286. The role of uterine natural killer cells in causing irregular bleeding in HT users

2005 ◽  
Vol 17 (9) ◽  
pp. 120
Author(s):  
M. Hickey ◽  
J. M. Crewe ◽  
D. Doherty ◽  
I. S. Fraser ◽  
L. A. Salamonsen
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Density ◽  
Absolute Number ◽  
Cell Populations ◽  
Unk Cells ◽  
Irregular Bleeding ◽  
Uterine Nk Cells ◽  
Unk Cell ◽  
Uterine Natural Killer

Menopausal hormone therapy (HT) causes irregular bleeding in up to 60% of user. This is extremely unpopular with patients, and commonly leads to invasive and expensive investigations to rule out underlying pelvic pathology. In most cases no cause is found. The aim of this study was to further elucidate the mechanisms of vascular fragility. Uterine NK cells are known to increase vascular fragility during the normal menstrual cycle. We hypothesise that HT is associated with an increase in uterine natural killer (uNK) cells. Eighty six endometrial biopsies were obtained from 59 postmenopausal users of continuous combined HT. Uterine NK cells were identified using immunohistochemistry as being CD56+. Image analysis was used to identify absolute number of CD56+ cells and their distribution within the stroma. Endometrial histology was classified using Noyes criteria. A statistically significant increase in endometrial uNK cell density was observed in HT users compared to postmenopausal women not using HT (P < 0.001). uNK cell populations were more marked in biopsies taken during a bleeding episode compared to those HT users with amenorrhoea (P = 031). uNK cells are a major regulator of endometrial vascular integrity and are known to be disrupted in irregular bleeding with progestin only contraceptives. This is the first study to report the presence of uNK cells in postmenopausal endometrium and the first to report a significant association between bleeding patterns and uNK cell density. We postulate that HT induces an increase in endometrial uNK cell populations and that their presence stimulates endometrial vascular fragility leading to bleeding.

scholarly journals Proliferation of Uterine Natural Killer Cells Is Induced by Human Chorionic Gonadotropin and Mediated via the Mannose Receptor

Endocrinology ◽  
2009 ◽  
Vol 150 (6) ◽  
pp. 2882-2888 ◽  
Author(s):  
Nicole Kane ◽  
Rodney Kelly ◽  
Philippa T. K. Saunders ◽  
Hilary O. D. Critchley
Keyword(s):  
Natural Killer ◽  
Mannose Receptor ◽  
Lh Receptor ◽  
Uterine Natural Killer Cells ◽  
Unk Cells ◽  
The Impact ◽  
Insight Into ◽  
Unk Cell ◽  
Uterine Natural Killer

The endometrial lining of the human uterus contains a population of phenotypically distinct (CD56bright, CD16dim), tissue-specific, natural killer [uterine natural killer (uNK)] cells that play a key role in the establishment of a successful pregnancy. An increase in the number of endometrial uNK cells occurs when the conceptus implants, and there is a further increase during the early stages of placentation. Here, we describe studies that have identified human chorionic gonadotrophin (hCG), a glycoprotein synthesized by the preimplantation conceptus, as a novel regulator of uNK cell proliferation. The impact of hCG on uNK cells was mediated via the mannose receptor (CD206) rather than by the classical hCG/LH receptor that was not expressed. The mannose receptor and hCG were colocalized on the surface of uNK cells, and proliferation did not occur if cells were incubated with deglycosylated hCG or intact hCG in the presence of excess d-Mannose. These novel observations provide new insight into the endocrine-immune dialogue that exists between the conceptus and immune cells within the receptive endometrium, and have implications for the role of uNK cell-trophoblast interactions and pregnancy outcome.

scholarly journals The Roles of Uterine Natural Killer (NK) Cells and KIR/HLA-C Combination in the Development of Preeclampsia: A Systematic Review

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Xiuhua Yang ◽  
Yahui Yang ◽  
Yiru Yuan ◽  
Lin Liu ◽  
Tao Meng
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Systemic Disease ◽  
Killer Cell ◽  
Inflammatory Factors ◽  
Placental Development ◽  
Multiple Organs ◽  
Unk Cells ◽  
Exact Etiology ◽  
Uterine Natural Killer

