A developing fetus is not genetically identical to its mother. However, it is not rejected as a foreign tissue, a phenomenon that makes organ transplantation highly difficult. This HerHaleness write-up provides the probable reasons why fetal rejection does not occur during pregnancy.
Certain fetal cells travel into the mother’s blood and are retained in the internal organs of her body for a long time, even after the birth of the baby. These cells have been suggested to play a vital role in repairing the injured maternal organs.
The immune system has a unique property to protect our body against any foreign substances, like microbes, foreign proteins, as well as non-self tissues. Different components of the immune system collectively recognize such foreign entities, and destroy them in order to prevent any harm to the normal body tissues.
Similar molecular events take place when donated tissues or organs are being transplanted into the body, resulting in the destruction of new tissue. This phenomenon is known as transplant rejection or tissue rejection. When the transplanted tissue or organ is obtained from a genetically non-identical donor, it is termed as an allograft or allogeneic transplant.
The fetus that grows inside the uterus of a pregnant woman is analogous to an allograft, or may be considered as semiallogeneic. Half of the fetal genome comprises paternal genes, and hence, the fetus is not genetically identical to the mother. Then, why doesn’t a mother’s body reject her fetus as a foreign tissue?
This genetically foreign fetus evades the pregnant woman’s body for nutrition and growth, but normally, the maternal immune system causes no harm to it. The destructive alloimmune response is modulated and reshaped so as to tolerate (not mount an immune response against) the fetus!
Maternal Acceptance of Fetus
Several studies in transplantation immunology as well as immunological events occurring during pregnancy have suggested the presence of certain mechanisms that avoid fetal rejection. Some molecular events take place before conception, whereas some are activated by the implantation of embryo into the uterine wall.
Certain tissues enable the fetus to hide from the immune system of the mother, whereas the supporting events suppress the maternal immune system, without rendering the mother susceptible to infections. The suggested probable mechanisms for the same have been explained below.
Immunological studies in murine models as well as in humans suggest that the maternal immune system is preconceptually prepared to tolerate paternal antigens. The seminal fluid provides the exposure to paternal antigens and induces a state of anergy against them. Several components present in the semen have been identified to possess immunomodulatory functions.
This theory has been further supported by the observation that preeclampsia is more common during first pregnancy, as well as in women undergoing in vitro fertilization (IVF) with a donor sperm. So, it would be safe to say that the father plays the protective role even before the birth of the child.
Suppression of Maternal Immunity
The implantation of embryo into the uterine walls initiates a series of pathways that suppress the maternal immune system and modulate the local immune reactions that take place in the uterus. Certain tissues present at the maternal-fetal interface are responsible for the systemic as well as local immunosuppression during pregnancy. These include:
i) Placenta: It is the tissue that connects embryo and uterine wall. It is selectively permeable, allows nutrients and other vital factors to enter the amniotic cavity, and facilitates exit of metabolic wastes.
ii) Chorion: It forms the outermost membrane that surrounds the embryo and fetus. It comprises an outer layer of trophoblast cells and an inner mesoderm layer, that is in direct contact with the amniotic fluid.
iii) Decidua: During pregnancy, the maternal uterine lining is termed as decidua. It forms the maternal component of the placenta.
These tissues secrete the hormone progesterone in large quantities, which leads to overall maternal immunosuppression. The placenta along with the trophoblast cells are resistant to attack by maternal immune cells. In addition, they also have the ability to induce cell death in the maternal immune cells that are capable of recognizing the fetal or paternal proteins and mounting an immune response against the fetus. They have also been shown to trigger formation of certain immune complexes (ICs) that block the vital receptors on maternal immune cells, thereby, altering their normal ability to recognize antigens.
Immunosuppression is also achieved by certain types of fetal cells that cross the placental barrier and enter the maternal circulatory system. These cells encounter immune cells in the maternal blood and induce immunotolerance against fetal antigens.
In addition to the above immunomodulatory functions, the placenta, chorion, and decidua serve as an anatomical barrier, and prevent the entry of maternal immune cells into the amniotic cavity.
The different layers formed by trophoblast cells play a vital role in forming a strong barrier. Some trophoblast cells fuse together to form a continuous outermost layer called syncytiotrophoblast. Immune cells have the ability to pass through the gaps between adjacent cells, in order to migrate through blood vessels and peripheral tissues. The absence of any intracellular spaces in the outermost syncytiotrophoblast prevents such an entry of immune cells.
Suppression of Fetal Antigens
Normally, T lymphocytes of our body can recognize foreign antigens, only when combined with specific surface molecules called major histocompatibility complex (MHC). All normal cells of the body express MHC class I molecules on their surface, whereas the MHC class II molecules are expressed only on antigen-presenting cells of the immune system. The trophoblast cells do not express MHC class I and class II molecules, thus, avoiding detection by the immune cells.
Why doesn’t the fetal immune system attack maternal cells or its own developing organs?
This is because the fetal and adult T lymphocytes develop from different stem cells. The fetal hematopoietic stem cells give rise to T-cell lineages that are tolerant to every antigen they encounter. It is after birth that the T cells develop from adult hematopoietic stem cells and are able to recognize antigens and mount an immune response.
Functions and molecular interactions of components of the immune system during pregnancy are extremely complex and are least understood even today. There is no single reason as to why a pregnant woman does not reject her fetus―it is the result of several overlapping mechanisms. Any failure in such maternal acceptance of the fetus, and fetal rejection by the maternal immune system leads to spontaneous abortion.
How the fetus escapes the maternal immune surveillance and why doesn’t a pregnant woman reject her fetus still remains an unsolved and challenging puzzle to the medical community world over. A clear understanding of the underlying mechanisms for fetal acceptance may provide clues to facilitate easy organ transplants.