Immunological tolerance during pregnancy

Placental mechanisms

The placenta is an immunological barrier between the mother and the fetus, creating immune privileges for the latter. Several mechanisms are known for this:

• secretion of , binding to , which inhibits the identification of foreign agents by the immune system. The same mechanism is used by some nematodes parasitizing in the host's body in order to avoid a collision with the immune system of the host ^[2] ;
• the fetus has small lymphocytes- suppressors that suppress the response of maternal T-killers to interleukin 2 ^[1] ;
• unlike other body cells, placental trophoblast cells do not express the classical main histocompatibility complex (MHC) class I and , which is why they are not recognized by T-killers as alien. At the same time, they have special isotypes and , which interfere with the work of maternal natural killers that destroy cells that do not express ^[3] . Moreover, trophoblasts also express the typical isotype ^[3] .
• The formation of syncytium without any intercellular space between the fetus and the mother limits the movement of the mother's mobile immune cells into the fetus. The epithelium in this case is not enough, since some immune cells are able to pass between neighboring epithelial cells. Apparently, cell fusion is caused by endosymbiotic ^[4] . Initially, one of the this virus was its ability to avoid contact with the immune system by creating isolated syncytium. In addition, it allowed the virus to spread by merging an infected cell with an uninfected one. It is assumed that the ancestors of live-bearing mammals appeared after infection with this virus, and as a result, the fetus received another level of protection against maternal immunity ^[5] .

However, the placenta passes the maternal IgG antibodies into the fetus, protecting it from infections . However, these antibodies do not act on the fetal cells until some of its cells have passed through the placenta, where they can meet with maternal B-lymphocytes , after which the latter will begin to produce antibodies against the fetal cells. In addition, the maternal body produces antibodies against cells of other blood groups using the ABO system, however, these antibodies usually belong to the IgM class ^[6] and therefore do not cross the placenta. In rare cases, ABO incompatibility is possible in which antibodies such as IgG directed against the fetus with another blood group penetrate the placenta; such cases occur during sensitization of mothers (usually with blood type 0) by antigens from food or bacteria ^[7] .

Other mechanisms

Placental mechanisms do not explain all the observed phenomena accompanying immunological tolerance during pregnancy. For example, fetal blood cells enter the mother’s bloodstream beyond the barrier created by the placenta ^[8] .

There is also the ( English Eutherian fetoembryonic defense system (eu-FEDS) ), according to which glycoproteins expressed in gametes dissolved in the cytoplasm and anchored in the membrane suppress any immune response to the fetus or placenta ^[9] . According to this model, specific oligosaccharides acting as “functional groups” in suppressing the immune response are covalently attached to these immunosuppressive glycoproteins. In this model, alpha-fetoprotein , CA-125 and glycodelin-A, also known as placenta protein 14 ( English placental protein 14, PP14 ) are considered as the main uterine and fetal glycoproteins in humans.

Other hypotheses suggest that regulatory T-lymphocytes ^[10] and humoral immunity ^[11] participate in tolerance mechanisms. It is also assumed that during pregnancy at the border of the maternal organism - the fetus, cellular immunity is suppressed and humoral immunity is activated ^[11] .

Spontaneous abortion can often be considered a transplant rejection reaction ^[1] , and a chronic lack of immunological tolerance towards the fetus can lead to infertility . In addition, conditions such as preeclampsia and Rhesus conflict are known.

• Rhesus conflict is caused by the appearance in the maternal body of antibodies (including the IgG class) against the Rh factor (Rh) - one of the red blood cell antigens. This occurs when the erythrocyte of the mother does not have a Rhesus factor, but the fetus has it, while a small amount of Rh-positive blood from past pregnancies entered the mother’s bloodstream, and as a result, antibodies like IgG against Rh-antigen began to be produced in the mother’s body . Maternal IgG is able to pass into the fetus through the placenta, and if the content of these antibodies is sufficient, the destruction of red blood cells of the Rh-positive fetus can occur, resulting in the development of hemolytic jaundice of newborns . The degree of development of this disease will be the higher, the more in the past the mother had Rh-conflict pregnancies.
• One reason for preeclampsia is the immune response against the placenta. It is believed that this condition can be prevented by introducing the partner’s seminal fluid , which has immunomodulating properties ^{[12] [13]} .

Pregnancies in which a fetus develops from a , that is, when a woman who bears a fetus, is less genetically related to it than a biological mother, are often complicated by pregnant hypertension and various ^[14] . With such a pregnancy, local and systemic immunological changes are also more pronounced than with a normal pregnancy; therefore, it was suggested that frequent complications of such pregnancies are due to reduced immunological tolerance on the part of the woman carrying the fetus ^[14] .

Other disorders of immunological tolerance leading to infertility and miscarriage are the presence of antiphospholipid and .

Antiphospholipid antibodies act on phospholipids of cell membranes. Antibodies against membrane phospholipids such as phosphatidylserine , phosphatidylcholine , , phosphatidylinositol and have been shown to act on . Antibodies against phosphatidylserine and phosphatidylethanoamine are directed against trophoblast ^[15] . These phosphalipids play an important role in retaining embryonic cells associated with uterine cells and undergoing implantation. If a woman has antibodies against these phospholipids, they will be destroyed during the immune response, and the fetus will not be able to attach to the wall of the uterus. These antibodies are also dangerous for the uterus itself, because they change the blood flow in it ^[15] .

Antinuclear antibodies cause inflammation in the uterus, which prevents the implantation of the embryo. Natural killers recognize germ cells as cancer cells and attack them. Women with such abnormalities develop endometriosis and infertility, accompanied by miscarriages , due to the high level of antinuclear antibodies. So, the presence of antiphospholipid and antinuclear antibodies have a destructive effect on the implantation of the embryo, which is not observed in the presence of antithyroid antibodies. A high level of these antibodies does not have such a detrimental effect, but it indicates a risk of miscarriage. A high content of antithyroid antibodies also indicates that a woman has disorders in the T-lymphocyte system , since it is an indicator of increased secretion of cytokines by T-lymphocytes, which leads to the development of inflammation in the uterine wall ^[15] .

Currently, there are still no drugs that prevent miscarriage by suppressing the mother’s immunity ^[16] .

Changes in immunity during pregnancy can cause increased sensitivity to a number of infectious diseases, for example, toxoplasmosis and listeriosis , as well as aggravate manifestations and increase mortality from diseases such as influenza and chickenpox ^[11] .

• Immune privileges
• Immunological tolerance
• Immune system of the eye
• Sertoli Cells