Variation of maternal $\textit{KIR }$ and fetal $\textit{HLA-C}$ genes in reproductive failure: too early for clinical intervention

Abstract

A distinctive type of (uterine) natural killer (NK) cell is present in the uterine decidua during the period of placental formation. Uterine NK cells express members of the killer immunoglobulin-like receptor ($\textit{KIR}$) family that bind to parental HLA-C molecules on the invading placental trophoblast cells. The maternal KIR genes and their fetal ligands are highly variable, so different $\textit{KIR/HLA-C}$ genetic combinations occur in each pregnancy. Some women only possess inhibitory KIR genes, whereas other women also express activating KIR genes. The overall signal that NK cells receive from paternal HLA-C on trophoblast depends on the ratio of activating and inhibitory KIR genes expressed by them. Therefore, NK cells provide a balance during placentation to ensure maternal survival and an adequately nourished fetus. Because inhibitory $\textit{KIR}$s are found more frequently in women with defective placentation, e.g. pre-eclampsia, fetal growth restriction or recurrent spontaneous abortion, some fertility clinics suggest that women should be 'tissue typed' for their $\textit{KIR}$ genotypes. We explain why, presently, it is premature to introduce $\textit{KIR}$ and $\textit{HLA-C}$ typing to predict pregnancy outcome. In future, however, selecting for certain combinations of $\textit{KIR}$ and $\textit{HLA-C}$ variants in surrogacy, egg or sperm donation may prove useful to reduce disorders of pregnancy.