ERAP, KIR, and HLA-C Profile in Recurrent Implantation Failure.

Karolina Piekarska,Andrzej Malinowski,Andrzej Wiśniewski,Paweł Radwan,Michał Radwan,Agnieszka Tarnowska,Jacek R Wilczyński,Izabela Nowak

doi:10.3389/fimmu.2021.755624

Abstract

The mother’s uterine immune system is dominated by uterine natural killer (NK) cells during the first trimester of pregnancy. These cells express killer cell immunoglobulin-like receptors (KIRs) of inhibitory or activating function. Invading extravillous trophoblast cells express HLA-C molecules, and both maternal and paternal HLA-C allotypes are presented to KIRs. Endoplasmic reticulum aminopeptidase 1 (ERAP1) and 2 (ERAP2) shape the HLA class I immunopeptidome. The ERAPs remove N-terminal residues from antigenic precursor peptides and generate optimal-length peptides to fit into the HLA class I groove. The inability to form the correct HLA class I complexes with the appropriate peptides may result in a lack of immune response by NK cells. The aim of this study was to investigate the role of ERAP1 and ERAP2 polymorphisms in the context of KIR and HLA-C genes in recurrent implantation failure (RIF). In addition, for the first time, we showed the results of ERAP1 and ERAP2 secretion into the peripheral blood of patients and fertile women. We tested a total of 881 women. Four hundred ninety-six females were patients who, together with their partners, participated in in vitro fertilization (IVF). A group of 385 fertile women constituted the control group. Women positive for KIR genes in the Tel AA region and HLA-C2C2 were more prevalent in the RIF group than in fertile women (p/pcorr. = 0.004/0.012, OR = 2.321). Of the ERAP polymorphisms studied, two of them (rs26653 and rs26618) appear to affect RIF susceptibility in HLA-C2-positive patients. Moreover, fertile women who gave birth in the past secreted significantly more ERAP1 than IVF women and control pregnant women (p < 0.0001 and p = 0.0005, respectively). In the case of ERAP2, the opposite result was observed; i.e., fertile women secreted far less ERAP2 than IVF patients (p = 0.0098). Patients who became pregnant after in vitro fertilization embryo transfer (IVF-ET) released far less ERAP2 than patients who miscarried (p = 0.0032). Receiver operating characteristic (ROC) analyses indicate a value of about 2.9 ng/ml of ERAP2 as a point of differentiation between patients who miscarried and those who gave birth to a healthy child. Our study indicates that both ERAP1 and ERAP2 may be involved in processes related to reproduction.

Highlights

Despite the substantial progress in assisted reproductive technologies (ARTs), a high percentage of embryos (50%) are lost at once after implantation or shortly after as miscarriage [1]
We found no statistically significant differences in the frequencies of both single killer cell immunoglobulin-like receptors (KIRs) genes, AA and Bx genotypes, and KIR divided into centromeric and telomeric regions between in vitro fertilization (IVF) patients and fertile control
Potential interactions were found between associated KIR and ERAP genes and HLA-C allotypes

Summary

Introduction

Despite the substantial progress in assisted reproductive technologies (ARTs), a high percentage of embryos (50%) are lost at once after implantation or shortly after as miscarriage [1]. The most stressful problem from the economic and psychological point of view for embryologists and infertile couples is recurrent implantation failure (RIF), which affects 10%–15% of couples having undergone several in vitro fertilization embryo transfers (IVF-ETs). RIF is commonly defined as a failure to achieve a pregnancy after three subsequent IVF cycles, in which four good-quality embryos were transferred in women under the age of 40 years [2,3,4]. The fetal trophoblast cells come into direct contact with the mother’s immune system in the uterus. They constitute the layer that surrounds the blastocyst [5, 6]. Insufficient invasion of trophoblasts and vascular alteration in the decidua are thought to be the primary defect in recurrent miscarriage, preeclampsia (PE), and fetal growth restriction [7, 8]

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