The immunological reaction during implantation

The process of implantation occurs when a fertilized egg, or embryo, attaches to the lining of the uterus. This process is critical for the successful establishment of pregnancy. However, it can also trigger an immunological response in the mother's body, which may affect implantation.

The immune system plays a critical role in the implantation process, as it is responsible for ensuring that the maternal body accepts and tolerates the developing embryo and for protecting against infections and other threats during this vulnerable stage of pregnancy. However, the immune system may also negatively react in ways that interfere with implantation. These include:

The implantation process can trigger an inflammatory response in the uterus, which is necessary to promote tissue remodeling and facilitate the attachment of the embryo. However, excessive inflammation can also interfere with implantation and lead to pregnancy loss.

Immune cell activation

During implantation, immune cells such as natural killer (NK) cells and macrophages are activated in the uterus. These cells play an important role in regulating the immune response and promoting implantation.

Uterine natural killer (uNK) cells, in particular, are believed to be crucial in facilitating implantation and early pregnancy. They promote the growth of blood vessels, which helps to supply nutrients and oxygen to the developing embryo. uNK cells also secrete cytokines and other signaling molecules that help to regulate the immune response and promote a tolerogenic environment, where the mother’s immune system doesn’t attack the developing embryo.

Macrophages also play an important role in promoting a tolerogenic environment during implantation. They help to clear away debris and damaged tissue, and also release cytokines and other signaling molecules that help to modulate the immune response.

Implantation of the blastocyst. Credit: Steve Atherton, Animations of embryological development.

However, abnormal activation of these cells during implantation can lead to pregnancy complications. For example, if there is an excessive immune response, it can damage the developing embryo and result in pregnancy loss. On the other hand, if there is an inadequate immune response, it can lead to implantation failure or fetal growth restriction.

It is therefore crucial that proper immune cell activation takes place during implantation for a successful pregnancy to occur. Abnormal immune responses may require immune treatment to support the pregnancy.

Immunological rejection 
The implantation process can trigger an immune response in the mother’s body, whereby the mother’s immune system identifies the developing embryo as a foreign object and attempts to reject it. This can lead to implantation failure and early pregnancy loss.

To prevent immunological rejection, the embryo does have a number of mechanisms to protect itself. For example, the trophoblast cells that form the placenta are not recognized by the mother’s immune system as foreign because they lack the typical markers of foreign cells. Additionally, the developing embryo produces immunosuppressive molecules that help to dampen the maternal immune response.

However, in some cases, the mother’s immune system may still recognize the embryo as foreign and mount an immune response against it. This can lead to complications such as implantation failure, miscarriage or stillbirth.

In some cases, after diagnosis and appropriate testing, immune treatments may be recommended to prevent immunological rejection of the embryo.

To manage immunological reactions during implantation, doctors may use medications to suppress the immune response, such as corticosteroids or immunoglobulin therapy. Additionally, other interventions such as embryo transfer timing, endometrial scratch, or use of specific types of drugs or supplements, may help improve the implantation process and reduce the risk of immunological rejection.

The immune system plays an essential role in implantation and successful pregnancy outcomes. Managing immunological reactions during implantation requires a personalized approach that takes into account the unique needs of each patient.

If you have any queries, please don’t hesitate to get in contact with us at Life Clinic so that we can answer your questions and offer medical support if required.

Tregs and NK cells during implantation

During embryo implantation, the mother’s immune system must tolerate the embryo, which contains foreign antigens from the father. This immune tolerance is a striking feature of pregnancy and is in sharp contrast to solid organ transplant where rejection is avoided only by  the patient taking immunosuppressive drugs. 

The immune system plays an important role in the success of embryo implantation by regulating the inflammatory response and promoting tissue repair. Two key factors involved in the immunological reaction during embryo implantation are the regulatory T cells (Tregs) and natural killer (NK) cells.

Regulatory T cells (Tregs)

The discovery of regulatory T (Treg) cells was a major breakthrough. They play a critical role in the success of pregnancy and implantation. These specialized immune cells help to regulate the maternal immune response and prevent the rejection of the developing embryo. There are various subsets of Tregs (e.g., Fox P3+) which have distinct roles at different points of pregnancy.

