Uterine natural killer cells in peri-implantation endometrium from women with repeated implantation failure after IVF
Introduction
The endometrial leukocyte population consists mainly of uterine natural killer cells (uNK), macrophages and T cells (Johnson et al., 1999) and is distinctly different to that of peripheral blood. In contrast to NK cells found in the peripheral blood the majority of uNK cells express CD56 and CD38, but not the classical T cell or NK cell markers CD3, CD4, CD8, CD16 and CD57 (Bulmer et al., 1991). The number of CD56+ cells varies through the menstrual cycle, with a dramatic increase in the mid-secretory phase starting 6–7 days after the LH surge, the beginning of the putative time of implantation. The number of CD56+ cells remains high during early pregnancy and comprises 70% of the lymphocytes at the interface between maternal decidua and the invading trophoblast (Bulmer, 1996).
Uterine NK cells can be divided into two populations. Approximately 10% of the cells are CD56+ CD16+, which are similar but not identical to peripheral NK cells, while 90% of the population are CD56+ CD16− in phenotype. CD56+ CD16+ and CD56+ CD16− uNK cells are functionally different; CD16+ cells are cytolytic whereas CD16− uNK cells secrete cytokines (Laird et al., 2003).
The number of cells present gives no indication of the activation status of these cells. CD69 is an early activation marker transiently present on lymphocytes including NK cells. It causes the triggering of lysis by activated NK cells. One study has shown that the numbers of CD69+ cells are constant through the cycle, with a decrease in early pregnancy (Vassiliadou and Bulmer, 1998), while another has suggested higher numbers of CD69+ cells in the secretory than the proliferative phase, and increased numbers in the decidua (Zabinska-Popiela et al., 2006).
One of the limiting steps in in vitro fertilization (IVF) is embryo implantation failure. This may be due to embryonic or endometrial factors or a combination of the two. For women who experience repeated implantation failure with good quality embryos it is likely that an endometrial factor may be the cause. Despite numerous studies including microarray and genomic analysis (Strowitzki et al., 2006, Aghajanova et al., 2008) the identification of the factors important for implantation remains elusive. Three immunocytochemical studies have shown a higher number of CD56+ cells in mid luteal endometrial biopsies taken from women with a history of repeated miscarriage compared to normal control women (Quenby et al., 1999, Clifford et al., 1999, Tuckerman et al., 2007). In one of these studies, the numbers of endometrial CD16+ cells and CD69+ cells (Quenby et al., 1999) were also higher in the women with RM compared to controls. Other studies have suggested that it is the CD56+ CD16+ subpopulation of CD56+ cells that are most important in pregnancy failure, particularly in miscarriage (Lachapelle et al., 1996, Emmer et al., 2002).
Recent studies have shown an increased number of CD56+ cells in the endometrium of women with repeated implantation failure after IVF (Ledee-Bataille et al., 2004, Ledee-Bataille et al., 2005). However in this study patients received oestradiol and progesterone during the study cycle. As far as we are aware the number of CD56+ cells in endometrium from women with recurrent implantation failure without steroid supplementation has not been described. In this study we compare the number of CD56+, CD16+ and CD69+ cells in timed, un-stimulated, secretory endometrium from 40 women with recurrent implantation failure and compare it to the number of CD56+, CD16+ and CD69+ cells in endometrium from 15 normal control women.
Section snippets
Subjects
Local ethical approval and written informed patient consent was obtained for this study. Recurrent implantation failure was defined as the failure of good quality embryos to implant after either at least 3 cycles of IVF, or 2 cycles of IVF plus 2 cycles in which frozen embryos were replaced. Biopsies were collected from 40 women with unexplained recurrent implantation failure who were attending the Assisted Conception Unit at the Jessop Wing, Sheffield Teaching Hospitals, Sheffield, UK. In
Hormone analysis in women with recurrent implantation failure and controls
Table 1 shows the age and serum hormone concentrations of control women and women with recurrent implantation failure. The mean age of the women in the recurrent implantation failure group was 35 (range 26–40) years, while that in the control group was 35 (range 29–40) years. There was no significant difference in the mean age of women in the two groups and the proportion of women over the age of 37 was also similar (10/40, 25% in the recurrent implantation failure group and 5/15, 33% in the
Acknowledgements
We would like to thank the staff at the assisted conception unit at the Jessop Wing, Sheffield Teaching Hospitals for their help in the collection of endometrial biopsy samples.
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2023, Reproductive BioMedicine OnlineEstablishment of reference intervals of endometrial immune cells during the mid-luteal phase
2023, Journal of Reproductive ImmunologyCD200S-positive granulated lymphoid cells in endometrium appear to be CD56-positive uterine NK cells
2022, Journal of Reproductive ImmunologyCitation Excerpt :In our opinion, this seems physiologically misleading. Even so, uNK cell counts that are above or below the range of normal fertile female endometrium has been related to infertility and recurrent miscarriages (Tuckermann et al., 2007, 2010; Drury et al., 2011; Santillan et al., 2015; Chen et al., 2017). A local inflammatory reaction is required for implantation of the blastocyst, but then as the embryo produces CD200L, the inflammatory process is suppressed, and from our data on EM (where infertility may be present), elevated concentrations of CD200S+ cells which persist in the post-implantation secretory endometrium could be predicted to cause embryo failure.