The idea that pregnancy is associated with immune suppression has created a myth of pregnancy as a state of immunological weakness and, therefore, of increased susceptibility to infectious diseases. A challenging question is whether the maternal immune system is a friend or a foe of pregnancy. In order to discuss this question we will first review some fundamental concepts associated with the immune system and pregnancy.
A fundamental feature of the immune system is to protect the host from pathogens. This function depends upon the innate immune system’s capacity to coordinate cell migration for surveillance and to recognize and respond to invading microorganisms. During normal pregnancy, the human decidua contains a high number of immune cells, such as macrophages, natural killer (NK) cells and, regulatory T cells (Treg) [1
]. B cells are absent from the adaptive immune system, but T lymphocytes constitute about 3–10% of the decidual immune cells [6
]. During the first trimester, NK cells, dendritic cells, and macrophages infiltrate the decidua and accumulate around the invading trophoblast cells [7
]. Interestingly, depletion of immune cells, instead of helping the pregnancy, terminates the pregnancy. Thus, deletion of macrophages, NK cells, or dendritic cells (DC) has deleterious effects on placental development, implantation, or decidual formation [9
]. In elegant studies, it has been shown that in the absence of NK cells, trophoblast cells are not able to reach the endometrial vascularity leading to termination of the pregnancy [12
]. These studies suggest that uNK cells are critical for trophoblast invasion in the uterus. Similarly, depletion of DCs prevented blastocyst implantation and decidual formation [15
]. Indeed, this study suggests that uDC are necessary for decidual formation and may affect the angiogenic response by inhibiting blood vessel maturation[15
More recently, Collins et al
. demonstrate that uDC association, with T cell responses to the fetal “allograft,” starkly contrast with their prominent role in organ transplant rejection [16
]. All of these data further support the idea that the fetal-maternal immune interaction is more complex than the comparison to transplant allografts [17
Consequently, the presence of immune cells at the implantation site is not associated with a response to the “foreign” fetus but is attracted to facilitate and protect the pregnancy. Therefore, the immune system at the implantation site is not suppressed—on the contrary it is active, functional, and is carefully controlled.
Is the systemic immunity of the mother suppressed? Although we can find numerous studies describing factors inducing immune suppression (including progesterone, defined as the natural immune suppressor)[18
], medical and evolutionary aspects are against the concept of immune suppression. Pregnancy represents the most important period for the conservation of the species; therefore, it is fundamental to strengthen all the means to protect the mother and the offspring. The immune system is one of the most important systems protecting the mother against the environment and preventing damage to the fetus. It is during pregnancy when the maternal immune system is characterized by a reinforced network of recognition, communication, trafficking, and repair; it is able to raise the alarm, if necessary, in order to maintain the well-being of the mother and the fetus. On the other side is the fetus that, without any doubt, provides a developing active immune system that will modify the way the mother responds to the environment, providing the uniqueness of the immune system during pregnancy. Therefore, it is appropriate to refer to pregnancy as a unique immune condition that is modulated but not suppressed [19
This unique behavior explains why pregnant women respond differently to the presence of microorganisms or its products (see Ref. 19
and below). Therefore, pregnancy should not imply more susceptibility to infectious diseases, instead it is a time of life where there is a modulation of the immune system, which leads to differential responses depending not only on the microorganisms but on the stages of the pregnancy.