  Tregs are involved in the immunological reaction during embryo implantation by suppressing the activity of other immune cells, such as effector T cells and NK cells, allowing the embryo to implant and develop without interference from the maternal immune system. They do this by secreting anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β), which inhibit the activation and proliferation of other immune cells that might otherwise attack the developing embryo. Tregs also promote the activity of dendritic cells, which play a key role in initiating the immune response.

In addition, Treg cells have been shown to be important for promoting the growth and differentiation of trophoblast cells, which are responsible for anchoring the embryo to the uterine lining and facilitating the exchange of nutrients and waste products between the maternal and fetal circulations.

Studies have shown that decreased numbers of Treg cells or dysfunctional Treg cells are associated with implantation failure, miscarriage and preeclampsia.
Treg Cell
Natural killer (NK) cells

NK cells are a type of lymphocyte (immune cell). During implantation their function is to help create a tolerant and supportive environment for the developing embryo, while also protecting the mother from any potential harm. There are several types of NK cells and it is thought that each has a distinct role during pregnancy.

NK cells play an important role in the early stages of pregnancy and implantation. During implantation, NK cells help to regulate the process of trophoblast invasion, which is the process by which the developing embryo burrows into the uterine lining.

NK cells help to maintain the integrity of the maternal-fetal interface by promoting the growth and differentiation of trophoblast cells, while also inhibiting the activity of maternal immune cells that might otherwise attack the developing embryo. In particular, NK cells produce a variety of cytokines and chemokines that attract other immune cells to the site of implantation and help to coordinate their activity.
In addition, NK cells are also thought to play a role in regulating blood flow to the developing placenta, which is important for ensuring adequate oxygen and nutrient supply to the developing embryo.

NK cells can also have a negative effect on implantation if they are too active. High levels of NK cells have been associated with implantation failure and recurrent miscarriage. 
NK cell

Disrupted endometrial microbiota and impaired embryo implantation

Of the factors that prevent normal implantation and pregnancy, embryo and endometrial quality share responsibility jointly. Here we discuss how an imbalance in the health of the endometrial microenvironment (microbiota) can causes recurrent implantation failure and infertility.

The endometrium

The endometrium is the innermost layer of the uterus. It is a dynamic tissue that undergoes cyclic changes in response to hormonal fluctuations during the menstrual cycle. It is composed of glandular tissue, blood vessels, and a specialised layer of cells called the epithelium. The glandular tissue consists of numerous small glands that secrete mucus and other substances to support embryo implantation and nourishment.

The endometrium is essential for reproductive health and fertility and it plays a crucial role in supporting embryo implantation and pregnancy. Abnormalities or disorders of the endometrium can contribute to infertility, menstrual irregularities, and other reproductive conditions.

Proliferation phase of the endometrium. Credit: Nephron, CC BY-SA 3.0, via Wikimedia Commons

The endometrial microbiota

The endometrial microbiota refers to the community of microorganisms that inhabit the endometrium (the lining of the uterus). These microorganisms include bacteria, viruses, fungi, and other microbes that reside within the endometrial tissue. Recent analyses of uterine microbiota have revealed endometrial biopsies with the proportions of bacteria (85%), fungi (10%), viruses (5%), and archaea (0.3%).

The concept of the endometrial microbiota is relatively new, as it was previously believed that the uterus and endometrium were sterile environments. However, recent studies have provided evidence of the presence of a unique microbial community in the endometrium.

The composition of the endometrial microbiota
The endometrial microbiota varies among individuals, but certain bacterial species are commonly identified. A number of studies describe the healthy state of the uterine microbiota in women of reproductive age, with most reporting dominance of Lactobacillus species that acts to stabilise the microenvironment of the endometrium. Other bacterial species commonly detected in endometrial fluid samples are Bifidobacterium, Gardnerella, Prevotella, Staphylococcus and Streptococcus.

