The dynamic changes in the number of uterine natural killer cells are specific to the eutopic but not to the ectopic endometrium in women and in a baboon model of endometriosis.

BACKGROUND: Endometriosis is a common condition associated with growth of endometrial-like tissue beyond the uterine cavity. Previous reports have suggested a role for uNK cells in the pathogenesis of endometriosis postulating that survival and accumulation of menstrual endometrial tissue in the peritoneal cavity may relate to a reduction in the cytotoxic activity of peripheral blood NK cells. We aimed to assess the differences in percentage of uNK cells and their phenotypical characterization in eutopic and ectopic endometrial samples from women with and without endometriosis and baboons with induced endometriosis. METHODS: Eutopic and ectopic endometrial samples from 82 women across the menstrual cycle with/without endometriosis and from 8 baboons before and after induction of endometriosis were examined for CD56 and NKp30 expression with immunohistochemistry, quantified using computer assisted image analysis. Curated secretory phase endometrial microarray datasets were interrogated for NK cell receptors and their ligands. In silico data was validated by examining the secretory phase eutopic endometrium of women with and without endometriosis (n = 8/group) for the immuno-expression of BAG6 protein. RESULTS: The percentage of uNK cells increased progressively from the proliferative phase with the highest levels in the late secretory phase in the eutopic endometrium of women with and without endometriosis. The percentage of uNK cells in ectopic lesions remained significantly low throughout the cycle. In baboons, induction of endometriosis increased the percentage of uNK in the ectopic lesions but not NKp30. Published eutopic endometrial microarray datasets demonstrated significant upregulation of NKp30 and its ligand BAG6 in women with endometriosis compared with controls. Immunohistochemical staining scores for BAG6 was also significantly higher in secretory phase eutopic endometrium from women with endometriosis compared with the endometrium of healthy women (n = 8/group). CONCLUSIONS: The dynamic increase in the percentage of uNK cells in the secretory phase is preserved in the endometrium of women with endometriosis. The low number of uNK cells in human and baboon ectopic lesions may be due to their exaggerated reduction in hormonal responsiveness (progesterone resistance).

Uterine Leukocyte Function and Dysfunction: A Hypothesis on the Impact of Endometriosis.

Endometriosis is a chronic inflammatory disease characterized by the growth of endometrial glands and stroma outside of the uterus. The disease affects approximately 10-15% of women of reproductive age and presents with clinical symptoms of pelvic pain and infertility. Changes in the leukocyte populations within the ectopic tissue and eutopic endometrium have been reported, and data suggest these alterations contribute to the pathology and symptoms of the disease. In this review, we discussed differences when comparing uterine NK cells and regulatory T cells within the eutopic endometrium between patients with endometriosis and healthy patients, and how these differences relate to implantation failure and/or decreased clearance of menstrual tissue in patients with the disease. The data demonstrate a critical need to examine endometrium and menstrual tissue in patients with endometriosis excluded from studies examining unknown causes of infertility and heavy menstrual bleeding. The information gathered from excluded patients will further enhance our understanding of how the immune system contributes to the pathophysiology of endometriosis and help to identify biomarkers for patients at higher risk for developing endometriosis-associated infertility.

Characterization of uterine NK cells in women with infertility or recurrent pregnancy loss and associated endometriosis.

PROBLEM: Uterine natural killer cells (uNK) have been thought to play a key role in endometriosis and infertility. We investigated the expression of CD56, CD16, and NKp46 in endometrial tissues from 61 women with unexplained recurrent pregnancy loss (uRPL) or infertility (UI) and correlated this with the presence or absence of endometriosis. The results from the patients with subfertility were compared with those from 10 fertile patients. METHOD OF STUDY: Mid-secretory phase endometrial biopsies were obtained, and the endometrial expression of CD56, CD16, or NKp46 was identified by immunohistochemistry and quantified (ImageJ Software). RESULTS: The percentage of CD16(+) cells was higher in women with uRPL (7.9 ± 3.2) and UI (9.0 ± 5.5), even when these conditions were associated with endometriosis (8.9 ± 5.3), compared with fertile patients (5.6 ± 2.4, P < 0.05). Likewise, the ratio of NKp46(+) :CD56(+) cells was higher in women with uRPL (0.28 ± 0.25) and UI (0.21 ± 0.2), even when these conditions were associated with endometriosis (0.19 ± 0.14), compared with fertile patients (0.1 ± 0.1, P < 0.05). No differences were observed when comparing CD56. CONCLUSIONS: Women, with or without endometriosis, who have larger populations of cytotoxic CD16(+) uNK cells and/or higher populations of NKp46(+) CD56(+) cells may be at greater risk of infertility disorders resulting from an inflammatory environment occurring during implantation or later during decidualization.