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

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.

Download Full-text

1. Heme Oxygenase‐1 Enzyme Deficiency Affects Uterine Natural Killer Cell Function During Murine Pregnancy

Inquiry@Queen's Undergraduate Research Conference Proceedings ◽

10.24908/iqurcp.7530 ◽

2017 ◽

Author(s):

Tracy Zhang

Keyword(s):

Natural Killer ◽

Heme Oxygenase ◽

Cell Function ◽

Recurrent Miscarriage ◽

Embryo Implantation ◽

Killer Cell ◽

Implantation Site ◽

Heme Oxygenase 1 ◽

Unk Cells ◽

Uterine Natural Killer

Recurrent miscarriage is a condition that affects 1% of all women, and rejection of the fetus by the mother's immune system is thought to be one of the underlying causes. The mechanisms of maternal tolerance vital to a successful pregnancy are not well understood; however, uterine natural killer (uNK) cells are implicated as they comprise over 70% of immune cells in the uterus during early pregnancy. Heme oxygenase‐1 (HO‐1) is an enzyme that is known to be immunosuppressive. Moreover, mice missing HO‐1 have extremely high abortion rates. This study is the first to analyze the effects of HO‐1 deficiency specifically on uNK cells. We posit that an absence of HO‐1 affects normal uNK cell‐mediated immunosuppression, and also possibly their ability to modify uterine spiral arteries supplying blood to the fetus. Our study analyzed embryos from mice lacking or deficient in HO‐1 on days 8, 10, and 12 of pregnancy. Both number of uNK cells and degree of vascularization were analyzed using immunohistochemistry staining. We observed a significantly higher number of uNK cells in one area of the embryo implantation site and a significantly lower number of cells in another, suggesting the uNK cells are failing to localize properly. Analysis of vascularization is currently ongoing. Since women with multiple miscarriages have been shown to down‐regulate HO‐1, confirmation that absence of HO‐1 leads to implantation site abnormalities could pave the way for future clinical treatments.

Download Full-text

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

Reproduction Fertility and Development ◽

10.1071/srb05abs286 ◽

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.

Download Full-text

Effects of diet-induced obesity on uterine natural killer cell function and placental development in early-mid pregnancy

Placenta ◽

10.1016/j.placenta.2017.07.210 ◽

2017 ◽

Vol 57 ◽

pp. 289

Author(s):

Jennet Baltayeva ◽

Barbara Castellana ◽

Eunice Chin ◽

Julian Christians ◽

Alexander Beristain

Keyword(s):

Natural Killer Cell ◽

Natural Killer ◽

Cell Function ◽

Killer Cell ◽

Natural Killer Cell Function ◽

Placental Development ◽

Diet Induced Obesity ◽

Uterine Natural Killer

Download Full-text

Uterine natural killer cells: supervisors of vasculature construction in early decidua basalis

Reproduction ◽

10.1530/rep-14-0271 ◽

2015 ◽

Vol 149 (2) ◽

pp. R91-R102 ◽

Cited By ~ 58

Author(s):

Matthew T Rätsep ◽

Allison M Felker ◽

Vanessa R Kay ◽

Leandra Tolusso ◽

Alexander P Hofmann ◽

...

Keyword(s):

Natural Killer ◽

Cell Activation ◽

De Novo ◽

Nk Cell ◽

Implantation Site ◽

Vascular Networks ◽

Placental Development ◽

Decidua Basalis ◽

Unk Cells ◽

Uterine Natural Killer

Mammalian pregnancy involves tremendousde novomaternal vascular construction to adequately support conceptus development. In early mouse decidua basalis (DB), maternal uterine natural killer (uNK) cells oversee this process directing various aspects during the formation of supportive vascular networks. The uNK cells recruited to early implantation site DB secrete numerous factors that act in the construction of early decidual vessels (neoangiogenesis) as well as in the alteration of the structural components of newly developing and existing vessels (pruning and remodeling). Although decidual and placental development sufficient to support live births occur in the absence of normally functioning uNK cells, development and structure of implantation site are optimized through the presence of normally activated uNK cells. Human NK cells are also recruited to early decidua. Gestational complications including recurrent spontaneous abortion, fetal growth restriction, preeclampsia, and preterm labor are linked with the absence of human NK cell activation via paternally inherited conceptus transplantation antigens. This review summarizes the roles that mouse uNK cells normally play in decidual neoangiogenesis and spiral artery remodeling in mouse pregnancy and briefly discusses changes in early developmental angiogenesis due to placental growth factor deficiency.

Download Full-text

CD56-Negative Aggressive NK Cell Leukemia Relapsing as Multiple Cranial Nerve Palsies: Case Report and Literature Review

Case Reports in Hematology ◽

10.1155/2017/3724017 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9

Author(s):

M. Guerreiro ◽

F. Príncipe ◽

M. J. Teles ◽

S. Fonseca ◽

A. H. Santos ◽

...

