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Second time's the charm. Pregnancy primes a mother's immune system for subsequent pregnancies, a new study finds.


Mom's Immune System Primed and Ready for Second Baby

Fewer photos aside, sometimes there's an upside to being the second kid: Mom's body may be primed to tolerate you. For many moms, pregnancy gets easier the next time around—and now researchers know part of the reason why. A new study in mice shows that a mother's immune system calls on a special set of cells to protect her growing fetus—and these cells linger long after birth to ease the way for a subsequent pregnancy. The discovery could help researchers develop treatments to prevent common pregnancy complications, such as preeclampsia and miscarriage.

When it comes to the mysteries of motherhood, scientists don't have many answers. First, there's the question of why a mother's immune system doesn't reject her fetus, which has unfamiliar DNA, as foreign. Most mothers' immune systems tolerate their pregnancies successfully, although some pregnancy complications, such as miscarriage and pregnancy-related hypertension, or preeclampsia, have been linked to an overactive immune response. And then there's the question of why these immune system-linked complications are less common in subsequent pregnancies than in a mother's first.

Past studies have revealed a few pieces of this puzzle. Researchers have found that pregnancy-related stress hormones shield the fetus by causing attacking immune system cells, or T cells, to self-destruct. Pregnancy also silences certain genes that promote these T cells, preventing them from accumulating in the first place. But no one had been able to decipher what regulates these processes, or why another kind of immune system cell, called a regulatory T cell, shows up in droves during pregnancy.

To sort out this bundle of mysteries, pediatrician Sing Sing Way of the Cincinnati Children's Hospital Medical Center in Ohio and colleagues followed a few thousand mouse mothers—before, during, and after pregnancy.

Pregnancy triggered the rodents' production of the regulatory T cells: They increased 100-fold during the course of the pregnancy. Those regulatory T cells, the researchers observed, specifically recognized antigens—compounds that cause an immune response—made by the fetus, and then suppressed the immune system's response. But an even more surprising observation was that the cells didn't go away—they hung around at a 10-fold increase over prepregnancy levels for more than 100 days after birth (the equivalent of 4 years to 5 years in humans).

If the mouse became pregnant a second time during this window, the number of T cells grew more rapidly—and reached higher levels—than the first time, conferring extra protection to the fetus. Even when the researchers injected the mice with a toxin that destroyed some of the regulatory T cells and threatened the pregnancy, the mothers proved more resilient during their second pregnancies than during their first.

The results suggest that these special cells recognize the fetus, regulate the mother's immune response to protect it—and then "remember" their response, easing the way for subsequent pregnancies, the team reports online today in Nature.

"The reason we can't prevent complications in pregnancy is because we don't yet know why a normal pregnancy happens," Way says. "This helps us understand that process, and it opens up the window to targeting these cells by designing vaccines that prevent autoimmunity." Such vaccines could ultimately help people avoid complications in pregnancy and in other medical situations, such as tissue transplants, that benefit from a tempered immune response, he says.

"It's interesting and very exciting to find a role for these regulatory T cells," which are not yet fully understood, says Alexander Rudensky, an immunologist at the Memorial Sloan-Kettering Cancer Center in New York City who was not involved in the study. "This study also answers the question of what is the fate of these special protector cells. No one has shown that before."

The study didn't test humans, and it doesn't solve all of motherhood's mysteries, Way acknowledges, but he hopes his team's future studies will determine how long the regulatory T cells' memory lasts and how to extend or boost the response. And he has strong motivation to do so—his wife is expecting.