Researchers Discover Antibody Signature Associated with Premature Delivery

Premature labor affects approximately one in ten pregnant women, representing the primary cause of newborn mortality globally. Despite its prevalence, medical professionals have lacked clear mechanisms to predict which pregnancies face the highest risk or understand why early delivery occurs. A new study from the University of California - San Francisco (UCSF) identifies a specific immune signal linked to these outcomes.

Identifying immune triggers

Scientists discovered that certain antibodies play a role in initiating early labor. These antibodies were found at elevated concentrations and appeared sooner during pregnancy in women who delivered before 37 weeks' gestation compared to those who carried their babies to term. The findings, published in Nature Immunology, utilized a novel immune profiling tool developed at UCSF. This technology may enable new screening methods for preterm birth risk and potential interventions to prevent it.

Joe DeRisi, PhD, the Gordon M. Tomkins Professor of Biochemistry and Biophysics at UCSF and senior author of the work, stated, "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."

Methodology and data analysis

The human immune system faces a unique challenge during pregnancy: the fetus is genetically distinct from the mother, yet must not be rejected. While the immune system typically tolerates this difference, DeRisi’s team investigated whether it might trigger some cases of preterm birth. First author Elze Rackaityte, PhD, formerly a postdoctoral researcher in the DeRisi lab and now an assistant professor at UCSF, led the effort. The team recruited volunteers from UCSF’s fertility clinic, collecting initial blood samples before tracking a subset of women following frozen embryo transfers.

Rackaityte explained the approach: "We wanted to capture the immune system before pregnancy, and then measure what changed. 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." The researchers employed PhIP-Seq, a technology substantially refined by the DeRisi lab, to analyze antibodies in blood samples and determine which proteins they recognized, including reactions to the body’s own proteins. This process identified a set of antibodies consistently appearing once pregnancy began.

To validate these findings, the team analyzed a larger dataset comprising blood samples from more than 2,000 pregnant women across eight cohorts. This included samples collected by California’s statewide prenatal screening program at 15 weeks of gestation. The goal was to determine if specific antibodies were associated with preterm birth rather than just pregnancy itself.

The role of IL-1RA antibodies

Data revealed that women who delivered prematurely experienced broader antibody changes earlier than those delivering at term. Within this signature, one antibody stood out: it reacted against IL-1RA, a protein known to control inflammation. IL-1RA functions by blocking IL-1β, a molecule driving inflammation that triggers uterine contractions. Acting as the body’s natural brake, IL-1RA keeps IL-1β in check. An antibody neutralizing IL-1RA removes this brake, allowing IL-1β and resulting inflammation to rise unchecked, potentially explaining early labor in affected women.

Rackaityte confirmed the significance by injecting IL-1RA antibodies into pregnant mice. The mothers’ blood showed rising IL-1β levels, and their placentas exhibited damage signs similar to those seen in human preterm deliveries. Further examination of human placental tissue revealed where IL-1RA normally accumulates: in junctions between cells lining placental blood vessels, where nutrients and oxygen transfer 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."

Potential treatment avenues

Anakinra, a synthetic form of the IL-1RA molecule, has been used for nearly two decades to treat inflammatory diseases such as rheumatoid arthritis. The new results suggest this already-approved drug could be investigated as a method to prevent preterm births by restoring the brake on IL-1, thereby preventing inflammation and premature uterine contractions.

Rackaityte noted, "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." However, the researchers caution that anti-IL-1RA antibodies were observed in only a fraction of preterm births, indicating other causes likely exist. It remains unclear whether these antibodies were present before pregnancy—triggered by prior infection or immune disease—or appeared after conception, as the women carrying the antibody signature were only followed post-conception.

In her new lab, Rackaityte plans to continue studying anti-IL-1RA antibodies and follow up on other antibodies identified in the preterm-birth-associated immune signature.