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

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.

ERAP/HLA-C and KIR Genetic Profile in Couples with Recurrent Implantation Failure

“…Moreover, in all study groups, both mother and fetus had a higher frequency of HLA-C2 compared to the control group [ 32 ]. In our previous study, we showed that the combination of KIR genes from the telomeric region A and HLA-C2C2 in women was associated with infertility and RIF, which confirms our considerations [ 25 ]. Additionally, this work demonstrated the role of the KIR / HLA-C gene system with the ERAP genes in implantation failure.…”

“…Moreover, we did not measure the level of ERAPs in the plasma of men. As we showed in our previous research, the concentration of ERAP2 in women’s plasma was associated with the pregnancy, and high levels of ERAP2 could be related with the miscarriage [ 25 ]. Unlike ERAP1 , the ERAP2 gene shows limited polymorphism.…”

“…Additionally, this work demonstrated the role of the KIR / HLA-C gene system with the ERAP genes in implantation failure. In that previous analysis, among all tested ERAP polymorphisms, rs26653 and rs26618 had the greatest influence on infertility and RIF in women carrying HLA-C2 [ 25 ].…”

“…In our previous work, we examined ERAP polymorphisms in the context of KIR and HLA-C genes only in women with RIF [ 25 ]. The aim of this study was to evaluate the association of combined KIR , HLA-C , ERAP gene polymorphisms in women and their partners with susceptibility to RIF.…”

To Be or Not to Be: The Case of Endoplasmic Reticulum Aminopeptidase 2

“…Among other conditions where associations of ERAP2 presence versus absence were observed, we may also list psoriasis, Crohn’s disease, hypertension, and birdshot chorioretinopathy ( 14 , 17 , 37 ). Similar associations were also described in gynecological diseases: preeclampsia ( 31 , 38 – 40 ) and recurrent implantation failure after in vitro fertilization ( 41 ).…”