Evidence for maternal autoantibodies in the pathogenesis of preterm birth

Preterm birth is associated with breakdown of maternal–fetal tolerance and remains the leading cause of global mortality in young children. However, the role of self-reactive antibodies has been limited to a handful of pathogenic allo- and autoantibodies linked to pregnancy complications. Here we identify a shared autoreactive signature of pregnancy in pregnant sera ( n = 2,719) relative to never-pregnant controls ( n = 130), using proteome-wide autoantibody profiling. Across eight human pregnancy cohorts, we define autoreactivities associated with preterm birth by comparing preterm ( n = 688) and term ( n = 1,505) pregnancies. Within the signature, antibodies to IL1 receptor antagonist (IL1RA) induce resorption, inflammation and vascular malperfusion in pregnant mice. IL1RA localizes to placental endothelial adherens junctions, suggesting a role in vascular integrity. These findings identify a term pregnancy humoral immune program and shared changes preceding preterm delivery, including anti-IL1RA, which may have direct pathogenic consequences.