Research puts the immune system front and center in controlling pregnancy. However, viruses and bacteria can outfox it, which sometimes leads to dire consequences.

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Suppression of the immune system was once thought to be essential for pregnancy.

During pregnancy, the mother's immune system is in constant flux.

Although it is now widely accepted that there is a finely tuned interaction between maternal and fetal cells to support a healthy pregnancy, many studies have used mouse models to investigate this - but mice are not humans.

New research published this week in the journal Science Immunology sheds new light on how the human immune system changes as pregnancy progresses.

In the study, Dr. Brice Gaudilliere - an assistant professor of anesthesiology, perioperative, and pain medicine at the March of Dimes Prematurity Research Center at Stanford University in California - and colleagues built a comprehensive model of how human immune cells behave during a normal pregnancy. Yet their long-term ambitions are to explore this even further.

Dr. Gaudilliere plans to conduct a similar study with women who experience preterm birth to see whether or not the team can pinpoint particular changes that might act as early warning signs.

Preterm birth - which is defined as birth before 37 weeks of pregnancy - is the leading cause of death in children under the age of 5, according to the World Health Organization (WHO). In 2015, this resulted in nearly 1 million deaths worldwide.

In the United States, the rate of preterm birth is 10 percent. And globally, the number of preterm births is on the increase. Those who survive can face life-long complications.

But why would the immune system play such a big role in pregnancy? And how is it linked to preterm birth?

Misconceptions corrected

For many years, the process of pregnancy was likened to that of organ transplantation, as Dr. Gil Mor - a professor of obstetrics, gynecology, and reproductive sciences at Yale School of Medicine in New Haven, CT - and colleagues explain in a recent article published in the journal Nature Reviews Immunology.

Scientists thought that the maternal immune system had to be repressed throughout pregnancy to stop it from rejecting the fetus. The presence of a host of immune cells at the site of implantation of the embryo was taken as evidence for this theory.

These cells were assumed to be battling the foreign embryonic cells, which were, in turn, trying to suppress this immune response. If the embryonic cells had the upper hand, implantation could proceed. But the battle continued throughout pregnancy.

If this process was not successful, it was thought to lead to miscarriages or preterm labor.

However, studies subsequently showed that the presence or recruitment of immune cells did not occur as a foreign-body response but was a requirement for successful implantation.

And it doesn't stop there; current thinking is that the interplay between fetal cells and the mother's immune response is a critical component throughout pregnancy.

Immune system in flux

To allow the developing embryo to implant, some of its cells actively invade the womb's lining. This leads to an inflammatory cascade, similar to the events that occur during wound healing.

If inflammation is prevented from occurring, implantation cannot proceed, highlighting the importance of inflammatory molecules and cells in this process.

This pro-inflammatory environment dominates the first 12 weeks of pregnancy. During the following 15 weeks, the developing fetus is in a state of rapid growth and development. Anti-inflammatory cells and molecules prevail.

Some fetal cells express cell surface markers, or antigens, that originate from the father. Under normal circumstances, the mother's immune system would recognize these as foreign and attack the cells.

Regulatory T cells (Tregs), which are a specialized form of white blood cell that promote an anti-inflammatory environment, actively protect such fetal cells.

Low levels of Tregs have been linked to miscarriage.

During the final stage of pregnancy, the immune system switches back to a pro-inflammatory state. Without this, the mother cannot go into labor. Preterm labor, in turn, may be associated with abnormal immune responses.

A host of factors influence how the immune system behaves during pregnancy, and increasingly, scientists believe that the mother's microbiome has a part to play.

Microbial passengers in the immune system

For many years, it was thought that the baby received its first dose of microbes during birth. However, recent studies have found microorganisms in the baby's first stool, which means that some transfer of microbial species from mother to fetus occurred before the baby was born.

Yet it is not only living microbes that can play a role in fetal development; fragments of microbes and the products of microbial digestion can be transferred via the placenta.

