New research suggests a fetal immune system gone awry is linked to early labor in moms.

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Could out-of-whack fetal immune systems prompt preterm labor?

For decades, the intricate dance between the immune system of a mother and that of her fetus has fascinated scientists: In most cases, the mother’s body accepts the life growing inside of her and vice versa, leading to a healthy pregnancy. But what happens when there are missteps in this choreography? New research suggests fetal immune cells can launch an aggressive response to mom, an outcome linked to premature birth. The work doesn’t prove that dysfunctional fetal immunity triggers preterm birth on its own, but it has researchers considering new ways to identify women at risk of early labor.

The research also underscores how much more of a player the fetal immune system is than once believed. It was previously thought to be “immature, inactive, nonfunctional,” says immunologist Mike McCune, a senior adviser to the Bill & Melinda Gates Foundation in Seattle, Washington, who recently retired from the University of California, San Francisco (UCSF). In part, that view was because so much fetal research was conducted in mice, where the fetal immune system isn’t as well developed in utero. In humans, it’s a different story. In 2008, McCune and his colleagues reported in Science that immune cells from the mother typically cross the placenta early during pregnancy, triggering the development of so-called T regulatory cells in the fetus. These cells allow it to tolerate the mother’s tissue.

That discovery got UCSF fetal and pediatric surgeon Tippi MacKenzie thinking. Were there situations in which the mother-fetus tolerance could be broken? The following year, MacKenzie, herself pregnant, went into early labor and spent 5 weeks on bed rest. (She later delivered a full-term baby girl.) While immobilized, MacKenzie read everything she could about early labor, and discovered it was mostly a mystery despite being the No. 1 killer of children worldwide. There were already hints that aberrant maternal immune responses might trigger early labor. MacKenzie wondered about the role of the fetus.

She embarked on what would become a years-long project. MacKenzie and her colleagues recruited 89 women with healthy pregnancies and 70 who went into preterm labor because of an early rupture of the amniotic sac—a condition known as preterm premature rupture of membranes. The researchers took blood from the mothers and blood from the umbilical cord after birth, because that cord blood provides a snapshot of the fetal immune system.

In the cord blood of preterm infants, UCSF postdoctoral fellow Michela Frascoli found an abundance of mature T cells and mature dendritic cells, which activate the immune system. There were also many more maternal cells in the cord blood samples. Further testing showed that the mature T cells were revved up against maternal antigens, molecules from the mother that evoke an immune response, the researchers report today in Science Translational Medicine. There were no immune activations in maternal blood for either group.

Despite these tantalizing pieces, the story is still a bit jumbled. It’s hard to know the order in which everything happens, MacKenzie acknowledges. “I think that the maternal cells must flow in and out throughout the pregnancy. But then what exactly triggers that fetal immune system to wake up? I don’t know if the trigger is the maternal cells, or if the maternal cells happen to be there and something else,” like an infection, is the culprit.

Proving that the immune factors in cord blood prompt preterm labor—as opposed to happening alongside it—isn’t easy. In the new study, MacKenzie’s team found that T cells in the preterm infants secrete two molecules, tumor necrosis factor (TNF)-α and interferon-γ, which are churned out when T cells get activated. Using uterine cells in the lab, the group discovered that applying TNF-α caused the cells to contract—just as the uterus does in labor. MacKenzie theorizes that when the fetal T cells secrete the TNF-α, that can cause uterine contractions in a pregnant woman.

Claire Chougnet, an immunologist at Cincinnati Children’s Hospital Medical Center in Ohio, says the finding that fetal immune cells can produce inflammatory molecules as though the mother is an invader is striking. So is the finding that extra maternal cells appear in the cord blood of the premature babies. One of the biggest challenges of a study like this one, though, is that the only way to glimpse the fetal immune system is through cord blood, Chougnet says. Immune cells in other parts of the body—like the gut and lymph nodes—could be reacting differently, but there’s no way to see them in action.

MacKenzie agrees that circulating blood, including cord blood, may offer an incomplete picture. This is true in mothers as well as their fetuses. Even though nothing jumped out in the maternal blood in MacKenzie’s study, “the mother is almost certainly contributing” to this process, she says, she just can’t say how.

Because the new work describes what happens late in the game, when the baby is born, MacKenzie is now hoping to look earlier, when fetal immunity first goes off the rails. “It’s important to look at events that happen long before the baby is born prematurely,” McCune says. And that, he concedes, is “a tricky thing to do.”

MacKenzie wants to try. Among other efforts, she hopes to recruit women at high risk of early labor weeks before problems strike, and then follow them over time. That might help her identify biomarkers that presage fetal immune problems. Another possibility is hunting for specific infections in women at high risk of early labor; infections could be what jump-start the abnormal immune response, MacKenzie suspects. Her ultimate hope: a better and more personalized approach to treating women who face preterm labor, just like she did.