KIR, LILRB and their Ligands' Genes as Potential Biomarkers in Recurrent Implantation Failure

Abstract

Reproductive failure in humans is a very important social and economic problem, because nowadays women decide to conceive later in life and delay motherhood. Unfortunately, with increasing age they have less chance for natural fertilization and maintenance of pregnancy. Many of them need assisted reproductive technology. Approximately 10% of women after in vitro fertilization-embryo transfers experience recurrent implantation failure (RIF). Multiple factors may contribute to RIF, including oocyte and sperm quality, parental chromosomal anomalies, genetic or metabolic abnormalities of the embryo, poor uterine receptivity, immunological disturbances in the implantation site, and some gynecologic pathologies such as endometriosis, uterine fibroids, hydrosalpinx and endometrial polyps. Moreover, the procedure of in vitro fertilization itself could adversely influence the implantation. Nowadays, many studies are focused on the role of natural killer (NK) cells in normal and pathologic pregnancy because NK cells constitute the dominant cell population in the endometrium and they come in close contact with the allogeneic extravillous trophoblast cells in early pregnancy decidua. The majority of these cells are of CD56^bright phenotype. These cells can express killer immunoglobulin-like receptors (KIRs), which, upon recognition of HLA class I molecules (HLA-C and HLA-G) on trophoblasts, may either stimulate or inhibit NK cells to produce soluble factors, and display low cytotoxicity necessary for maintenance of the allogeneic embryo and fetus in the next steps of pregnancy. Moreover, some members of the leukocyte immunoglobulin-like receptor (LILR) family, also named ILT (immunoglobulin-like transcript), are present in the human placenta. LILRB1 (ILT2) was described mainly on stromal cells, while LILRB2 (ILT4), in addition to stromal cells, was also found around vessels in the smooth muscle layer. In this review we focus on the possible role of polymorphism of KIR, LILRB and their ligands (HLA-C, HLA-G) in susceptibility to recurrent implantation failure, which could serve as diagnostic biomarkers of this disease.

Keywords: HLA; In vitro fertilization; KIR; LILRB; Polymorphism; Recurrent implantation failure.

Fig. 1

Schematic diagram of centromere and telomere KIR haplotypes