Keyword(s):

Nk Cells ◽

Natural Killer ◽

Nk Cell ◽

Systemic Disease ◽

Killer Cell ◽

Cranial Nerves ◽

Cell Leukemia ◽

Multiple Tumor ◽

Infection Pattern ◽

Cranial Nerve Palsies

Background. Aggressive natural killer cell leukemia (ANKL) is extremely rare and habitually manifests as a systemic disease with multiorgan failure that rapidly evolves to death. The neoplastic natural killer (NK) cells usually harbor the Epstein-Barr virus (EBV) with a latent viral infection pattern type II; they often have a cytoplasmic CD3ε+and surface CD3−, CD2+, and CD56+immunophenotype, and they show complex genetic abnormalities affecting multiple tumor suppressor genes and oncogenes. We present a rare case of CD56-negative ANKL and review the clinical and laboratorial criteria for the diagnosis, as well as the available therapies.Case Presentation. A European 36-year-old male presented with acute onset fever, pallor, weakness, and jaundice. He had hepatosplenomegaly, severe pancytopenia, hepatic cytolysis, and very high serum lactic dehydrogenase levels. The bone marrow studies resulted in the diagnosis of an EBV-positive, CD56-negative ANKL. The patient failed to respond to gemcitabine and cisplatin-based polychemotherapy, dying three months later with leukemic meningitis and multiple cranial nerves palsies.Conclusions. The diagnosis of ANKL is difficult and requires both clinical suspicion and an extensive laboratorial approach. Absence of CD56 expression on the neoplastic NK cells may impose difficulties in the diagnosis, which requires morphological, immunophenotypic, histopathological, immunohistochemical, cytogenetic, and molecular studies.

Download Full-text

Beyond Uterine Natural Killer Cell Numbers in Unexplained Recurrent Pregnancy Loss: Combined Analysis of CD45, CD56, CD16, CD57, and CD138

Diagnostics ◽

10.3390/diagnostics10090650 ◽

2020 ◽

Vol 10 (9) ◽

pp. 650 ◽

Cited By ~ 1

Author(s):

Maia Chiokadze ◽

Christin Bär ◽

Jana Pastuschek ◽

Boris V. Dons’koi ◽

Kseniia G. Khazhylenko ◽

...

Keyword(s):

Natural Killer ◽

Pregnancy Loss ◽

Recurrent Pregnancy Loss ◽

Plasma Cells ◽

Immune Cell ◽

Killer Cell ◽

Cell Counts ◽

Unk Cells ◽

Uterine Natural Killer

Changes in the number and cytotoxic potential of uterine Natural Killer (uNK) cells have been associated with reduced fertility. To provide a better characterization of immunophenotypes in the endometrium of women with uRPL (unexplained recurrent pregnancy loss), we examined the applicability of a set of five immune cell markers. The concentration (cells/mm2) of CD45+ leukocytes, CD56+ uNK cells, and CD138+ plasma cells as well as of CD16+ and CD57+ cells, which indicate high cytotoxic uNK cells, were assessed by immunohistochemistry in endometrial biopsies from 61 uRPL patients and 10 controls. Control fertile endometria presented 90–300 CD56+ uNK cells/mm2. uRPL cases were classified in subgroups of low (uRPL-CD56low < 90 cells/mm2), normal (uRPL-CD56normal 90–300 cells/mm2), and high uNK cell counts (uRPL-CD56high > 300 cells/mm2). Some cases from the uRPL-CD56low and uRPL-CD56normal subgroups showed elevated proportions of cytotoxic CD16+ and CD57+ cells in relation to CD56+ cells. In the uRPL-CD56high subgroup, the CD57/CD56 ratio was reduced in most samples and the CD16/CD56 ratio was unaltered. Analysis of CD138 excluded the influence of chronic endometritis on these observations. Our results reinforce a link between uRPL and a dysfunctional endometrial environment associated with distinct immune cell profiles.

Download Full-text

The conceptus increases secreted phosphoprotein 1 gene expression in the mouse uterus during the progression of decidualization mainly due to its effects on uterine natural killer cells

Reproduction ◽

10.1530/rep-07-0085 ◽

2007 ◽

Vol 133 (6) ◽

pp. 1213-1221 ◽

Cited By ~ 18

Author(s):

Jennifer L Herington ◽

Brent M Bany

Keyword(s):

Gene Expression ◽

Natural Killer ◽

Killer Cell ◽

Cell Types ◽

Mouse Uterus ◽

Cell Functions ◽

Uterine Natural Killer Cells ◽

Unk Cells ◽

Secreted Phosphoprotein 1 ◽

Uterine Natural Killer

Within the mouse endometrium, secreted phosphoprotein 1 (SPP1) gene expression is mainly expressed in the luminal epithelium and some macrophages around the onset of implantation. However, during the progression of decidualization, it is expressed mainly in the mesometrial decidua. To date, the precise cell types responsible for the expression in the mesometrial decidua has not been absolutely identified. The goal of the present study was to assess the expression of SPP1 in uteri of pregnant mice (decidua) during the progression of decidualization and compared it with those undergoing artificially induced decidualization (deciduoma). Significantly (P<0.05) greater steady-state levels of SPP1 mRNA were seen in the decidua when compared with deciduoma. Further, in the decidua, the majority of the SPP1 protein was localized within a subpopulation of granulated uterine natural killer (uNK) cells but not co-localized to their granules. However, in addition to being localized to uNK cells, SPP1 protein was also detected in another cell type(s) that were not epidermal growth factor-like containing mucin-like hormone receptor-like sequence 1 protein-positive immune cells that are known to be present in the uterus at this time. Finally, decidual SPP1 expression dramatically decreased in uteri of interleukin-15-deficient mice that lack uNK cells. In conclusion, SPP1 expression is greater in the mouse decidua when compared with the deciduoma after the onset of implantation during the progression of decidualization. Finally, uNK cells were found to be the major source of SPP1 in the pregnant uterus during decidualization. SPP1 might play a key role in uNK killer cell functions in the uterus during decidualization.

Download Full-text

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

Journal of Experimental Medicine ◽

10.1084/jem.192.2.259 ◽

2000 ◽

Vol 192 (2) ◽

pp. 259-270 ◽

Cited By ~ 525

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.

Download Full-text