The association of HLA-G and immune markers in recurrent miscarriages

Eskicioğlu, Fatma; Özdemir, Alper Tunga; Özdemir, Rabia Bilge Özgül; Turan, Gülüzar Arzu; Akan, Zafer; Hasdemir, Solmaz P.

doi:10.3109/14767058.2015.1114085

Cited by 14 publications

(10 citation statements)

References 30 publications

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“…, 2014 ; Sotnikova et al , 2014 ; Wang et al. , 2014 ; Almasry et al , 2015 ; Eskicioğlu et al , 2016 ; Radović Janošević et al , 2016 ; Chen et al , 2017 ; Kuon et al , 2017b ; El-Azzamy et al , 2018 ; Liu et al , 2019 ; Marron and Harrity 2019 ; Wei et al ., 2020 ; Lyzikova et al 2020 ; Zhao et al , 2020 ), nine studies on CD56+CD16− cells ( Lachapelle et al. , 1996 ; Yamamoto et al.…”

Section: Resultsunclassified

Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis

Woon

Greer

Shah

et al. 2022

Human Reproduction Update

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BACKGROUND Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focussed on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal–foetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared with controls. OBJECTIVE AND RATIONALE The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared with controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared with controls. SEARCH METHODS MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger’s test. OUTCOMES Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared with controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples (standardized mean difference (SMD) 0.49, CI 0.08, 0.90; P = 0.02; I2 88%; 1100 women). Meta-analysis of CD56+ uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women). There was no difference in pregnancy outcome in women with RM/RIF stratified by uNK level, and no significant correlation between pNK and uNK levels in women with RM/RIF. There was wide variation in studies conducted on uNK activity, which can be broadly divided into regulation and receptors, uNK cytotoxicity, cytokine secretion and effect of uNK on angiogenesis. These studies were largely equivocal in their results on cytokine secretion, but most studies found lower expression of inhibitory receptors and increased expression of angiogenic factors in women with RM. WIDER IMPLICATIONS The observation of significantly increased uNK level in endometrium of women with RM and RIF may point to an underlying disturbance of the immune milieu culminating in implantation and/or placentation failure. Further research is warranted to elucidate the underlying pathophysiology. The evidence for measuring pNK as an indicator of uNK behaviour is sparse, and of limited clinical use. Measurement of uNK level/activity may be more useful as a diagnostic tool, however, a standardized reference range must be established before this can be of clinical use.

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Section: Resultsunclassified

Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis

Woon

Greer

Shah

et al. 2022

Human Reproduction Update

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“…31 However, the results of some other studies are not consistent with this study. 32 Bhalla and colleagues evaluated the expression of HLA-G using immunohistochemistry staining in placental tissue of the subjects with RM samples compared with the healthy control group. The results showed that the rate of HLA-G expression is not significantly different between 2 groups.…”

Section: Resultsmentioning

confidence: 99%

The Study of HLA-G Gene and Protein Expression in Patients withRecurrent Miscarriage

et al. 2019

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Purpose: Although it has been frequently confirmed that HLA-G plays an important role in thereproduction and pregnancy, the pattern of HLA-G gene and its protein expression are rarelyaddressed in studies. Therefore we conducted this study in regard to evaluate the HLA-G geneand its protein expression in the women’s placenta with recurrent miscarriage.Methods: Placental samples were obtained from the women who were admitted for deliveryor abortion in Al Zahra and Taleghani hospitals, Tabriz, Iran. HLA-G gene expression wasdetermined by real-time polymerase chain reaction (PCR) and HLA-G protein expression wasassessed by western blotting and immunofluorescence staining in the tissue samples.Results: The results showed a significant decrease in the expression of gene and proteins ofHLA-G in the women with recurrent miscarriage compared to the control placental tissues.Conclusion: According to the obtained results, it was concluded that the decrement of HLA-Ggene and protein expressions are associated with recurrent miscarriage. Since there areconflicting results from other studies, it is suggested to conduct a more comprehensive similarstudy with greater sample size.

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“…A null mutation that results in no functional HLA-G1 or G5 protein isoforms has been associated with increased risk of recurrent miscarriage (Aldrich et al , 2001; Pfeiffer et al , 2001); HLA-G 725 promoter polymorphism is a risk factor for recurrent miscarriages. In the same line, Eskicioğlu et al (2016) encountered a significant increase in TNF expression in patients with recurrent miscarriages, (Eskicioğlu et al , 2016), and consequently increased cytotoxic activity in the maternal immune system that explained the miscarriages. In these patients, even with no change in HLA-G expression, the maternal immune system is unresponsive to HLA-G immunosuppressive signals from the embryo and fetus.…”

Section: Discussionmentioning

confidence: 94%

Embryo sHLA-G secretion is related to pregnancy rate

Díaz

Zamora

Sánchez

et al. 2019

Zygote

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SummaryHLA-G expression has been detected in early preimplantation embryos and it has been postulated that a relationship between embryonic expression of this factor and successful pregnancy may exist. Forty-six patients were prospectively selected from our centre ‘Unidad de Reproducción Humana, Hospital Universitario de Canarias’ for conducting this study. In all cases, metaphase II (MII) oocytes were fertilized using intracytoplasmic sperm injection 2–4 h after retrieval. Embryos were cultured individually in 20 µl droplets of G-1 medium (VitroLife) under oil at 37°C and a 6% CO2 environment. Fertilization was assessed at 18 h postinsemination and all oocytes fertilized were passed into a new culture plaque individually in 300 µl culture medium until day 3 of culture. The culture medium was examined for the expression and secretion of sHLA-G with a sandwich enzyme-linked immunosorbent assay kit (BioVendor, Heidelberg, Germany) according to the manufacturer’s instructions. We found statistical significance between higher levels of sHLA-G secretion and pregnancy rate. When both groups were compared there was no difference in embryo quality of transferred embryos, but a significant difference in the number of oocytes and the embryo quality of the cohort existed that was greater in the pregnant group. A standardized sHLA-G assay with a specifically defined range and standard units provides a non-invasive method to identify the most competent embryos for transfer.

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The association of HLA-G and immune markers in recurrent miscarriages

Cited by 14 publications

References 30 publications

Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis

Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis

The Study of HLA-G Gene and Protein Expression in Patients withRecurrent Miscarriage

Embryo sHLA-G secretion is related to pregnancy rate

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