Immune phenotype of the endometrium in patients with recurrent implantation failures after the transfer of genetically tested embryos in assisted reproductive technology programs

Sudoma, I.; Goncharova, Y.; Dons’koy, Borys; Mykytenko, Dmytro

doi:10.1016/j.jri.2023.103943

Cited by 8 publications

(8 citation statements)

References 86 publications

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“…At the same time, we hypothesized that if the increased number of CD56+CD16+CD57+ uNK cells was greater than the decreased number of CD56+CD94+ uNK cells, this would result in increased CD56+ uNK cells in women with RIF, and if the decreased number of CD56+CD94+ uNK cells was greater than the increased number of CD56+CD16+CD57+ uNK cells, this would result in decreased numbers of CD56+ uNK cells in women with RIF. Others have found no statistical difference in CD56+ uNK cells between the two populations of RIF and fertile, 44 which is consistent with our findings. Therefore, it may be more meaningful to study CD56+ NK cell subpopulations rather than CD56+ NK cells.…”

Section: Discussionsupporting

confidence: 93%

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Decreased CD56+CD16‐CD94+uNK cells in the mid‐luteal phase in women with recurrent implantation failure are associated with IL‐15 deficiency

Zhang,

2023

American J Rep Immunol

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ProblemWhether the abnormal development of uterine natural killer (uNK) cells contributes to women with recurrent implantation failure (RIF) remains unclear.Method of studyWe characterized the development of uNK cells and peripheral blood NK cells (pbNK) in the mid‐luteal phase in women with RIF (n = 31) and controls (n = 14) by flow cytometry. Endometrial IL‐15 mRNA expression was studied by quantitative reverse transcription‐PCR. The GSE58144 dataset was used to validate the correlation results.ResultsWe found decreased proportions of stage 4 CD56+CD16‐CD94+ uNK cells (median: 9.56% vs. 17.78%, P .014) and increased proportions of stage 6 CD56+CD16+CD57+ uNK cells (median: 1.54% vs. 0.74%, P = .020) in the mid‐luteal endometrium of women with RIF compared to fertile women. We also found that there was no quantitative correlation between uNK cells and the corresponding pbNK cell subpopulations (P > .05). In addition, IL‐15 mRNA levels in the mid‐luteal endometrium were positively correlated with the proportion of CD56+ uNK cells (r = .392, P = .008), especially with stage 4 uNK cell populations (r = .408, P = .005).ConclusionsWe showed that the proportion of stage 4 uNK cells decreased in the RIF group compared to controls, and the decrease in stage 4 uNK cells correlated positively with low IL‐15 mRNA expression. We suggest that the reduced stage 4 uNK cells in women with RIF are associated with IL‐15 deficiency.

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Section: Discussionsupporting

confidence: 93%

“…However, one study found no difference in IL-15 mRNA and IL-18 mRNA expression between the two groups. 44,65 IL-15 expression was also found to be higher in RIF than in the control group. 62 We hypothesized that this may be due to different test methods and reagents, which may contribute to different results.…”

Section: Discussionmentioning

confidence: 83%

Decreased CD56+CD16‐CD94+uNK cells in the mid‐luteal phase in women with recurrent implantation failure are associated with IL‐15 deficiency

Zhang,

2023

American J Rep Immunol

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“…25 Studies have demonstrated a role of uterine NK cells in pathologies such as recurrent pregnancy loss, RIF, and infertility overall. 13,24,[26][27][28][29] However, it is not known how uterine NK cells gain their way to the lumen of the uterine cavity and what is their impact on the implantation. In our study, we have conducted for the first time an assessment of the cellular composition of uterine fluid, revealing that immune cells within the uterine cavity, not solely confined to the endometrium, may play a crucial role in supporting implantation of the blastocyst.…”

Section: Discussionmentioning

confidence: 99%

Assessment of immune cells in the uterine fluid at the time of the embryo transfer

Strbo,

Rodriguez,

Padula

et al. 2024

American J Rep Immunol

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ProblemAlthough endometrial receptivity is a key factor in influencing implantation in both naturally conceived and assisted reproductive technology (ART) cycles, very little is known about the endometrium milieu around the time of implantation. Previous studies have demonstrated the presence of several cytokines in the endometrium that affect implantation. However, there is lacking data about the presence of immune cell subtypes within the endometrium and in the uterine cavity at the time of implantation.Method of studyThis study was approved by the Institutional Review Board (# 225589). The study was designed as a prospective observational cohort study between May 2021 and December 2022 at a single academic‐based fertility center. All patients underwent at least one In Vitro Fertilization (IVF) cycle and have frozen embryos. Twenty‐four participants were recruited for this study which was conducted during the frozen embryo transfer (FET) cycle regardless of the outcome of previous cycles. Two samples were acquired from each subject, denoted as lower and upper. A trial transfer catheter was introduced under ultrasound guidance into the lower uterine segment. Upon removal, the tip was rinsed in IMDM medium containing 10% FBS (lower uterus). A transfer catheter was then loaded with the embryo that was placed in the upper uterus under ultrasound guidance. The tip of the transfer catheter was rinsed in separate aliquot of the above media (upper uterus). After centrifugation, pelleted cells were stained for the following surface markers: CD45, CD3, CD19, CD4, CD8, gamma delta TCR, CD25, CD127, CD66b, CD14, CD16, CD56 and acquired on Sony SP6800 Spectral Analyzer.ResultsUpon staining the pelleted cells, we were able to identify viable leukocytes from samples obtained from both, upper and lower uterus (0.125 × 106 cells ± SD 0.32), (0.123 × 106 cells ± SD 0.12), respectively. Among total viable cells, there was no significant difference in both percent and number of CD45+ cells between the upper and lower uterus (9.88% ± 6.98 SD, 13.67% ± 9.79 SD, p = .198) respectively. However, there was significantly higher expression of CD3+ (p = .006), CD19+ (p = .032) and CD14+ (p = .019) cells in samples collected from upper compared to lower uterus. Within all CD3+ cells, we found that gamma delta T cells (GDT) were the major population of T cells in both upper and lower uterus. In contrast, CD8+ T cells were significantly higher in the lower uterus when compared to the upper uterus (p = .009). There was no statistically significant difference in the expression of CD4+ T cells, T regulatory cells (CD4+CD25+CD127‐), NK cells (CD56+), neutrophils (CD66b+) and FcγRIII+ cells (CD16+) between upper and lower uterus.ConclusionsWe believe the immune milieu at the time of embryo transfer will affect implantation. Understanding the composition of immune cells will guide further research in identifying optimal immune milieus that favor implantation. Comprehensive analysis of endometrium is expected to lead to new diagnostic and therapeutic approaches to improve IVF outcomes.

