Functional prominence of natural killer cells and natural killer T cells in pregnancy and infertility: A comprehensive review and update

Shojaei, Zeinab; Jafarpour, Roghayeh; Mehdizadeh, Saber; Bayatipoor, Hashem; Pashangzadeh, Salar; Motallebnezhad, Morteza

doi:10.1016/j.prp.2022.154062

Cited by 12 publications

(4 citation statements)

References 221 publications

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“…TBNK cells refer to the lymphocyte subpopulation comprising T cells, B cells, and NK cells in the human body. NK cells play a crucial role in female reproduction by facilitating embryo acceptance and maintenance, participating in placenta formation, and promoting trophoblast cell growth and differentiation [23]. An elevated number of NK cells can exert cytotoxic effects on trophoblast cells leading to immune-mediated reproductive failure [24].…”

Section: Discussionmentioning

confidence: 99%

Causal Relationship Between Immune Cells and Female Infertility: A Mendelian Randomisation Study

XIE,

ZHANG,

YIN

2024

Preprint

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Background: Observational and retrospective studies have demonstrated that aberrant immune responses and dysregulation of immune cell populations may be implicated in female infertility. However, the precise relationship between distinct subtypes of immune cells and female infertility remains elusive. Method: In this study, we conducted a two-sample Mendelian randomization (MR) analysis to examine the causal relationship between 731 immune phenotypes and female infertility. The inverse variance weighting method was employed as the primary estimator, complemented by MR-Egger and weighted median approaches. To address potential bias from single nucleotide polymorphisms (SNPs), we utilized MR-PRESSO. Additionally, Cochran's Q test and MR-Egger intercept analysis were performed to detect heterogeneity and horizontal pleiotropy. Results: We detected a causal role of fourteen immune phenotypes with female infertility, including CD11c+ CD62L- monocyte AC (OR=1.042,95%CI=1.002-1.083,P=0.037), CD62L-CD86+myeloid DC AC (OR=1.048,95%CI=1.010-1.088,P=0.013),CD62L-CD86+myeloid DC %DC(OR=1.052,95%CI=1.012-1.094,P=0.010), HLA DR++ monocyte AC(OR=1.038,95%CI=1.000-1.078,P=0.049),Activated&restingTregAC(OR=0.900,95%CI=1.838-0.959,P=0.001), Activated&secreting Treg%CD4 Treg(OR=1.009,95%CI=1.001-1.017,P=0.028),CD25hi%CD4+(OR=0.936,95%CI=0.895-0.978,P=0.004),TCRgd AC(OR=1.053,95%CI=1.003-1.106,P=0.039),HLA DR+CD4+%T cell(OR=0.922,95%CI=0.869-0.978,P=0.007),HLA DR+NKAC(OR=0.926,95%CI=0.864-0.993,P=0.031),CD28-DN(CD4-CD8-)%T cell(OR=1.048,95%CI=1.000-1.098,P=0.049),CD19 on IgD+ CD38- unsw mem(OR=1.056; 95%CI=1.026-1.087; p=0.0002),CD24 on IgD+ CD38- unsw mem(OR=0,967,95%CI=0.937-0.997,P=0.033) and CD25 on IgD+CD38- unsw mem(OR=0,977,95%CI=0.964-1.000,P=0.049). Conclusion:The study demonstrates a causal association between 14 genetically determined immune cell phenotypes and female infertility, thereby identifying novel drug targets for the prevention and treatment of this condition.

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Section: Discussionmentioning

confidence: 99%

Causal Relationship Between Immune Cells and Female Infertility: A Mendelian Randomisation Study

XIE,

ZHANG,

YIN

2024

Preprint

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“…Among these, NK cells and macrophages—comprising approximately 70% and 20%–30% of decidual leukocytes in the first trimester, respectively—predominate at the maternal‐foetal Interface 46,47 . NK cells exert significant influence over trophoblast invasion, spiral artery remodelling and placental development, 48,49 while macrophages play a pivotal role in implantation, trophoblast invasion, angiogenesis and pathogen clearance. These macrophages can be further divided into classically activated (M1) and alternatively activated (M2) subtypes 50 .…”

Section: Discussionmentioning

confidence: 99%

Demystifying the impact of prenatal tobacco exposure on the placental immune microenvironment: Avoiding the tragedy of mending the fold after death