Lactobacillus, endometrium. Credit: Dr. Horst Neve, Max Rubner-Institut, CC BY-SA 3.0 DE, via Wikimedia Commons.

How endometrial microbiota can affect fertility

It is suggested that a healthy endometrial microbiota contributes to the maintenance of a balanced and stable environment within the endometrium. Importantly, some bacteria, particularly Lactobacillus species, are beneficial in helping to regulate immune responses, prevent overgrowth of harmful pathogens, and contribute to overall endometrial health.

Disruptions or imbalances in the endometrial microbiota are implicated in infertility and reproductive disorders. The presence of a healthy and diverse endometrial microbiota is thought to play a role in maintaining optimal conditions for successful conception and pregnancy.

When the balance of the endometrial microbiota is disrupted, it can affect fertility in a number of critical ways, such as:

  • Inflammation and immune response
    Imbalances in the endometrial microbiota can trigger an inflammatory response in the endometrium. Chronic inflammation in the reproductive tract can interfere with normal implantation of the fertilised embryo and increase the risk of implantation failure and recurrent miscarriages.

  • Impaired embryo implantation
    The endometrial microbiota is believed to influence the receptivity of the endometrium to implantation. Alterations in the microbial composition or diversity may affect the expression of certain genes and the production of molecules necessary for successful embryo implantation.

  • Altered hormonal environment
    The endometrial microbiota can interact with hormonal signalling in the reproductive tract. Disruptions in the microbiota can affect the balance of hormones, such as oestrogen and progesterone, which are essential for regulating the menstrual cycle and maintaining a receptive endometrium for implantation.
  • Increased susceptibility to infections
    Imbalances in the endometrial microbiota may increase the risk of infections in the reproductive tract. Infections, such as pelvic inflammatory disease (PID) or sexually transmitted infections (STIs), can damage the endometrium, fallopian tubes, and other reproductive structures, leading to infertility.

Chronic ‘hidden’ infections of the endometrial microbiota

Under normal conditions the endometrium is colonised predominantly by Lactobacilli.

However, under specific conditions such as immunological imbalance (both inherited or acquired) or invasive procedures, the uterine environment can be disturbed and a number of abnormal microbiota populations can develop and colonise the endometrium. In most of these cases, especially acute situations, symptoms are characteristic and become immediately apparent. Following a required course of treatment, a healthy uterine biome is restored.

In some cases, however, the developed abnormal and imbalanced microbiota population falls under a partial control of the immune system. This condition means that smaller populations of invasive bacteria manage to survive within the biota (the immune system preventing an explosion of population but at the same time not removing them completely). These partly controlled populations of microbes are difficult to diagnose as they often cause mild symptoms or asymptomatic conditions. Woman with this chronic condition don’t show obvious or characteristic symptoms of uterine microbiota imbalance but it can have an adverse effect on a future pregnancy.

In cases where immunological imbalance is suspected and the woman suffers from repeated implantation failures, it is useful to the perform endometrial microbiota analysis to detect the present of asymptomatic abnormal bacterial populations in the uterus.

If you have any queries, please don’t hesitate to get in contact with us at Life Clinic so that we can answer your questions and offer medical support if required.

Our story

Signs of an abnormal immune system

Abnormal immunological reactions during pregnancy can lead to a variety of complications that may affect both the mother and the developing fetus.

Such immune reactions may not always cause symptoms that are noticeable to the mother. In other cases, an immune reaction can lead to symptoms including Recurrent miscarriage, Abnormal vaginal bleeding, Abnormal placenta development, Preterm labor, Intrauterine growth restriction and others.

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Life Clinic Athens

About us

Life Clinic is an infertility, IVF and Gynaecological Clinic in Athens, Greece, with top success rates and specialisation in immunological disorders and unexplained infertility.

We offer IVF, Egg Donation, Embryo Donation, Egg freezing, PGD/PGS and extensive investigation, treatment and monitoring for the immunological disorders that affect fertility.

Life Clinic is lead by Dimitri Papanikolaou, Obstetrician Gynaecologist specialised in Reproductive Medicine and Reproductive Immunology.

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