Preeclampsia (PE) is termed as a systemic disease that involves multiple organs; however, the exact etiology is still quite unclear. It is believed that the poor remodeling of uterine spiral arteries triggers PE, thereby causing failed placentation and producing inflammatory factors. The decline of blood flow results in lowering the nutrients and oxygen received by the fetus and augmenting the placental pressure in PE. Decidual immune cells, especially uterine natural killer (uNK) cells, are involved in the process of placentation. Decidual NK (dNK) cells significantly contribute to the vascular remodeling through the secretion of cytokines and angiogenic mediators in normal placental development. The abnormal activation of NK cells in both the peripheral blood and the decidua was counted among the causes leading to PE. The correlation existing between maternal killer cell immunoglobulin-like receptor (KIR) and HLA-C in trophoblast cells constitutes a robust evidence for the genetic etiology of PE. The combinations of the two kinds of gene systems, together with the KIR genotype in the mother and the HLA-C group in her fetus, are likely to exactly decide the pregnancy outcome. The women, who have the inappropriate match of KIR/HLA-C, are likely to be prone to the augmented risk of PE. However, the combinations of KIR/HLA-C in PE undergo ethnic changes. The extensive prospective research works in Europe, Asia, and Africa are required for providing more findings in PE patients.

scholarly journals Gene Expression Profiling of the Paracrine Effects of Uterine Natural Killer Cells on Human Endometrial Epithelial Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Xin Gong ◽  
Zhenzhen Chen ◽  
Yanxia Liu ◽  
Qiudan Lu ◽  
Zhe Jin
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Natural Killer ◽  
Paracrine Effects ◽  
Unk Cells ◽  
Interleukin 15 ◽  
Factor C ◽  
Unk Cell ◽  
Endometrial Epithelial Cells ◽  
Uterine Natural Killer

The endometrium contains a population of immune cells that undergo changes during implantation and pregnancy. The majority of these cells are uterine natural killer (uNK) cells; however, it is unclear how these cells interact with endometrial epithelial cells. Therefore, we investigated the paracrine effects of the uNK cell-secretion medium on the gene expression profile of endometrial epithelial cellsin vitrothrough microarray analysis. Our results, which were verified by qRT-PCR and western blot, revealed that soluble factors from uNK cells alter the gene expression profiles of epithelial cells. The upregulated genes included interleukin-15 (IL-15) and interleukin-15 receptor alpha (IL-15RA), which result in a loop that stimulates uNK cell proliferation. In addition, vascular endothelial growth factor C (VEGF-C) and chemokine (C-X-C motif) ligand 10 (CXCL-10) were also determined to be upregulated in epithelial cells, which suggests that uNK cells work synergistically with epithelial cells to support implantation and pregnancy. In addition, oriental herbal medicines have been used to treat infertility since ancient times; however, we failed to find that Zi Dan Yin can regulate these endometrial paracrine effects.

scholarly journals 4307 Role of Pre-pregnancy Uterine Natural Killer Cells in Human Embryo Implantation

2020 ◽  
Vol 4 (s1) ◽  
pp. 102-102
Author(s):  
Jessica Kanter ◽  
Sneha Mani ◽  
Scott Gordon ◽  
Monica Mainigi
Keyword(s):  
Natural Killer ◽  
Tunel Staining ◽  
Spiral Artery ◽  
Secretory Phase ◽  
Potential Marker ◽  
Unk Cells ◽  
Artery Remodeling ◽  
Unk Cell ◽  
Uterine Natural Killer

