Background
Recurrent miscarriage (RM) is defined as two or more spontaneous abortions prior to 20 weeks of gestation (1). It affects approximately 1-3% of women of child-bearing age in worldwide. The etiology of RM is often unknown and the prognosis is always frustrating. Embryo implantation and growth are fundamental for a normal pregnancy, and cytokines, hormones, and endometrial factors are involved in the regulation of both stages (2).
As a large granular lymphocyte in the innate immune system, peripheral natural killer (pNK) cell can be in contact with the villus through the intervillous space. In addition, pNK cells are recruited by the endometrium to participate in the decidualization. Moreover, pNK cells were believed to do harm to pregnancy by exerting cytotoxicity. Some studies showed that the absolute number and ratio of pNK are increased in RM patients, when compared to fertile women (3, 4). However, other studies showed that there was no significant difference in pNK cytotoxicity between healthy controls and women with RM or infertility (5, 6). Therefore, the association between pNK cytotoxicity and RM remains controversial and further research is needed.
The cytotoxic activity of pNK is exerted by the production of cytotoxic granules such as granzymes, granulysin, and perforin. Granulysin with positive charge binds the negatively charged cell membrane, leading to membrane damage (7). Perforin binds to the cell membrane of the target cell to form cylindrical pores that allow the passive diffusion of pro-apoptotic proteases (8) such as the granzymes, which induce cell apoptosis by activating the caspases (9). A higher level of perforin expressed by the uterine NK cells was found in cases of human sporadic miscarriage (10). However, it is still unclear whether the expression of granulysin, perforin, and granzymes are altered in pNK cells of RM patients.
The balance between activating receptors and inhibitory receptors regulates the release of cytotoxic granules from pNK cells (11). The activating receptors NKp30, NKp46 and NKG2D, activate and regulate the secretion of cytotoxic granules (12-14). The inhibitory receptors CD158a and CD158b, transmit inhibitory signals by their immunoreceptor tyrosine-based inhibitory motifs (15). The balance between these two types of receptors determines the cytotoxic activity of NK cells. However, up to now, little is known regarding the expression of these activating and inhibitory receptors in the peripheral blood NK cells in women with RM.
Therefore, in this study, the potential correlations between RM and the percentage and cytotoxicity of pNK cells were investigated, together with the expression of cytotoxic granules, surface activating receptors and inhibitory receptors in pNK.