Antibodies that neutralize the anti-inflammatory protein IL1RA appeared earlier and at higher levels in women who delivered before 37 weeks' gestation, according to UCSF researchers publishing in Nature Immunology. The finding comes from immune profiling of blood samples from more than 2,000 pregnant women across eight cohorts, including specimens collected at 15 weeks of gestation by California's statewide prenatal screening program.

Preterm birth affects roughly one in 10 pregnancies and is the leading cause of newborn deaths worldwide. First author Elze Rackaityte, PhD, now an assistant professor at UCSF, and senior author Joe DeRisi, PhD, the Gordon M. Tomkins Professor of Biochemistry and Biophysics, used phage immunoprecipitation sequencing (PhIP-seq) — a broad antibody-profiling technology refined in the DeRisi lab — to ask whether the immune system triggers some early deliveries.

"We built our tool to find exactly these kinds of hidden immune signals," DeRisi said. "The fact that it's pointing us toward why some pregnancies go wrong is an exciting result."

How the study was built

Rackaityte recruited volunteers at UCSF's fertility clinic, collecting baseline blood samples and tracking women after conception via frozen embryo transfers — a design that pins down the timing of pregnancy to within days. "We wanted to capture the immune system before pregnancy, and then measure what changed," Rackaityte said.

The team first identified a set of antibodies that appeared consistently once pregnancy began, then scaled to the 2,000-sample dataset to separate pregnancy-related antibody changes from those specific to preterm delivery. Women who delivered prematurely showed broader antibody changes earlier than those who delivered at term. One antibody stood out: one reacting against IL1RA, the body's natural brake on IL1β, an inflammation driver known to trigger uterine contractions.

What did the mouse and tissue experiments show?

To test causality, Rackaityte injected the IL1RA antibodies into pregnant mice. IL1β levels rose in the mothers' blood, and their placentas showed damage patterns also seen in human preterm deliveries. "Consistent with our hypothesis, anti-IL1RA injected dams also exhibited profound reproductive defects," the team wrote.

In human placental tissue, IL1RA accumulated at the junctions between cells lining placental blood vessels, where nutrients and oxygen cross from mother to fetus. "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."

What are the limits of the claim?

The caveats matter for anyone weighing screening or therapeutic implications. The anti-IL1RA antibodies turned up in only a fraction of preterm births, so other causes likely dominate the rest. The researchers also can't yet say whether the antibodies predated pregnancy — triggered by prior infection or immune disease — or emerged after conception, since the women carrying the signature were followed only post-conception.

Still, the mechanism points to a drug already on the market. Anakinra, a synthetic IL1RA used for nearly two decades in rheumatoid arthritis and other inflammatory diseases, could in principle restore the brake on IL-1 and prevent inflammation-driven preterm contractions. "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.

That suggestion remains a hypothesis, not a trial result — the paper reports no anakinra data in pregnant patients.

In their conclusion, the authors frame the result more broadly: pregnancy itself elicits "a broad and shared program of humoral autoreactivity," and preterm birth is distinguished by a markedly expanded antibody signature targeting proteins essential for placental function, vascular remodeling and immune regulation.

Rackaityte's new lab plans to continue studying anti-IL1RA antibodies and to follow up on the other antibodies identified in the preterm-birth-associated immune signature.