Of all the miracles of life, here’s by far the most miraculous of all: Women’s bodies, for the most part, do not attack and destroy the fetus growing inside them.
From an immunologic point of view, the fetus is an alien. Like a germ. Or an organ transplant. And your body is programmed to mount an assault on foreigners. But my fetus is half me, you say. And so, you may suspect—as others have before you—that the “half-me” part signals the body to avoid all-out warfare. This makes emotional sense! But the success of surrogate moms and donor eggs—with women gestating babies produced by the eggs of other women, their bodies accepting the presence of a fetus that is not “half-them”—proves that idea wrong.
So that leads us to the big question: Why does pregnancy even work?
Pregnancy, as Yale School of Medicine’s Harvey Kliman sees it, is a metaphor for marriage. The placenta is controlled by the father’s genes, the embryo by the mother’s. Each side has its own agenda. Yet, the key to a successful union—whether it be mother and fetus, or husband and wife—is compromise. The details of this compromise have always been a mystery, but in the past few years, scientists seem to be edging closer to understanding the specific negotiations that occur deep within the cells of the women’s body that allow the fetus to escape destruction.
For years, doctors have been eyeing T cells, the immune cells that attack and destroy invaders (which should include the fetus). A few years ago, a team of researchers at NYU School of Medicine, lead by Adrian Erlebacher in the department of pathology, discovered something that had never been seen before: In pregnant mice, even when the T cells were experimentally nudged into attack mode, they did not bite.
These early studies prompted the NYU team to dig deeper, trying to figure out the chain of events that would stop the T-cell attack. They eyed a certain family of genes that, when working properly, recruit and send T cells marching toward invaders. But in the pregnant mouse, the genes were silenced in the decidua—the tissue surrounding the fetus and the placenta—by a chemical that attached to the genes’ proteins, altering the way the genes look and therefore how they act. With this physical change, the genes can no longer communicate “attack!” to the T cells.
The upshot: In a pregnant mouse, at least, the genes can’t do their job, which means that the cascade of events that would lead to an immune assault on the fetus never happens.
Erlebacher says that he and his team found “a fundamentally new way to think about the maternal-fetal interface,” and they recently published their findings in the June 8 issue of Science. Next the NYU team plans to prove that what they discovered in mice holds up in humans as well.
“This is a very exciting finding for us because it gives a satisfying explanation for why the fetus isn’t rejected during pregnancy,” Erlebacher notes, “which is a fundamental question for the medical community with clear implications for human pregnancy.”
And not just for pregnancy: These recent discoveries may not only reveal mysteries of pregnancy and offer novel ways to prevent miscarriages and preeclampsia, but they also might lead to clues to treat cancer and autoimmune illnesses. (Tumors grow, in part, by avoiding immune assault. And contrarily, autoimmune illnesses are caused by an über-revved up immune system.)
Erlebacher’s not the only one studying this stuff. Kliman, the Yale researcher, also investigated human placentas, and his findings suggest an entirely different mechanism in play. Kliman suspects that a specific protein in pregnant women, called PP13, acts as a decoy of sorts to trick the mom’s immune system to stay away from the baby. His findings were published in the October issue of the Journal of Reproductive Sciences. Kliman spotted a cluster of PP13 flooding dead tissue in the placenta of women who had just had abortions. (Kliman studied the placenta within moments of the abortion so he believes that what he saw is what happens during an ongoing pregnancy.) Kliman’s theory is that the PP13 drive immune cells to this area of the placenta, away from the growing fetus, allowing the fetus to escape attack.
Another theory comes from Koji Yoshinaga, the program director of the reproductive sciences branch of the National Institute of Child Health and Human Development. Yoshinaga has been studying, among other things, BIEFs, or blastocyst implantation essential factors—the factors that impact the interaction between embryo and uterus. He believes—as he writes in a scientific paper in the Journal of Reproduction and Development—that these factors signal to the mother that her body must provide nutrients without attacking. As he sees it, pregnancy is a huge balancing act between the mother’s body revving up certain systems to nourish the baby and stanching other systems that could hurt the baby. It’s a complex dance between hormones and the immune system. For instance, Yoshinaga says that prolactin—the hormone that stimulates milk production—also revs up T-cell production. But progesterone, another key pregnancy hormone, triggers something called PIFB, pregnancy-induced binding factor, which seems to protect the embryo from those revved up cells. Still, we really don’t know precisely how progesterone does the trick.
So how do all of the various findings coalesce into one big picture? No one knows yet. The ultimate answers, Yoshinaga says, will come when scientists who are experts in the immune system work closely with scientists who know hormones to develop one unified way of thinking about pregnancy and fetal survival.
(One thing scientists do know is that the old wives’ tale, about pregnancy compromising a woman’s entire immune system, is fiction. You may not fight off the fetus, but you can fight off a cold. The reason pregnant women often feel like their bug lasts forever is probably because pregnant women are hyperattuned to their bodies, obsessing on symptoms more so than when not pregnant.)
Researchers seem to be on the right path when it comes to figuring out the complicated compromises between mother and fetus. How those compromises play out after birth—you may have heard of a complex interface called the “mother-daughter relationship”?—remains a deep, dark secret, however, one that may confound science for all time.
