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

Autor: Kaur G; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Porter CBM; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ashenberg O; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Lee J; Department of Biomedical Engineering, School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK., Riesenfeld SJ; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA.; Department of Medicine, University of Chicago, Chicago, IL, USA., Hofree M; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Aggelakopoulou M; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK., Subramanian A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Kuttikkatte SB; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK., Attfield KE; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK., Desel CAE; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.; University Department of Neurology, University Hospital Magdeburg, Magdeburg, Germany., Davies JL; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK., Evans HG; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK., Avraham-Davidi I; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Nguyen LT; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Dionne DA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Neumann AE; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Jensen LT; Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark., Barber TR; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK., Soilleux E; Department of Pathology, Tennis Court Rd, University of Cambridge, Cambridge, England., Carrington M; Basic Science Program, Frederick National Laboratory for Cancer Research in the Laboratory of Integrative Cancer Immunology, National Cancer Institute, Bethesda, MD, USA.; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA., McVean G; Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, UK., Rozenblatt-Rosen O; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Genentech, 1 DNA Way, South San Francisco, CA, USA., Regev A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aregev@broadinstitute.org.; Massachusetts Institute of Technology, Department of Biology, Cambridge, MA, USA. aregev@broadinstitute.org.; Howard Hughes Medical Institute, Chevy Chase, MD, USA. aregev@broadinstitute.org.; Genentech, 1 DNA Way, South San Francisco, CA, USA. aregev@broadinstitute.org., Fugger L; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. lars.fugger@ndcn.ox.ac.uk.; Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK. lars.fugger@ndcn.ox.ac.uk.; Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark. lars.fugger@ndcn.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jul 29; Vol. 13 (1), pp. 4398. Date of Electronic Publication: 2022 Jul 29.
DOI: 10.1038/s41467-022-32171-w
Abstrakt: Fetal growth restriction (FGR) affects 5-10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicate KIR and HLA genes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.
(© 2022. The Author(s).)
Databáze: MEDLINE
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