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“…The disadvantage of the histopathological approach is that uNK cell counting is mostly semi-quantitative, which depends on both the quality and representativeness of the biopsy sample, as well as on the experience of the examining physician (pathologist). The second laboratory approach—which is of significant importance in everyday clinical practice—is the endometrial immune phenotyping of biopsy samples or uterine lavage fluid (and eventually experimentation with menstrual blood) in women with unexplained recurrent implantation failure through flow cytometry [ 61 , 62 , 63 , 64 , 65 ]. More recently, molecular biological approaches (e.g., using single-cell RNA sequencing or mass spectrometry-based proteomics) may also be suitable for making detailed molecular and cellular maps of endometrium in health and disease [ 66 ].…”

Section: Current Histological Knowledge and Immunohistochemistry Of U...mentioning

confidence: 99%

The Neglected Uterine NK Cells/Hamperl Cells/Endometrial Stromal Granular Cell, or K Cells: A Narrative Review from History through Histology and to Medical Education

Lapides

Varga

Csöbönyeiová

et al. 2023

IJMS

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Reproductive immunology is at the forefront of research interests, aiming to better understand the mechanisms of immune regulation during gestation. The relationship between the immune system and the implanting embryo is profound because the embryo is semi-allogenic but not targeted by the maternal immune system, as expected in graft-versus-host reactions. The most prominent cell population at the maternal–fetal interface is the population of uterine natural killer (uNK) cells. Uterine NK cells are two-faced immunologically active cells, bearing comparison with Janus, the ancient Roman god of beginnings and endings. Their first face can be seen as natural killer cells, namely lymphocytes, which are critical for host defense against viruses and tumors. Even though uNK cells contain cytolytic molecules, their cytotoxic effect is not applied to classical target cells in vivo, playing a permissive rather than a defensive role. Their second face is crucial in maintaining physiological gestation—uNK cells show critical immunomodulatory functions with the potential to control embryo implantation and trophoblast invasion, regulate placental vascular remodeling, and promote embryonic/fetal growth. Therefore, we believe that their current designation “natural killer cells” (the first “cytotoxic” Janus’s face) is misleading and inappropriate, considering their principal function is supporting and maintaining pregnancy. In this narrative review, we will focus on three lesser-known areas of knowledge about uNK cells. First, from the point of view of histology, we will comprehensively map the history of the discovery of these cells, as well as the current histological possibilities of their identification within the endometrium. To be brief, the discovery of uNK cells is generally attributed to Herwig Hamperl, one of the most influential and prominent representatives of German pathology in the 20th century, and his co-worker, Gisela Hellweg. Secondly, we will discuss the interesting aspect of terminology, since uNK cells are probably one of the human cells with the highest number of synonymous names, leading to significant discrepancies in their descriptions in scientific literature. From the first description of this cell type, they were referred to as endometrial granulocytes, granular endometrial stromal cells, or large granular lymphocytes until the end of the 1980s and the beginning of the 1990s of the last century, when the first publications appeared where the name “uterine NK cells” was used. The third area of present review is medical teaching of histology and clinical embryology. We can confirm that uNK cells are, in most textbooks, overlooked and almost forgotten cells despite their enormous importance. In the present narrative review, we summarize the lesser-known historical and terminological facts about uNK cells. We can state that within the textbooks of histology and embryology, this important cell population is still “overlooked and neglected” and is not given the same importance as in fields of clinical research and clinical practice.

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Immune phenotype of the endometrium in patients with recurrent implantation failures after the transfer of genetically tested embryos in assisted reproductive technology programs

Cited by 8 publications

References 86 publications

Decreased CD56+CD16‐CD94+uNK cells in the mid‐luteal phase in women with recurrent implantation failure are associated with IL‐15 deficiency

Decreased CD56+CD16‐CD94+uNK cells in the mid‐luteal phase in women with recurrent implantation failure are associated with IL‐15 deficiency

Assessment of immune cells in the uterine fluid at the time of the embryo transfer

The Neglected Uterine NK Cells/Hamperl Cells/Endometrial Stromal Granular Cell, or K Cells: A Narrative Review from History through Histology and to Medical Education

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