OBJECTIVES/GOALS: Human placentation requires complex coordination between maternal and fetal cell types but remains incompletely understood. We hypothesize that uterine natural killer (uNK) cells, an immune cell type that increases in abundance during the implantation window, is essential for appropriate implantation and placentation. METHODS/STUDY POPULATION: We plan to examine stromal cell (SC) decidualization, spiral artery remodeling, and EVT invasion, processes vital for early pregnancy establishment, in the presence or absence of secretory phase uNK cells. Fetal extravillous trophoblasts (EVTs) will be isolated from first trimester pregnancy tissue; maternal SCs, endothelial cells (ECs) and uNK cells will be obtained from secretory phase uterine tissue. SCs will be placed in monoculture and coculture with uNK cells and prolactin will be measured to evaluate decidualization. To study EVT invasion, we will utilize our novel “implantation-on-a-chip” device to determine how addition of uNK cells affects EVT migration through a collagen-matrigel matrix. In this system, we will also examine spiral artery remodeling with or without uNK cells via TUNEL staining. RESULTS/ANTICIPATED RESULTS: We anticipate that uNK cell addition to SCs will lead to a significant increase in SC prolactin levels, suggesting a role of uNK cells in endometrial decidualization. In vitro, we expect the addition of uNK cells will increase EC apoptosis and promote EVT invasion. DISCUSSION/SIGNIFICANCE OF IMPACT: Although decidual NK cells are known to participate in placentation, the role of pre-pregnancy uNK cells is unknown. uNK cell involvement in processes important for the earliest stages of pregnancy would provide a potential marker for abnormal placentation and offer avenues for intervention to decrease placentation associated perinatal morbidity.

scholarly journals Elevated Periimplantation Uterine Natural Killer Cell Density in Human Endometrium Is Associated With Impaired Corticosteroid Signaling in Decidualizing Stromal Cells

2013 ◽  
Vol 98 (11) ◽  
pp. 4429-4437 ◽  
Author(s):  
Keiji Kuroda ◽  
Radha Venkatakrishnan ◽  
Sean James ◽  
Sandra Šućurović ◽  
Biserka Mulac-Jericevic ◽  
...  
Keyword(s):  
Natural Killer ◽  
Cell Density ◽  
Stromal Cells ◽  
Target Genes ◽  
Killer Cell ◽  
Surface Epithelium ◽  
Transport Pathway ◽  
Unk Cell ◽  
Uterine Natural Killer

Background: Decidualizing human endometrial stromal cells (HESCs) profoundly up-regulate 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1), the enzyme that converts inert cortisone to active cortisol. We postulated that the induction of a cortisol gradient upon decidualization of the periimplantation endometrium may impact on the uterine natural killer (uNK) cell population and on local expression of corticosteroid-dependent target genes. Methods: Midluteal endometrial biopsies (n = 55) were processed for uNK cell (CD56) analysis and primary HESC cultures. The cultures remained either untreated or were decidualized for 4 or 8 days. A tissue microarray was constructed from endometria with normal (n = 18) and elevated uNK cell (n = 18) scores. An abnormal uNK cell test was defined as greater than 5% CD56+ cells in the subluminal stroma. Results: Increased uNK cell density was associated with lower endometrial expression of 11βHSD1 and mineralocorticoid receptor (MR) but not glucocorticoid receptor in vivo. Elevated uNK cell density also corresponded to impaired induction of key decidual markers (11βHSD1, prolactin, and insulin-like growth factor binding protein-1) and MR-dependent enzymes (dehydrogenase/reductase member 3 and retinol saturase) in differentiating HESC cultures. Increased uNK cell density in vivo was not associated with increased in vitro expression of either IL-15 or IL-11, two cytokines implicated in uNK cell regulation. Conclusions: Elevated levels of uNK cells in the stroma underlying the surface epithelium are associated with inadequate cortisol biosynthesis by resident decidualizing cells and suboptimal induction of key MR-dependent enzymes involved in lipid biogenesis and the retinoid transport pathway. Our observations suggest that uNK cell testing identifies those women at risk of reproductive failure due to relative uterine cortisol deficiency.

scholarly journals α-actin Down Regulation and Perforin Loss in Uterine Natural Killer Cells From LPS-Treated Pregnant Mice

2015 ◽  
pp. 427-432 ◽  
Author(s):  
B. ZAVAN ◽  
A. M. DO AMARANTE-PAFFARO ◽  
V. A. PAFFARO
Keyword(s):  
Natural Killer ◽  
Cell Types ◽  
Normal Pregnancy ◽  
Down Regulation ◽  
Uterine Arteries ◽  
Uterine Natural Killer Cells ◽  
Unk Cells ◽  
Pregnant Mice ◽  
Unk Cell ◽  
Uterine Natural Killer

