Defining the role of haplotypes and rejection pathways in placental villitis

Chronic villitis of unknown etiology (VUE) is commonly diagnosed in the placenta and key features during histologic evaluation are the infiltration of T lymphocytes into the villous parenchyma and corresponding trophoblast necrosis. VUE is seen in the context of adverse fetal outcomes (i.e., fetal growth restriction, NICU admission, neurodevelopmental delays) and seemingly normal outcomes. As our understanding of the cause of this inflammation is not well defined, it is difficult to understand the spectrum of fetal outcomes associated with a VUE diagnosis and develop useful clinical management strategies which could be employed during pregnancy to positively impact health. The current hypothesis for VUE is that it represents a breakdown of immunologic tolerance to the fetal allograft resulting in maternal T cell targeting of paternal (fetal) antigens in the placenta. We and others have previously shown that there are histologic and immunologic changes associated with villitis, specifically as it relates to human leukocyte antigen (HLA) expression; however, we still cannot predict or prevent VUE from harming a fetus, which is particularly significant for couples worried about recurrent villitis. Therefore, this study aims to provide stronger evidence to delineate the immunology of VUE based on severity and immune mediated rejection pathways. Our hypothesis is that VUE represents an immunogenic pathology resembling organ rejection and that certain maternal-infant HLA types lead to increased risk of disease and poor fetal outcomes. We will address this hypothesis in two Specific Aims: 1) evaluate the associations between maternal-infant haplotype and VUE (adverse fetal outcomes vs. normal outcomes); and 2) determine whether VUE placentae have activation and upregulation of organ rejection genes/pathways in the absence of infectious stimuli. By studying the underlying VUE pathogenesis associated with positive and negative fetal outcomes, we will be able to discover better therapeutic targets, create valuable risk stratification tools and even identify biomarkers of placental inflammation which could be used to manage VUE in utero and prevent the poor neonatal outcomes associated with this pathology. Project Number: 1R21HD116957-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Elizabeth Ann Enninga (+1 co-PI) | Institution: MAYO CLINIC ROCHESTER, ROCHESTER, MN | Award Amount: $443,850 | Activity Code: R21 | Study Section: Pregnancy and Neonatology Study Section[PN] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HD11695701