Maternal antibody repertoires in preeclampsia revealed by phage immunoprecipitation sequencing

Objectives Preeclampsia (PE) is a pregnancy-associated hypertensive disorder characterized by maternal systemic inflammation and endothelial dysfunction. Although aberrant maternal-fetal immunotolerance plays a role in the pathogenesis, the breadth and specificity of maternal antibody responses remain poorly defined. Methods We performed phage immunoprecipitation sequencing (PhIP-Seq) to profile antibody reactivity against 42,692 peptides representing 16,296 proteins across 661 species in women with PE (n = 15) and control pregnancies (n = 33). Selected autoantigens were further evaluated using germline and placental expression datasets and RT-qPCR in independent placental samples. Results Maternal antibody repertoires in PE differed from controls at the level of individual antigens despite a similar overall number of antibody targets. Among 59 endogenous targets enriched in PE, 48 showed male germline associated expression, including CATSPERZ, DCAF8L2, and NBPF3. Many of these targets also showed expression in placental and vascular tissue, and placental expression of selected targets was confirmed by RT-qPCR in an independent cohort. In addition, selective differences in microbial and viral antibody reactivity were observed, including enrichment of Streptococcus dysgalactiae , EBV and influenza A virus antigens in PE, and reduced recognition of HSV-1 antigens. Conclusion PE is associated with an altered maternal antibody profile characterized by autoreactivity to placental and developmental antigens. The overlap between antibody targets and placental expression identifies a previously unrecognized pattern of maternal immune recognition involving shared placental and male germline-associated antigen programs in PE. These findings suggest that maternal immune responses are associated with disease pathophysiology.