One of the most abundant immunologic cell types in early decidua is the uterine natural killer (UNK) cell that despite the presence of cytoplasmic granules rich in perforin and granzymes does not degranulate in normal pregnancy. UNK cells are important producers of angiogenic factors that permit normal dilation of uterine arteries to provide increased blood flow for the growing feto-placental unit. Gram-negative bacteria lipopolysaccharide (LPS) administration can trigger an imbalance of pro-inflammatory and anti-inflammatory cytokines impairing the normal immune cells activity as well as uterine homeostasis. The present study aimed to evaluate by immunohistochemistry the reactivity of perforin and α-actin on UNK cell from LPS-treated pregnant mice. For the first time, we demonstrate that LPS injection in pregnant mice causes α-actin down regulation, concomitantly with perforin loss in UNK cells. This suggests that LPS alters UNK cell migration and activates cytotoxic granule release.

scholarly journals Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling

Reproduction ◽  
2003 ◽  
pp. 149-160 ◽  
Author(s):  
BA Croy ◽  
H He ◽  
S Esadeg ◽  
Q Wei ◽  
D McCartney ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Lymphoid Tissues ◽  
Lymphoid Aggregate ◽  
Ifn Gamma ◽  
Uterine Natural Killer Cells ◽  
Decidua Basalis ◽  
Unk Cells ◽  
Implantation Sites ◽  
Unk Cell

In primates, including women, and in rodents, natural killer lymphocytes (NK cells) have a unique relationship with the decidualizing uterus. Implantation sites from genetically modified and transplanted mice have proven useful models for understanding potential mechanisms involved in the recruitment, activation and functions of human CD56(bright) uterine (u)NK cells. Key findings are reviewed in this article. In mice, uNK precursor cells are recruited from secondary lymphoid tissues and are activated coincident with their uterine arrival. uNK cells proliferate, produce cytokines (interferon gamma (IFN-gamma) and interleukin 18 (IL-18) and IL-27), and terminally differentiate into granulated lymphocytes. Many uNK cells proliferate within the myometrium at each implantation site forming a structure, the mesometrial lymphoid aggregate of pregnancy (MLAp) that surrounds blood vessels servicing each placenta. Post-mitotic uNK cells are abundant within decidua basalis; frequently (<25%) associating with spiral arteries, intramurally and intraluminally. From mid-gestation, numbers of uNK cells decline. Studies of implantation sites in mice lacking uNK cells, IFN-gamma, components of IFN-gamma-induction and -signalling pathways or IFN-gamma-regulated genes indicate that uNK cell-derived IFN-gamma is essential in triggering pregnancy-induced spiral artery modification. Decidual maintenance and uNK cell death are additional effects of uNK cell-derived IFN-gamma. Thus, during the first half of gestation, uNK cells contribute to and sustain important changes in the maternal placental bed.

scholarly journals Uterine natural killer cells: Time for a re-appraisal?

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 999 ◽  
Author(s):  
Judith N. Bulmer ◽  
Gendie E. Lash
Keyword(s):  
Natural Killer Cells ◽  
Natural Killer ◽  
Cell Phenotype ◽  
Cell Populations ◽  
Decidual Cell ◽  
Killer Cells ◽  
Unk Cells ◽  
Wide Range ◽  
Uterine Natural Killer

The presence of unusual natural killer cells in human endometrium has been recognized for 30 years, but despite considerable research effort, the in vivo role of uterine natural killer (uNK) cells in both normal and pathological pregnancy remains uncertain. uNK cells may differentiate from precursors present in endometrium, but migration from peripheral blood in response to chemokine stimuli with in situ modification to a uNK cell phenotype is also possible. uNK cells produce a wide range of secretory products with diverse effects on trophoblast and spiral arteries which may play an important role in implantation and early placentation. Interactions with other decidual cell populations are also becoming clear. Recent evidence has demonstrated subpopulations of uNK cells and the presence of other innate lymphoid cell populations in decidua which may refine future approaches to investigation of the role of uNK cells in human pregnancy.

