I constantly receive inquiries from “confused” patients with unexplained recurrent IVF failure, unexplained infertility, recurrent pregnancy loss etc. (where an immunologic implantation dysfunction (IID) is often underlying) as to the relevance of measuring Killer Cell immunoglobulin Receptors (KIR) and Human Leukocyte Antigens (HLA).

Below is my attempt to explain the interactivity between KIR, HLA, their effect on to natural killer cell activation (NKA) and how this may affect human Embryo implantation. However before initiating the read, please understand that in the final analysis, successful implantation will in large part be determined by NK cell activation (NKa) and while interactivity between KIR and HLA-C profoundly influences such NKa. This is readily measurable and determinative. Simply stated, it is NKa that threatens the survival of the embryo and accordingly aside from measuring autoantibodies (antiphospholipid antibodies and antithyroid antibodies) and lymphocyte immunophenotype, it is measurement of NK activity rather than KIR/HLA l that is required to make rational clinical decisions.

HLA (human leukocyte antigen) proteins, also known as MHC (major histocompatibility complex) proteins, are a group of proteins found on the surface of cells in the body. They play a critical role in the immune system by presenting foreign substances, such as proteins from viruses or bacteria, to immune cells so that they can be recognized and destroyed.

HLA proteins are highly variable and diverse, with many different types and variations found within the human population. This diversity allows the immune system to recognize and respond to a wide range of foreign substances, and also plays a role in transplant rejection, as the immune system can recognize and attack cells that express HLA proteins that are different from its own.

There are two main types of HLA proteins: class I and class II. Class I HLA proteins are found on the surface of most cells in the body and present antigens to CD8+ T cells, while class II HLA proteins are found primarily on immune cells and present antigens to CD4+ T cells. The interaction between HLA proteins and T cells is critical for the recognition and destruction of foreign substances by the immune system, and abnormalities in HLA expression or function can lead to immune system dysfunction and disease.

HLA (human leukocyte antigen)-C proteins on the surface of the embryo’s trophoblast (root system) are involved in embryo implantation by interacting with immune cells, such as uterine natural killer (NK) cells that play a critical role in the process.

During implantation, the developing embryo must attach itself to the uterine lining, a process that can be hindered by the maternal immune system, which may recognize the embryo as foreign and attempt to reject it. However, HLA-C proteins expressed on the surface of the trophoblast cells, which are the outermost layer of the developing embryo, can interact with maternal immune cells and modulate their activity. In fact, this interaction between HLA proteins on trophoblast cells and maternal immune cells, particularly NK cells, plays a critical role in successful implantation. Specifically, HLA-C, which is a type of HLA protein expressed on the surface of trophoblast cells, has been implicated in regulating NK cell activity during implantation. It is thought that HLA-C on trophoblast cells interacts with KIR (killer cell immunoglobulin-like receptor) proteins on maternal NK cells, leading to the suppression of NK cell activity and the promotion of successful implantation.

The exact mechanisms by which KIRs and HLA-C molecules interact and contribute to embryo implantation are not yet fully understood, but several hypotheses have been proposed.

  1. One hypothesis is that KIRs on maternal NK cells recognize and bind to HLA-C molecules on the surface of fetal trophoblast cells, which are the cells that make up the outer layer of the developing embryo. This interaction is thought to promote the invasion of trophoblast cells into the maternal endometrium, which is necessary for successful implantation.
  2. Another hypothesis is that KIRs on maternal NK cells may recognize and bind to HLA-C molecules on the surface of immune cells in the maternal endometrium, leading to the suppression of immune responses that could interfere with implantation. This could include the suppression of inflammatory responses and the promotion of the development of a specialized type of immune cell known as regulatory T cells, which can help to prevent the rejection of the developing embryo.

While the interactions between KIRs and HLA-C molecules likely play a critical role in the complex interplay between the immune system and early pregnancy, helping to ensure the successful implantation and development of the embryo, further research is needed to fully understand the mechanisms by which these molecules contribute to implantation and early pregnancy.