Watch the webinar recording with Dr Fernando Sánchez, Clinic Director at Ginemed, Spain, who has explained the immune factor and its impact on embryo implantation in IVF treatment.
Nowadays, everybody is talking about the immune factors in reproduction. However, the implantation depends on a lot of different factors. One of them is related to embryo quality, some are related to the transfer and materials we use, and some are related to endometrial receptivity. Probably, the embryo quality is the most important because sometimes we have implantation in the tubes. Endometrial receptivity is not depending only on immunological aspects, it depends on a lot of factors like the window of implantation, thrombophilic, metabolic, infections, etc. The immunologic aspect of implantation is only one part of the implantation. According to Dr Sánchez, the immunologic factor is one of the most significant parts of the implantation because the relationship between the embryo and the mother is made through the mother’s immunologic system. Therefore, we need to have a very good immunologic system to help the embryo implant.
Types of immunity
There are two types of immunity. The first one is the natural immunity system, which is related to the implantation and the infection like virus or bacteria, and then there is an adaptative immunity, which works with antibodies, cells that can prevent disease in the future by remembering what those substances look like. These cells and antibodies also produce some substances called cytokines, and these cytokines are chemical mediators in the body to help the body to do different things like, for example, opening the vessels at the time of implantation.
Types of immune response
Depending on the immune response, there is an immune response with antibodies or an immune response mediated by cells. All of these are very important because depending on that we are going to have one kind of immune response or the other. This immune response is also mediated by the ID the cells have. The embryo has an ID, and this ID is mediated by what we call HLA antigens. This HLA antigen is the identification of the embryo and this identification of the embryo is recognized by the immune system of the mother, especially by the natural killer cells (NK).
Therefore, you need to remember about HLA C or HLA G or HLA F, that is some information that the embryo gives to the mother’s immune system to answer to this embryo.
Preparation for implantation begins with the action of semen, which reaches the uterus, and when these spermatozoa, which are different to the mother, reaches the uterus, a number of immunological changes happen in the uterus to help the embryo to implant.
When IUI (Intrauterine insemination) is performed on a woman with a man, the chances of implantation are a bit higher. It’s due to the seminal fluid that reaches the endometrium. Once these changes begin, all the cells in the endometrium begin to change, and these changes are very important. The main cell in the endometrium, especially at the time of implantation, is the uterine natural killer cells.
The endometrium is an immune organ and is as significant as can be another immune organ in the body. It is a door for an embryo to implant, and it’s related mainly to these natural uterine natural killer cells. These cells change during pregnancy and the cycle. It’s important to know that because when we study this kind of cells, we start to study them in the blood, and there is no correlation between the values of these cells in the blood compared with values of these cells in the uterine cavity. We need to only consider the values in the uterine cavity, not in the blood.
When we are talking about the uterine NK cells, these are the cells that are mainly producing cytokines to help the embryo implant. When we are talking about the peripheral NK cells, these are mainly high cytotoxic, but they are mainly in the blood, not in the uterus.
These uNK cells produce cytokines, and growth factors and these growth factors help the implantation (G-CSF, GSF-1, IFN-α), etc. There are only two: Interleukin-2 (IL-2) and Tumour necrosis factor alpha (TNF-α) that are inhibiting the implantation, but most of them are helping the implantation.
The embryo is genetically different from the mother, and the immune system helps the implantation. The communication between the maternal immune system and the embryo is done through the innate immune system, mainly through NKs that account for up to 70% of all immune cells at the time of implantation. The embryo communicates with the natural killers through HLA antigens, mainly HLA C, HLA E, HLA F and G. The natural killers identify this HLA through the KIR receptor
(Killer cell immunoglobulin-like receptors), this receptor identifies the embryo, and they are classified into 2 groups, KIR A and KIR B. Depending on the combination between the identification of the embryo HLA C-1 or HLA C -2, the natural killer response helps the implantation or makes it more difficult. Therefore, depending on this combination between KIR and HLA, the embryo implants or not.
These changes that the cytokines do are mainly in the endometrium and are mainly related to the blood vessels because we need to open these blood vessels to give enough blood for the embryo to implant. After all, if we don’t have these cytokines reaching the blood vessels, we can have implantation failures, abortions, prematurity, preeclampsia or intrauterine growth retardation. All of these are related to bad communication between the embryo and the natural killers in the endometrium. Depending on the time of the pregnancy, the cells are changing.
When the communication between the embryo and the antibodies is good, and we have a normal pregnancy, it is called TH2, and if the answer is TH1, it is not good, there will be problems with implantation, abortion, preeclampsia or premature deliveries.
It’s possible to study the immune system, but there is no clinical evidence, it has to be assessed individually because there is no study for everybody with one clear answer. We have to have biological plausibility when we are talking about the treatments we need to do. The KIR of the mother needs to be checked, as well as ANA (Antinuclear Antibodies), NK cells at the uterine level and parental HLA-C compatibility. The main diagnostic we have is clinical. We have to look at the clinical symptoms, not the analysis because if we only look at the analysis, it’s not going to work.
There are a lot of treatments for immunological symptoms, but you have to remember the concept, of homeostasis concept, we can have exacerbated immunity, and we have to reduce this immunity to help the implantation. We can have an inhibited immunity, and we have to increase this immunity to help the implantation, or we can have some imbalance in the immunity, and we have to modulate this immunity to help the implantation. The treatment options for exacerbated immunity (IVIG, anti-TFN-α, corticoids, etc.) are very good for this kind of situation, but they’re very bad if we have inhibited immunity. It’s very important to classify what we’re dealing with and what we need to do.