scholarly journals Involvement of uterine natural killer cells in the natural selection of human embryos at implantation

2020 ◽  
Author(s):  
Chow-Seng Kong ◽  
Alexandra Almansa Ordoñez ◽  
Sarah Turner ◽  
Tina Tremaine ◽  
Joanne Muter ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Natural Killer ◽  
Cell Activity ◽  
Human Embryos ◽  
Endometrial Stromal Cells ◽  
Uterine Natural Killer Cells ◽  
Decidual Cells ◽  
Unk Cells ◽  
Unk Cell ◽  
Uterine Natural Killer

AbstractDecidualizing endometrial stromal cells (EnSC) critically determine the maternal response to an implanting conceptus, triggering either menstruation-like disposal of low-fitness embryos or creating an environment that promotes further development. However, the mechanism that couples maternal recognition of low-quality embryos to tissue breakdown remains poorly understood. Recently, we demonstrated that successful transition of the cycling endometrium to a pregnancy state requires selective elimination of pro-inflammatory senescent decidual cells by activated uterine natural killer (uNK) cells. Here we report that uNK cells express CD44, the canonical hyaluronan (HA) receptor, and demonstrate that high-molecular weight HA (HMWHA) inhibits uNK cell-mediated killing of senescent decidual cells. By contrast, low-molecular weight HA (LMWHA) did not attenuate uNK cell activity in co-culture experiments. Killing of senescent decidual cells by uNK cells was also inhibited upon exposure to medium conditioned by IVF embryos that failed to implant, but not successful embryos. Embryo-mediated inhibition of uNK cell activity was reversed by recombinant hyaluronidase 2 (HYAL2), which hydrolyses HMWHA. We further report a correlation between the levels of HYAL2 secretion by human blastocysts, morphological scores, and implantation potential. Taken together, the data suggest a pivotal role for uNK cells in embryo biosensing and endometrial fate decisions at implantation.

scholarly journals Interferon γ Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy

2000 ◽  
Vol 192 (2) ◽  
pp. 259-270 ◽  
Author(s):  
Ali A. Ashkar ◽  
James P. Di Santo ◽  
B. Anne Croy
Keyword(s):  
Natural Killer ◽  
Killer Cell ◽  
Normal Pregnancy ◽  
Interferon Γ ◽  
Unk Cells ◽  
Implantation Sites ◽  
Ifn Γ ◽  
Unk Cell ◽  
Uterine Natural Killer

The dominant lymphocytes in human and murine implantation sites are transient, pregnancy-associated uterine natural killer (uNK) cells. These cells are a major source of interferon (IFN)-γ. Implantation sites in mice lacking uNK cells (alymphoid recombinase activating gene [RAG]-2−/− common cytokine receptor chain γ [γc]−/−) or IFN-γ signaling (IFN-γ−/− or IFN-γRα−/−) fail to initiate normal pregnancy-induced modification of decidual arteries and display hypocellularity or necrosis of decidua. To investigate the functions of uNK cell–derived IFN-γ during pregnancy, RAG-2−/−γc−/− females were engrafted with bone marrow from IFN-γ−/− mice, IFN-γ signal-disrupted mice (IFN-γRα−/− or signal transducer and activator of transcription [Stat]-1−/−), or from mice able to establish normal uNK cells (severe combined immunodeficient [SCID] or C57BL/6). Mated recipients were analyzed at midgestation. All grafts established uNK cells. Grafts from IFN-γ−/− mice did not reverse host vascular or decidual pathology. Grafts from all other donors promoted modification of decidual arteries and decidual cellularity. Grafts from IFN-γRα−/− or Stat-1−/− mice overproduced uNK cells, all of which were immature. Grafts from IFN-γ−/−, SCID, or C57BL/6 mice produced normal, mature uNK cells. Administration of murine recombinant IFN-γ to pregnant RAG-2−/−γc−/− mice initiated decidual vessel modification and promoted decidual cellularity in the absence of uNK cells. These in vivo findings strongly suggest that uNK cell–derived IFN-γ modifies the expression of genes in the uterine vasculature and stroma, which initiates vessel instability and facilitates pregnancy-induced remodeling of decidual arteries.

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