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.