A typical pregnancy lasts 40 weeks, but for about 1 in 10 pregnant women labor begins too soon. Premature or preterm birth is the leading cause of newborn deaths worldwide. Yet doctors have struggled to understand why preterm birth occurs – or how to predict which pregnancies are at highest risk.<\/p>\n
Now, researchers at UC San Francisco have discovered antibodies that\u00a0play a role in\u00a0triggering\u00a0early labor. The antibodies were present in higher levels and appeared earlier in pregnancy in women who went on to give birth to their babies before 37 weeks’ gestation compared to women who delivered their babies at term.<\/p>\n
The research was published in\u00a0Nature Immunology\u00a0and carried out using a new immune profiling tool built at UCSF. It could lead to both new ways of screening for preterm birth risk and new interventions to stop it.<\/p>\n
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We built our tool to find exactly these kinds of hidden immune signals. The fact that it’s pointing us toward why some pregnancies go wrong is an exciting result.”<\/p>\n
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Joe DeRisi, PhD, the Gordon M. Tomkins Professor of Biochemistry and Biophysics,\u00a0UCSF and senior author of the new work<\/p>\n
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An immune system puzzle<\/p>\n
Every pregnancy presents a puzzle for the human immune system: a fetus is not genetically identical to a mother, yet her body must not reject it. In most cases, the immune system knows not to attack. But DeRisi’s team wondered whether the immune system could be triggering some cases of preterm births.<\/p>\n
To find out, the team – led by first author\u00a0Elze Rackaityte, PhD, formerly a postdoctoral researcher in the DeRisi lab and now an assistant professor at\u00a0UCSF – recruited volunteers who were being seen at UCSF’s fertility clinic. The researchers collected initial blood samples and then tracked a handful of women after they became pregnant from frozen embryo transfers.<\/p>\n
“We wanted to capture the immune system before pregnancy, and then measure what changed,” Rackaityte said. “This patient population was particularly well suited to answering that question, because the timing of pregnancy following a frozen embryo transfer could be closely tracked.”<\/p>\n
The researchers used a technology called PhIP-Seq, which the DeRisi lab has substantially refined and advanced. PhIP-Seq allows researchers to take a broad look at the antibodies in a person’s blood and determine which proteins they recognize – including, in this case, whether any are reacting to the body’s own proteins. In this work, they used it to identify a set of antibodies that appeared consistently once pregnancy began.<\/p>\n
With that baseline established, the team then turned to a much larger dataset: blood samples from more than 2,000 pregnant women across eight cohorts, including samples collected by California’s statewide prenatal screening program at 15 weeks of gestation. This could show whether any antibodies were specifically associated with preterm birth, not just with pregnancy itself.<\/p>\n
A signature for preterm birth risk<\/p>\n
The data showed that women who went on to deliver prematurely experienced broader antibody changes earlier than those who delivered at term.<\/p>\n
Within the broader antibody signature seen in women with preterm deliveries, one antibody stood out: it reacted against a protein called IL-1RA, which is known to control inflammation<\/a> in the body.<\/p>\n IL-1RA works by blocking a molecule called IL-1\u03b2, which drives a kind of inflammation known to trigger uterine contractions. IL-1RA is the body’s natural brake to keep IL-1\u03b2 in check. An antibody that neutralizes IL-1RA removes that brake, allowing IL-1\u03b2 and the inflammation it causes to rise unchecked. This could explain why some women with the antibody go into labor too early.<\/p>\n To confirm the significance, Rackaityte injected the IL-1RA antibodies into pregnant mice. IL-1\u03b2 levels rose in the mothers’ blood, and their placentas showed signs of damage – something also seen in human preterm deliveries.<\/p>\n Wondering how the immune molecule was linked to placental health, Rackaityte next examined human placental tissue to find where IL-1RA was normally located. She found it accumulated in the junctions between cells lining placental blood vessels where nutrients and oxygen cross from mother to fetus.<\/p>\n “The placenta is basically stocking up on this inhibitor to protect the pregnancy, and it’s deposited in these strings that go along with the flow of blood,” Rackaityte said. “The first time I looked under the microscope, I thought something went wrong because I had never seen a protein organized like this before.”<\/p>\n Toward a treatment<\/p>\n Anakinra, a synthetic form of the IL-1RA molecule, has already been used for nearly two decades to treat inflammatory diseases including rheumatoid arthritis. The new results suggest that the already-approved drug could\u00a0be\u00a0worth investigating as a potential way to prevent preterm births, by putting the brakes back on IL-1, preventing inflammation and preterm uterine contractions.<\/p>\n “Just the fact that this drug has been around for a while, and that we have decades of safety data on it, is very compelling for use in pregnancy,” Rackaityte said.<\/p>\n The researchers caution that the anti-IL-1RA antibodies were seen in only a fraction of preterm births, so there are likely many other causes. They also don’t yet know whether the antibodies were already present before pregnancy – triggered by previous infection or immune disease – or appeared after conception, since the women who carried the antibody signature were only followed after they conceived.<\/p>\n In her new lab, Rackaityte plans to continue studying anti-IL-1RA antibodies as well as follow up on other antibodies that were found in the preterm-birth-associated immune signature.\u00a0<\/p>\n Source:<\/p>\n University of California – San Francisco<\/a><\/p>\n Journal reference:<\/p>\n