Zhao,

Jiang,

et al. 2023

J Cellular Molecular Medi

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Prenatal tobacco exposure (PTE) correlates significantly with a surge in adverse pregnancy outcomes, yet its pathological mechanisms remain partially unexplored. This study aims to meticulously examine the repercussions of PTE on placental immune landscapes, employing a coordinated research methodology encompassing bioinformatics, machine learning and animal studies. Concurrently, it aims to screen biomarkers and potential compounds that could sensitively indicate and mitigate placental immune disorders. In the course of this research, two gene expression omnibus (GEO) microarrays, namely GSE27272 and GSE7434, were included. Gene set enrichment analysis (GSEA) and immune enrichment investigations on differentially expressed genes (DEGs) indicated that PTE might perturb numerous innate or adaptive immune‐related biological processes. A cohort of 52 immune‐associated DEGs was acquired by cross‐referencing the DEGs with gene sets derived from the ImmPort database. A protein–protein interaction (PPI) network was subsequently established, from which 10 hub genes were extracted using the maximal clique centrality (MCC) algorithm (JUN, NPY, SST, FLT4, FGF13, HBEGF, NR0B2, AREG, NR1I2, SEMA5B). Moreover, we substantiated the elevated affinity of tobacco reproductive toxicants, specifically nicotine and nitrosamine, with hub genes through molecular docking (JUN, FGF13 and NR1I2). This suggested that these genes could potentially serve as crucial loci for tobacco's influence on the placental immune microenvironment. To further elucidate the immune microenvironment landscape, consistent clustering analysis was conducted, yielding three subtypes, where the abundance of follicular helper T cells (p < 0.05) in subtype A, M2 macrophages (p < 0.01), neutrophils (p < 0.05) in subtype B and CD8+ T cells (p < 0.05), resting NK cells (p < 0.05), M2 macrophages (p < 0.05) in subtype C were significantly different from the control group. Additionally, three pivotal modules, designated as red, blue and green, were identified, each bearing a close association with differentially infiltrated immunocytes, as discerned by the weighted gene co‐expression network analysis (WGCNA). Functional enrichment analysis was subsequently conducted on these modules. To further probe into the mechanisms by which immune‐associated DEGs are implicated in intercellular communication, 20 genes serving as ligands or receptors and connected to differentially infiltrating immunocytes were isolated. Employing a variety of machine learning techniques, including one‐way logistic regression, LASSO regression, random forest and artificial neural networks, we screened 11 signature genes from the intersection of immune‐associated DEGs and secretory protein‐encoding genes derived from the Human Protein Atlas. Notably, CCL18 and IFNA4 emerged as prospective peripheral blood markers capable of identifying PTE‐induced immune disorders. These markers demonstrated impressive predictive power, as indicated by the area under the curve (AUC) of 0.713 (0.548–0.857) and 0.780 (0.618–0.914), respectively. Furthermore, we predicted 34 potential compounds, including cyclosporine, oestrogen and so on, which may engage with hub genes and attenuate immune disorders instigated by PTE. The diagnostic performance of these biomarkers, alongside the interventional effect of cyclosporine, was further corroborated in animal studies via ELISA, Western blot and immunofluorescence assays. In summary, this study identifies a disturbance in the placental immune landscape, a secondary effect of PTE, which may underlie multiple pregnancy complications. Importantly, our research contributes to the noninvasive and timely detection of PTE‐induced placental immune disorders, while also offering innovative therapeutic strategies for their treatment.

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“…It was found that the number of dNK cells increased in the endometrial secretory phase and early pregnancy, especially in extravillous trophoblast and decidua around the spiral artery, 12 but it decreased in the third trimester of pregnancy. 13 An in vitro study found that there was no significant difference in dNK cells number and angiogenic factor production between the first (6-12 weeks) and second trimester (13-20 weeks), but the expression of dNK cell-activating receptors, NKp80 and NKG2D, at 13−20 weeks is significantly higher than that at 6−12 weeks, related to interactions between trophoblast and dNK cells, which suppressed dNK cells activation and was conducive to the maintenance of trophoblast invasion and immune tolerance. 14 Another study showed that the number of dNK cells significantly decreased in term pregnancy, but the cytolytic capacity was increased with lower capacity to respond to HCMV-infected cells compared to first-trimester dNK cells.…”

Section: The Dynamic Of Dnk Cells In Pregnancymentioning

confidence: 99%

The function of decidua natural killer cells in physiology and pathology of pregnancy

Jin

Liu

Cheng

et al. 2023

American J Rep Immunol

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The role of decidual natural killer (dNK) cells in maintaining immune tolerance at the maternal‐fetal interface during pregnancy is a significant topic in reproductive health. Immune tolerance is essential for a successful pregnancy and involves a complex immune response involving various immune cells and molecules. DNK cells comprise the largest population of lymphocyte subsets found in the decidua and play important roles in maintaining immune tolerance. These cells exert multiple functions to maintain homeostasis of the decidual microenvironment, including modulation of trophoblast invasion, promotion of fetal development, regulation of endometrial decidualization and spiral artery remodeling. DNK cells can also be divided into different subsets based on their functions as NKtolerant, NKcytotoxic, and NKregulatory cells. However, the relationship between dNK cells function and pregnancy outcomes is complex and poorly understood. In this review, we will focus on the physiological role of dNK cells during pregnancy and highlight the potential role in pathological pregnancies and therapeutic approaches.

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Functional prominence of natural killer cells and natural killer T cells in pregnancy and infertility: A comprehensive review and update

Cited by 12 publications

References 221 publications

Causal Relationship Between Immune Cells and Female Infertility: A Mendelian Randomisation Study

Causal Relationship Between Immune Cells and Female Infertility: A Mendelian Randomisation Study

Demystifying the impact of prenatal tobacco exposure on the placental immune microenvironment: Avoiding the tragedy of mending the fold after death

The function of decidua natural killer cells in physiology and pathology of pregnancy

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