Dr. Andrew Macpherson, a professor of medicine and director of gastroenterology at the University Hospital of Bern in Switzerland, and colleagues explain in a recent article published in the journal Nature Reviews Immunology that this process might be crucial for the immune system of the newborn.

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Genetically engineered mice and bacteria allow researchers to put the spotlight on the role of the microbiome in immunity.

Mice that are kept under germ-free conditions do not have an immune system. Using clever genetic engineering, Dr. Macpherson and his team were able to expose pregnant mice to Escherichia coli bacteria for a limited period.

By the time the mice gave birth, they were once again germ-free, and therefore they did not pass any E. coli to their offspring.

Mice born this way have increased levels of antibacterial molecules in their gut, more developed immune cells, and a more mature metabolism.

However, it's not all rosy; microbes can be detrimental to fetal health in some cases.

Are viruses at the center of complications?

Dr. Mor has a theory about viruses. He thinks that they knock out the beneficial effects that the normal microbiome provides, leaving both the mother and fetus at risk.

According to this "double-hit hypothesis," viruses deactivate immune signaling processes that are crucial for the interaction between the immune system and bacteria. This leaves the mother at risk of bacterial infection in addition to the virus already in the system.

Using a mouse model, his team showed that exposure to a common bacterial toxin on top of a viral infection leads to preterm birth.

In fact, 40 percent of human preterm deliveries are associated with some form of infection.

Dr. Mor also points to evidence that links viral and bacterial infections during pregnancy to an increased risk of the child developing schizophrenia, autism spectrum disorder, and allergies later in life.

What might be the cause? Scientists think that the high levels of activation of the mother's immune system in response to an infection are to blame for the irreversible damage caused to the fetus.

Dr. Mor and his team showed that even if an infection is not directly passed on by the mother, the levels of inflammatory markers in the fetus shoot up in such cases. In mouse studies, this is accompanied by abnormalities in development.

New study provides detailed insights

With their new study, Dr. Gaudilliere and his colleagues add to the existing body of knowledge about which of the diverse populations of immune cells are present during pregnancy.

The study involved 18 women who had normal pregnancies and donated blood samples during each of the trimesters, as well as 6 weeks after giving birth.

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A new blood test could help to detect those most at risk of preterm delivery.

Using a technique called mass cytometry, the researchers were able to gain a whole host of information from these samples, including which cells were present in the blood, how these reacted to compounds similar to viruses and bacteria, and which signaling pathways were most active.

By incorporating this information into an advanced statistical model, the team could build a sophisticated map of how the immune system adapts throughout pregnancy.

Next on the list is a comparable study using blood samples from women who gave birth prematurely to see whether this is accompanied by consistent changes in the immune system.

The team hopes to use this knowledge to develop a blood test that can indicate the risk of a mother going into preterm labor.

"We're especially interested in understanding more precisely what is happening very early and very late in pregnancy," Dr. Gaudilliere explains. "We'd like to see if there is really a switch we can catch, a sweet spot where deviation from the norm would be maximal with pathology."

"The immune system does not act in isolation, and we're now very interested in profiling its interplay with other aspects of mothers' biology, such as their genetics, metabolism, and the body's microbial communities to come up with a holistic biological clock of pregnancy."

Lead study author Nima Aghaeepour, Ph.D.

What does the future hold?

There is plenty of evidence to suggest that a Western diet and modern lifestyle have a detrimental effect on the microbial passengers that are intricately linked to our health.

A decrease in microbial diversity has been linked to a host of medical conditions. One question that remains is whether or not this also has an effect on the immune system during pregnancy.

Does a low microbial diversity increase the risk of miscarriages or preterm delivery?

Only time will tell. What is clear, though, is that researchers are using new and innovative tools to shine the spotlight on the link between our immune system, those factors that influence it, and the health of mother and baby during and after pregnancy.