells have a high-density surface expression of CD56 without CD16 expression (CD56brightCD16-) (Cooper et al., 2001). CD56dim pNK cells are predominantly cytotoxic, while the CD56bright NKs have an immunoregulatory function.

Studies have suggested that women with dysregulated pNK cells have a higher risk of RM and recurrent implantation failure (RIF) (Cai et al., 2022, Kwak-Kim et al., 2022, Salazar et al., 2022, Von Woon et al., 2022). The abnormalities in pNK cells can be identified by determining cell numbers and proportion, cell surface receptors, including those for activation and maturation, intracellular proteins and mediators, NK cell repertoire, gene expression, and evaluation of effector functions (King et al., 2010, Viel et al., 2013, Kwak-Kim et al., 2022). Determining the percentage and number of pNK cells by flow cytometry is a relatively simple way to identify NK cell disorders, bringing in multiple studies of pNK cell abnormalities in women with RM and infertility. The meta-analysis by Seshadri and Sunkara revealed a higher proportion (%) and a number of pNK cells in women with RM and a significantly higher number of pNK cells in women with infertility than controls. However, the live birth rates in women undergoing IVF did not differ between women with and without elevated NK cell numbers or activity, limiting its clinical application (Seshadri and Sunkara, 2014, Kwak-Kim et al., 2022).

Determining cytotoxicity by measruing the percentage of dead target cells is an established method of evaluating pNK effector function (Pross and Maroun, 1984, Viel et al., 2013). Several methods for evaluating NK cell cytotoxicity (NKC) have been assessed. The 51chromium release assay (51CrRA) was initially considered the gold standard for measuring NKC (Pross and Maroun, 1984). Later, due to the risk of radiation exposure during 51CrRA, other non-radioactive methods were developed, such as flow cytometry-based methods (Kane et al., 1996, Gilman-Sachs et al., 1999). The pNKC assay by flow cytometry investigates pNKC (defined as effector cells [E]) to K562 cells (defined as target cells [T]), without using radioactive dyes in different E:T ratios (Gilman-Sachs et al., 1999). K562 cells, human erythromyelocytic leukemia cells, are characterized by not expressing the major histocompatibility complex, which is necessary to inhibit NK cell activity, and can be easily killed by NK cells (Lozzio and Lozzio, 1975, Kane et al., 1996, Gilman-Sachs et al., 1999).

Several studies have reported a progressive reduction in pNKC in all trimesters of uncomplicated pregnancies (Kane et al., 1996, Yamada et al., 2001). On the other hand, the increase in the cytotoxic activity of pNK cells has been associated with a high risk of miscarriage and implantation failure (Yamada et al., 2001, Kwak-Kim et al., 2022). Thus, regulating pNKC before and during pregnancy may improve pregnancy outcomes. However, the safety and efficacy of the routine use of immunotherapies, such as intravenous human immunoglobulin (IVIG), lymphocyte immunotherapy (LIT), and corticosteroids, for women with unexplained RM (uRM) still need to be investigated further (Wong et al., 2014; Anon, 2018; Saab et al., 2021; Francisco et al., 2022; Ma et al., 2022). The main challenge is the lack of criteria for selecting candidates for these therapeutic approaches. The recent meta-analysis of women with RM and RIF revealed that women with abnormal NK cell levels and immune abnormalities have significantly higher live birth rate with IVIg treatment than controls (Abdolmohammadi-Vahid et al., 2019, Woon et al., 2020). Some authors argue that the NKC assay can be used as a screening tool to select patients with uRM and RIF for immunotherapies and monitor the response (Katano et al., 1997, Roussev et al., 2007, Kwak-Kim et al., 2022).

Thus, the objectives of this systematic review and meta-analysis are (1) to determine if women with RM have different pNKC than those without RM and (2) to assess whether immunotherapies can decrease the pNKC in RM patients.

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