The first step in achieving a successful pregnancy is the successful implantation of the embryo in the mother’s uterus. This process occurs early in gestation, when the outer cells of the developing embryo, known as trophoblast cells, invade the uterine tissue and remodel the uterine spiral arterioles (arteries that supply blood to the endometrium). This action is essential for the development of the placenta and the correct supply of nutrients and oxygen to the embryo, thus establishing an interaction between mother and foetus that must be tolerated by the maternal immune system, as these are two genetically distinct entities. When this interaction fails, immune rejection can occur, which has been linked to implantation failure, infertility, recurrent miscarriage and obstetric complications such as pre-eclampsia and intrauterine growth retardation.
Among the cells of the maternal immune system involved in this interaction are the uterine Natural Killer (uNK) cells, which account for up to 70% of the lymphocyte cells present in the maternal decidua (gestation-specific endometrium). These uNK cells will be responsible for releasing substances that promote placental development and foetal growth, thus becoming a key factor in maternal-fetal compatibility. To carry out these functions, uNKs must recognise and interact with the HLA-C antigens present on the outer membrane of the embryo’s trophoblast cells. The way in which they are able to recognise these HLA-C molecules is because, on their surface, uNKs have specific receptors called KIR receptors.
There are two types of KIR receptors that an uNK cell can present: activating and inhibitory, depending on the effect they exert on the function of the cell itself. In addition, there are many genes that can give rise to KIR receptors, so that, depending on the combination of genes (haplotype) present in the pregnant woman, her KIR genotyping is determined as KIR AA, KIR AB or KIR BB; where haplotype A implies a greater presence of inhibitory type receptors of the uNK cell functions and haplotype B a greater presence of activator type receptors. On the other hand, HLA-C antigens can be of the HLA-C1 or HLA-C2 type, with the embryo presenting a combination of alleles inherited from the progenitors that can be HLA-C1C1, HLA-C1C2 or HLA-C2C2. The great variability of these molecules means that there are numerous possible KIR-HLA-C combinations between mother and foetus. When this combination is the right one, implantation, placenta formation and pregnancy outcome are correct. However, there are risky combinations for pregnancy. These combinations are those in which the pregnant woman presents a KIR AA genotype and the embryo presents HLA-C2 type antigens, the risk being greater when the origin of this HLA-C2 allele is not maternal (paternal origin or from donated gametes).
KIR-HLA-C genotyping is a powerful tool based on the study of the KIR-HLA-C genotyping of the mother and the HLA-C genotyping of the father, thus making it possible to determine whether there is an adequate match between the maternal KIR recipients and the embryonic HLA-C antigens. Similarly, in cases of gamete donation, this technique allows the selection of donors compatible with the recipient.
In those cases in which there is immunological incompatibility, it is recommended to limit the number of embryos transferred to a single embryo and/or select donors who are immunologically compatible with the pregnant woman, in order to reduce the HLA-C2 antigenic load present in the embryo, increasing maternal-fetal compatibility and the possibility of achieving an evolving pregnancy. Furthermore, these results should be assessed by a specialist in order to evaluate, in each case, the incorporation of additional support treatments during pregnancy.
In conclusion, KIR-HLA-C interactions between mother and foetus during implantation are essential for the development of the pregnancy. Therefore, genotyping of both partners is a very useful tool to determine maternal-fetal tolerance, thus preventing gestation from being compromised.
