Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

• DOI: 10.1038/s41467-022-32171-w
• Publication Date: 2022-07-29T09:02:51Z
• Authors: Gurman Kaur; Caroline B. M. Po...; Orr Ashenberg; Jack Lee; Samantha J. Riese...; Matan Hofree; Maria Aggelakopoulou; Ayshwarya Subrama...; Subita Balaram Ku...; Kathrine E. Attfield; Christiane A. E. ...; Jessica L. Davies; Hayley G. Evans; Inbal Avraham-Davidi; Lan T. Nguyen; Danielle A. Dionne; Anna E. Neumann; Lise Torp Jensen; Thomas R. Barber; Elizabeth Soilleux; Mary Carrington; Gil McVean; Orit Rozenblatt-R...; Aviv Regev; Lars Fugger
• Keywords: Linkage Disequilibrium; Trophoblast; Pathogenesis

Abstract Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother child. Prevention treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR HLA genes in FGR, however, linkage disequilibrium, genetic influence from parents, challenges with investigating human pregnancies make the risk alleles their functional effects difficult to map. Here, we demonstrate that interaction between maternal KIR2DL1, expressed on uterine natural killer (NK) cells, paternally inherited HLA-C*0501, fetal trophoblast leads a humanized mouse model. We show KIR2DL1 C*0501 pathogenic arterial remodeling modulation NK cell function. This initial effect cascades altered transcriptional expression intercellular communication at maternal-fetal interface. These findings provide mechanistic insight into specific alleles, avenues prevention treatment.