Expression of Natural Cytotoxicity Receptors on Peritoneal Fluid Natural Killer Cell and Cytokine Production by Peritoneal Fluid Natural Killer Cell in Women with Endometriosis

Funamizu, Ayano; Fukui, Atsushi; Kamoi, Mai; Fuchinoue, Kohei; Yokota, Megumi; Fukuhara, Rie; Mizunuma, Hideki

doi:10.1111/aji.12206

Cited by 50 publications

(49 citation statements)

References 30 publications

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“…However, most of the studies to date have focused primarily on secreted chemokine profiles (20) or immune cells resident in the peritoneal cavity (macrophages, NK cells) or isolated from circulation (T lymphocytes, NK cells) (33, 34). We performed here the first comprehensive immune gene expression analysis of pelvic inflammation to date, using a collection of 511 Nanostring probes and RNA extracted from affected tissues.…”

Section: Discussionmentioning

confidence: 99%

Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer

Suryawanshi

Huang

Elishaev

et al. 2014

Clinical Cancer Research

101

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Purpose Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC). Experimental design RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n=32), benign endometriosis (n=30), atypical endometriosis (n=15) and EAOC (n=43). Serous tumors (n=15) were included as non-endometriosis associated controls. The immune microenvironment was profiled using Nanostring and the nCounter® GX Human Immunology Kit, comprising probes for a total of 511 immune genes. Results One third of the endometriosis patients revealed a tumor-like inflammation profile, suggesting that cancer–like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial (OSE) cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation. Conclusions These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC.

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Section: Discussionmentioning

confidence: 99%

Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer

Suryawanshi

Huang

Elishaev

et al. 2014

Clinical Cancer Research

101

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“…It has been stated that an increase in the killer inhibitory receptor (KIR) on NK cells, leads to a reduction of their cytotoxic activity over the endometrial cells [51,52]. Other NK receptors such as natural cytotoxicity receptors have also been studied and showed differences between patients and controls [53]. …”

Section: Discussionmentioning

confidence: 99%

Soluble Ligands for the NKG2D Receptor Are Released during Endometriosis and Correlate with Disease Severity

et al. 2015

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BackgroundEndometriosis is a benign gynaecological disease. Abundant bulk of evidence suggests that patients with endometriosis have an immunity dysfunction that enables ectopic endometrial cells to implant and proliferate. Previous studies show that natural killer cells have a pivotal role in the immune control of endometriosis.Methods and FindingsThis is a prospective laboratory study conducted in a tertiary-care university hospital between January 2011 and April 2013. We investigated non-pregnant, younger than 42-year-old patients (n= 202) during surgery for benign gynaecological conditions. After complete surgical exploration of the abdominopelvic cavity, 121 women with histologically proven endometriosis and 81 endometriosis-free controls women were enrolled. Patients with endometriosis were classified according to a surgical classification in three different types of endometriosis: superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA) and deep infiltrating endometriosis (DIE). Peritoneal fluid samples were obtained from all study participants during the surgery in order to detect soluble NKG2D ligands (MICA, MICB and ULBP-2). When samples with undetectable peritoneal fluid levels of MICA, MICB and ULBP-2 were excluded, MICA ratio levels were significantly higher in endometriosis patients than in controls (median, 1.1 pg/mg; range, 0.1–143.5 versus median, 0.6 pg/mg; range, 0.1–3.5; p=0.003). In a similar manner peritoneal fluid MICB levels were also increased in endometriosis-affected patients compared with disease-free women (median, 4.6 pg/mg; range, 1.2–4702 versus median, 3.4 pg/mg; range, 0.7–20.1; p=0.001). According to the surgical classification, peritoneal fluid soluble MICA, MICB and ULBP-2 ratio levels were significantly increased in DIE as compared to controls (p=0.015, p=0.003 and p=0.045 respectively). MICA ratio levels also correlated with dysmenorrhea (r=0.232; p=0.029), total rAFS score (r=0.221; p=0.031) and adhesions rAFS score (r=0.221; p=0.031).ConclusionsWe demonstrate a significant increase of peritoneal fluid NKG2D ligands in women with endometriosis especially in those cases presenting DIE. This study suggests that NKG2D ligands shedding is a novel pathway in endometriosis complex pathogenesis that impairs NK cell function.

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“…50 Peritoneal fluid from women with endometriosis exposed to NK cells in vitro reduced cytotoxicity in NK cells, 51 Studies that focus on cytokines in the peritoneal cavity may give insight into the immune-modulating properties of the peritoneal fluid. 52,58,59 Interestingly, a correlation between TNF-a levels and endometriosis-related pain has been described. However, studies are conflicting showing IFN-c levels in the peritoneal fluid to be increased, 52 reduced 53,54 and unchanged.…”

Section: Cytokines and Chemokines In The Peritoneal Cavity: Relevancementioning

confidence: 99%

Natural Killer Cells: Key Players in Endometriosis

Thiruchelvam

Wingfield

O’Farrelly

2015

American J Rep Immunol

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Endometriosis affects more than 10% of women, causing significant pain and morbidity. It is also a significant cause of infertility. The aetiology of the disease remains an enigma, and the mechanisms responsible for the associated infertility are unclear. A role for immune cells in endometriosis has been postulated, with attention directed towards natural killer (NK) cells and macrophages. NK cells kill tumours and infected cells but also have roles in tissue remodelling in several organs including the uterus and are key to successful pregnancy. Here, we explore evidence (from peer-reviewed published articles) of phenotypic and functional abnormalities in NK cell subpopulations of women with endometriosis. It is clear that peripheral blood NK cells and peritoneal NK cells have reduced cytotoxic function in women with endometriosis. Uterine NK cells have a vital role in infertility, but very little research has been carried out in this area. We propose that abnormal u NK cell activity may contribute to the pathogenesis of endometriosis and its associated infertility and that future research should focus on this complex area.

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Expression of Natural Cytotoxicity Receptors on Peritoneal Fluid Natural Killer Cell and Cytokine Production by Peritoneal Fluid Natural Killer Cell in Women with Endometriosis

Cited by 50 publications

References 30 publications

Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer

Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer

Soluble Ligands for the NKG2D Receptor Are Released during Endometriosis and Correlate with Disease Severity

Natural Killer Cells: Key Players in Endometriosis

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