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|78.3 - Spring 2005|
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> Spring 2005 > Articles
How We Defy Biology and Survive Pregnancy
By Sobia Sarmast
The birth of a child is truly a miracle. Scientists are boggled by the mechanisms responsible for early pregnancy and implantation inside the uterus. Biology would predict the quick death of a sixteen-celled blastocyst struggling to implant inside the mother, but child after child is successfully conceived. Although the blastocyst contains both maternal and foreign, paternal genetic material, it is able to invade the mother during implantation, take over her body, and somehow escape deadly immune response. When pathogenic bacteria enter the body, the immune system quickly releases cytolytic T-cells and macrophages to destroy the invaders. However, though the blastocyst is also a foreign invader, it is spared in order to permit a successful pregnancy. What are the mechanisms responsible for this defiance of biology?Survival of the Fittest
Researchers at the Yale School of Medicine (YSM) have been trying to uncover why the fetus is able to survive inside the mother. From a biological perspective, the fetus is an allograft (foreign tissue) that theoretically should theoretically be rejected by the mother’s immune system. At the very early stages of implantation, a blastocyst must first attach itself to the endometrium (lining of the uterus) in order to continue development into a fetus. Many unsuccessful pregnancies result from implantation failure. Once the blastocyst implants, the placenta – the lifeline of the baby – forms from the trophoblast, an outer layer of the blastocyst. Through the production of cytokines and chemokines, the placenta, composed of mainly paternal proteins due to genetic imprinting, maintains direct contact with the mother and provides nourishment for the fetus. In this sense, the placenta must defends itself against the mother to escape rejection.Unlocking the Mystery: One Hypothesis at a Time
Several hypotheses have been proposed as to how the cells expressing paternal genes can survive inside the mother. Scientists initially thought that a mechanical barrier prevented fetal cells from contacting maternal cells. The mother would never detect these foreign cells; hence there would be no immune response. However, fetal cells were detected in different maternal tissues throughout the body, implying that fetal stem cells have the capability to integrate themselves into maternal tissue during pregnancy! To some extent, the father’s DNA becomes incorporated into the mother’s DNA as a result of pregnancy.
Another hypothesis suggested that the mother’s immune system was suppressed during pregnancy. At a glance, this seems to make sense: if a poor immune system cannot respond to foreign cells, the placental cells are not endangered. However, research suggests that the immune system of a woman is actually stronger while she is carrying a child. If the immune system were suppressed, delivering healthy babies in third world nations – where the majority of pregnant women are exposed to harmful pathogens – would be quite rare.
Further research suggested that perhaps the paternal cells were effectively invisible to the mother. Just like fingerprints, every person has a unique major histocompatibility complex (MHC), and the immune system recognizes cells as foreign if they carry a different MHC. Thus, researchers hypothesized that placental cells did not express this distinctive protein, making them “neutral” and thus invisible to immune cells. This hypothesis, however, was also found to be false.The Scientific Process in Action
Researchers at the Yale School of Medicine have been at the forefront of reproductive immunology research for quite some time, developing one hypothesis after another. Dr. Gil Mor, associate professor of reproductive sciences and the head of research in the Reproductive Immunology Department at the School of Medicine, has spent the last ten years trying to uncover why the fetus is not rejected by the mother. Until recently, Mor believed that cytolytic T-cells were being killed before they were a chance to kill targeted fetal cells. He proposed a Fas-Fas ligand mechanism responsible for the apoptosis (programmed cell death) of T-cells at the site of implantation. Placental cells express a Fas ligand while T-cells express Fas receptors. When T-cells try to attack placental (trophoblast) cells, the Fas ligand binds to the Fas receptor, inducing apoptosis of the T-cells and thus saving the placenta and fetus. Mor describes this process in simpler terms as a battle between the fetus and the mother, in which the fetus is victorious.
In a lecture given to biology students this past fall, Mor presented his Fas-Fas ligand hypothesis as the most current advancement in this field. Just several months later, however, Mor’s team has produced results contradicting of his original hypothesis. Mor now sees the placental and maternal cells, first considered “enemies,” as “good friends.” In fact, his new hypothesis considers the immune response as necessary for a successful pregnancy. This hypothesis change was supported by results showing that pregnancies lacking macrophages and natural killer cells would abort. Moreoever, from an evolutionary perspective, it is unlikely that the maternal immune system and placental cells would not have adapted to each other, and it would make more sense for the placental cells to have learned to benefit from the mother’s immune system.
On the right, a Fas ligand has binded to a Fas receptor on a T-cell. This results in apoptosis of the T-cell, as shown on the left. (Credit: Vanessa Cervantes)
During pregnancy, the placenta and mother must both protect the baby against infection. New findings show that the placenta regulates the mother’s immune system rather than attacking it. The Mor lab confirmed the expression of TLR-2 (toll-like receptor)and TLR-4 genes in both trophoblasts and cells of the maternal immune system. Typically, activation of TLR genes such as TLR-4 promotes the production of cytokines and antimicrobial factors upon bacterial infection. However, activation of the TLR-2 gene by a pathogen induces apoptosis of trophoblast cells. Pregnant women with intrauterine infection-induced preterm labor or preeclampsia, a condition characterized by swelling and high blood pressure, tend to carry fetuses with increased trophoblast cell death. This suggests a link between the expression of the TLR-2 and the presence of intrauterine infections.The Road to Recovery
Following these newest findings, the Mor lab will focus on characterizing how the placenta is cooperates with the mother’s immune system to protect against infection. This insight will help treat and prevent otherwise devastating pregnancy complications such as preterm labor and preeclampsia. Mor also believes that some of these complications may actually result from abnormal responses from the TLR receptors. His lab is looking for either polymorphisms for the receptors or the induction of a specific type of cytokine that can be blockedin pregnancies with these complications. “We are characterizing how the placenta is coordinating the immune system. Knowing how it is protecting against infection will help us treat pregnancy complications.”
In fact, his research may have implications beyond reproductive medicine. All diseases of the human body could be associated with an incorrect regulation of immune system; thus, many disciplines may benefit from this research.
For Mor, this change of hypotheses is far from a setback. It exemplifies what science is all about: proposing hypotheses and trying to disprove them. Although confident about his current findings, Mor understands that in science, you can never speak too soon. He exclaims, “We try to create dogmas, but we have to be humble and accept the data and change our explanations.”About the Author
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