Evidence for Maternal Autoantibodies in the Pathogenesis of Preterm Birth

Complications from preterm birth are the leading cause of global mortality in children under age five^1,2. Spontaneous preterm labor is the most common cause of preterm delivery and is associated with a breakdown of maternal-fetal tolerance^3-5. However, the current understanding of the role of autoantibodies in this process has been limited to a handful of examples of pathogenic antibodies that occur with pregnancy complications^6-14. Here, we employ proteome-wide autoantibody profiling via phage display immunoprecipitation and sequencing (PhIP-seq) to identify autoreactivities associated with pregnancy as well as term or preterm delivery outcomes in maternal sera across eight cohorts of human pregnancy (n=2,194). We find that preterm pregnancies exhibit greater proteome-wide autoreactivity, validated by placental proteome immunoprecipitation mass spectrometry analysis using patient sera. Within the preterm birth associated autoreactive signature, we find enrichment for pathways known to be critical for normal pregnancy outcomes, including vascular development, reproductive hormones, and regulators of inflammation. Further analysis of autoreactive targets revealed involvement of the IL1β inflammatory cytokine cascade. IL1β is one of the few inflammatory cytokines sufficient to rapidly induce labor in animals^15-24 and it is also elevated in preterm human pregnancies^25-29. Across these eight cohorts, antibodies to cytokine IL1 receptor antagonist (IL1RA), a natural antagonist to IL1β are significantly enriched in roughly 7% of preterm pregnancies. Sera from these patients functionally neutralize IL1RA activity in vitro and anti-IL1RA induces greater resorption, inflammation, and vascular malperfusion in timed-pregnant mice in vivo. These findings suggest utility for serologic diagnostics as one approach to stratify risk of spontaneous preterm delivery in addition to interventional strategies for restoring control of IL1β during pregnancy.