Reproductive Immunology Unit

What is reproductive immunology?

The immune system can be defined as the set of defence mechanisms that act in response to external aggressions.  There are two types: the innate immunity that all living beings have and the acquired immunity that retains defence responses. When there is renewed contact with a given source, the immune system generates a swift and coordinated response.

The immune system consists of:

• white blood cells and leukocytes
• proteins, such as immunoglobulins and antibodies
• other chemical mediators such as cytokines

What is the Immunology Unit’s role?

The Reproduction Immunology Unit at Instituto Bernabeu studies and schedules the necessary steps for diagnosis and treatment. The aim is to ensure that the immune system does not become a barrier for gestation and a successful pregnancy.

Is it possible that I am rejecting my embryos and this is why I am not getting pregnant?

One of the immune system’s most developed functions is the ability to differentiate between the organism’s own proteins and structures and those which are foreign to it. Pregnancy is a challenge for immune system function. For nine months, it must tolerate and maintain the presence of a new organism which is immunologically different to all the other maternal tissues.

There is a widespread but unfounded belief that the immune system behaves in the same way when there is an embryo present as it would following an organ transplant. The latter is artificial (our biology is not designed to receive organ transplants) but pregnancy is an entirely natural occurrence that has been accounted for by evolution. As such, it is possible for an organism that is foreign to a woman to grow and develop naturally inside her.

Whilst the intricacies of the process in humans have not yet been fully understood, we do know that the immune system plays an active role in developing essential organs during pregnancy, including the placenta. Any errors in how it functions cause illness or issues during pregnancy.

What immunology-related issues might explain why a woman is failing to get pregnant?

Once the most common issues that might explain why a couple is having issues having children (chromosomal abnormalities in spermatozoa or in ova, or anatomical and endocrine issues) have been ruled out, there are numerous pathologies or immunology-related malfunctions that may be having an impact on normal development of pregnancy.

The most common of these is an auto-immune disease called Antiphospholipid Syndrome. In such cases, antibodies, or antibodies that attack the organism’s own proteins, develop and this should not occur. At some point during an immune response to a series of proteins that are linked to phospholipids in blood vessel membranes, they have been permitted to synthesise and then retained. Antiphospholipid Syndrome is commonly related to an increased risk of coagulation issues such as thrombosis in arteries and veins. It can also be linked to recurrent pregnancy loss when thrombosis does not develop, premature birth and delayed foetal growth.

How can immunology-related issued that are linked to fertility be treated?

Treatment depends on the pathology. It is personalised depending on the patient’s medical background and the results of laboratory tests.

The Reproductive Immunology Unit at Instituto Bernabeu assesses patients and provides prenatal, postnatal and ongoing treatment during pregnancy.

Immunological factors:

• Studying Antiphospholipid Syndrome can sometimes prove complex. The range of antibodies that need to be tested has been increasing over the last few years and results are not often interchangeable across the different diagnostic techniques.
• Other immunological factors that have been demonstrated to play a role in onset of the disease during gestation include the so-called KIR genotype and HLA-C typing. The genotype involves studying the genetic variants in a given gene or set of genes.

In this case, the analysed genes lead to a type of white blood cell receptor called the NK cell (natural killer cells). These cells play an active and beneficial role in gestation. The NK cell belongs to a group of lymphocytes. However, unlike the T and B lymphocytes, they do not have specific receptors for concrete infectious agents. They depend on activation of a set of receptors that stimulate or inhibit the cell. As such, exposure to different molecules integrates into an activating or inhibiting signal. The so-called KIR receptors are included in these receptors. The molecules that stimulate them tend to be from the HLA, more specifically the HLA-C, group. HLA molecules make it possible for the immune system to know what is going on inside each cell. It is a kind of viewing window through which the immune system can perform observations, much like a quality control system. By doing so, it knows if a cell is manufacturing suitable proteins or if, on the contrary, it is synthesising abnormal proteins (for example, in cancer) or foreign proteins (such as in a viral infection).

HLA molecules are bound to the manufactured proteins and are exposed to immune system control. During pregnancy, NK cells are found in uterus mucous and the HLA-C molecules on the surface of the cells that come from the embryo or trophoblast. Interaction between the HLA-C molecules and the KIR receptors of the NK cells facilitate a series of changes that are geared towards ensuring the baby receives appropriate nutrition. Whilst it remains a matter for further research, certain HLA-C and KIR genotype combinations can give rise to issues in the changes to structures that need to take place in order for normal gestation to go ahead. Furthermore, over the last few years, they have also been linked to recurrent pregnancy loss. However, we are a long way off being able to confirm an absolute causal relationship between these factors and implantation failure or pregnancy loss. Therefore, for the time being, the studies remain experimental.

What role do other autoimmune disorders play in embryo implantation? How are they diagnosed? 

Diseases such as the following can have an impact on normal development of a pregnancy:

• autoimmune hypothyroidism
• celiac disease with repeat exposure to gluten
• and numerous other autoimmune diseases such as lupus, multiple sclerosis, Chron’s disease and so on.

Clinical studies and analyses

It is important to carry out a clinical and analytical study aimed at ruling out the diseases that could have some impact on correct gestation.

In order to carry out studies of this kind, certain parameters in the immune system need to be measured, either sporadically or repeatedly. Not all the available tests for studying the immune system are needed in order to diagnose a potential immunological factor that is complicating reproduction or that can explain failures.

A detailed medical history indicating whether or not additional specialist tests are needed is of huge importance. For example, quantification of functionality of certain immune system cells and cytokines.

These are generally requested for cases such as immune deficiency or systemic autoimmune diseases but they are not necessary for most couples experiencing reproduction issues.