KIR genotype and HLA-C typing

Natural killer (NK) cells are a type of white blood cell (leukocyte) that are part of the group of cells that make up lymphocytes, which also includes B lymphocytes – the cells that start the production of antibodies – and T lymphocytes – the cells that orchestrate the immune system’s responses and defend us from aggressions that have reached the interior of our cells.

Although their name may lead to misunderstandings about their function in embryonic implantation and the development of pregnancy in the first trimester, NK cells have a beneficial role for pregnancy that we have only just begun to glimpse. This role has to do with the adaptation of a series of changes in the vascular and endometrial architecture.

KIR (Killer-Immunoglobulin like-Receptors) receptors are proteins that are found on NK cells and are arranged both outside the cell and inside the cell. They can be activating (named with an S, since activating signals are added to their intracellular portion) or inhibitory (coded with an L, since inhibitory signals approach their intracellular portion). Unlike other lymphocytes, NK cells do not have a specific receptor that recognizes specific germs, but rather make the decision to activate based on the number of KIR receptors that are activated. If activating KIR receptors (2DS1, 2DS2, 2DS3…) predominate, the NK cell tends to activate. If inhibitory KIR receptors (2DL1, 2DL2, 2DL3…) predominate, the NK cell tends to inhibit itself.

The KIR genotype test is an analytical test in which the genetic material is studied, in the case of Reproductive Immunology, of the woman who wants to become pregnant. It consists of a blood draw like any other analytical test, in which DNA (or DNA) is extracted and the presence or absence of the various KIR genes is sought. The same person can have inherited different KIR genes in their DNA. The set of KIR genes of a person is called KIR genotype and would be like the instruction manual for manufacturing KIR receptors. Different is the KIR phenotype, that is, the protein expression of the activity of these genes, or the real presence of KIR receptors on the NK cell membrane. We are working to be able to offer KIR phenotype studies that help us to understand some situations.

I have expanded on KIR receptors, activators and inhibitors but nothing about who stimulates such receptors. The stimuli for KIR receptors are varied, but in the embryo’s environment, only one type of molecule acts as a «ligand» or stimulus for KIR receptors. This type of molecule is called «HLA-C». HLA molecules are something like a large showcase in which proteins are loaded in small pieces. In this way, the cells show their internal activity to the immune system. The fundamental idea behind all this is to ensure that the cells are manufacturing proteins in a correct way. If this were not the case, the immune system would recognize these changes or mutations and would be able to end this threat.

We could say that NK cells are blind to the protein that is loaded in HLA-C molecules, and that they only recognize a certain amino acid that never varies in position 80 of HLA-C molecules. If that amino acid is Aspartic acid, the HLA-C molecule is classified as C1 (HLA-C1). If the amino acid were Lysine, the HLA-C molecule is classified as C2 (HLA-C2). Thus, the different HLA-C molecules are classified as C1 and C2.

HLA-C molecules classified as C1 (HLA-C1) are able to bind and stimulate KIR 2DS2, 2DL2 and 2DL3 receptors, among others. HLA-C molecules classified as C2 (HLA-C2) are able to bind and stimulate KIR 2DS1 and 2DL1 receptors, fundamentally.

However, the strength of the stimulus does not always occur, with inhibitory stimuli being stronger than activating ones. In this way, we know that there are some HLA-C and KIR genotype combinations that result in an increased frequency of obstetric problems such as implantation failure and early miscarriages, preeclampsia, intrauterine growth restriction or at the other extreme, higher birth weight.

The best known combination that can be associated with reproductive failure is the one that translates the absence of activating KIR receptors (KIR AA genotype) and embryonic HLA-C type C2 provided by the man (or sperm donor and/or egg, depending on the situation), although there are other KIR genotype combinations that could also behave functionally as an AA result.

Therefore, it would be interesting to evaluate the KIR genotype and HLA-C typing of the people who will provide genetic material to the embryo at the same time. These studies are still under development and as I have stressed before, there are some situations that we do not understand in depth. It is necessary to weigh the risk that an adverse combination could pose and to assess it thoroughly, together with the couple’s reproductive history, the treatments administered previously and the presence of other risk factors or causes that justify or explain in part the reproductive failure.

Group C1: HLA-C01, HLA-C03, HLA-C07, HLA-C08, HLA-C12, HLA-C14 and HLA-C*16

Group C2: HLA-C02, HLA-C04, HLA-C05, HLA-C06, HLA-C15, HLA-C17 and HLA-C*18