Establishing the etiology of chronic placental villitis of unknown etiology

Chronic villitis of unknown etiology (VUE) is an inflammatory placental diagnosis comprised of the infiltration of maternal CD8+ T cells into the chorionic villi with corresponding trophoblast death. This inflammation accompanies 40-60% of fetal growth restriction (FGR) cases, 20-30% of stillbirths, and infants with a VUE diagnosis are 4 times more likely to be neurodevelopmentally delayed. Importantly, approximately 55% of patients with a VUE diagnosis will have recurrent disease, making this a clinically significant placental finding. However, consequences of this diagnosis are rarely considered clinically due to the paucity of data surrounding the biologic mechanisms promoting VUE. These gaps have resulted in significant barriers for prediction and prevention of new and recurrent disease. The proposed studies seek to determine the inflammatory factors and antigens driving T cell infiltration and trophoblast death in VUE. We hypothesize that VUE is a breakdown of placental immune tolerance driven by maternal CD8 T cell recognition of foreign fetal ligands and antigens expressed locally by villous trophoblasts and systemically by circulating antigen presenting cells (APCs). This is supported by our recent work demonstrating that CD8 T cell responses in VUE are independent of viral infection and have a highly activated and cytotoxic phenotype, similar to allograft rejection responses. We also observed that VUE placentas downregulate T cell inhibitory ligands and upregulate human leukocyte antigen (HLA), which would promote T cell antigen recognition mechanisms. Our preliminary data demonstrates that genes and pathways critical for allorecognition and inflammatory interferon- signaling are increased in CD8 T cells and trophoblasts during VUE compared to controls. We also observe differences in T cell populations in the blood of pregnant patients who go on to have VUE diagnosed at delivery, compared to those that do not. This suggests not only a local, but also a systemic response to this pathology is generated. We will test our hypothesis with two Specific Aims: 1) define the local cell signaling and antigens that promote T cell cytotoxicity and trophoblast death in VUE, and 2) determine how systemic maternal T cell activation and expansion contributes to VUE. This study will provide transformative insights into the etiology of VUE and will contribute directly to the identification of targets to predict and treat VUE in utero. Project Number: 1R01AI195606-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Elizabeth Ann Enninga | Institution: MAYO CLINIC ROCHESTER, ROCHESTER, MN | Award Amount: $689,081 | Activity Code: R01 | Study Section: Pregnancy and Neonatology Study Section[PN] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI19560601