Frontiers in Immunology (Aug 2018)
Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia
- Nandor Gabor Than,
- Nandor Gabor Than,
- Nandor Gabor Than,
- Nandor Gabor Than,
- Nandor Gabor Than,
- Nandor Gabor Than,
- Roberto Romero,
- Roberto Romero,
- Roberto Romero,
- Roberto Romero,
- Roberto Romero,
- Adi Laurentiu Tarca,
- Adi Laurentiu Tarca,
- Adi Laurentiu Tarca,
- Adi Laurentiu Tarca,
- Katalin Adrienna Kekesi,
- Yi Xu,
- Yi Xu,
- Zhonghui Xu,
- Zhonghui Xu,
- Zhonghui Xu,
- Kata Juhasz,
- Gaurav Bhatti,
- Gaurav Bhatti,
- Ron Joshua Leavitt,
- Zsolt Gelencser,
- Janos Palhalmi,
- Tzu Hung Chung,
- Balazs Andras Gyorffy,
- Laszlo Orosz,
- Amanda Demeter,
- Anett Szecsi,
- Eva Hunyadi-Gulyas,
- Zsuzsanna Darula,
- Attila Simor,
- Katalin Eder,
- Szilvia Szabo,
- Szilvia Szabo,
- Vanessa Topping,
- Vanessa Topping,
- Haidy El-Azzamy,
- Haidy El-Azzamy,
- Christopher LaJeunesse,
- Christopher LaJeunesse,
- Andrea Balogh,
- Andrea Balogh,
- Andrea Balogh,
- Gabor Szalai,
- Gabor Szalai,
- Gabor Szalai,
- Susan Land,
- Olga Torok,
- Zhong Dong,
- Zhong Dong,
- Ilona Kovalszky,
- Andras Falus,
- Hamutal Meiri,
- Sorin Draghici,
- Sorin Draghici,
- Sonia S. Hassan,
- Sonia S. Hassan,
- Sonia S. Hassan,
- Sonia S. Hassan,
- Tinnakorn Chaiworapongsa,
- Tinnakorn Chaiworapongsa,
- Tinnakorn Chaiworapongsa,
- Manuel Krispin,
- Martin Knöfler,
- Offer Erez,
- Offer Erez,
- Offer Erez,
- Offer Erez,
- Graham J. Burton,
- Chong Jai Kim,
- Chong Jai Kim,
- Chong Jai Kim,
- Chong Jai Kim,
- Gabor Juhasz,
- Zoltan Papp
Affiliations
- Nandor Gabor Than
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Nandor Gabor Than
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Nandor Gabor Than
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States
- Nandor Gabor Than
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
- Nandor Gabor Than
- Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary
- Nandor Gabor Than
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- Roberto Romero
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Roberto Romero
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Roberto Romero
- Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States
- Roberto Romero
- Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, United States
- Roberto Romero
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States
- Adi Laurentiu Tarca
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Adi Laurentiu Tarca
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Adi Laurentiu Tarca
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States
- Adi Laurentiu Tarca
- 0Department of Computer Science, College of Engineering, Wayne State University, Detroit, MI, United States
- Katalin Adrienna Kekesi
- 1Laboratory of Proteomics, Department of Physiology and Neurobiology, ELTE Eotvos Lorand University, Budapest, Hungary
- Yi Xu
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Yi Xu
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Zhonghui Xu
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Zhonghui Xu
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Zhonghui Xu
- 2Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard University, Boston, MA, United States
- Kata Juhasz
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
- Gaurav Bhatti
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Gaurav Bhatti
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Ron Joshua Leavitt
- 3Zymo Research Corporation, Irvine, CA, United States
- Zsolt Gelencser
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
- Janos Palhalmi
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
- Tzu Hung Chung
- 3Zymo Research Corporation, Irvine, CA, United States
- Balazs Andras Gyorffy
- 1Laboratory of Proteomics, Department of Physiology and Neurobiology, ELTE Eotvos Lorand University, Budapest, Hungary
- Laszlo Orosz
- 4Department of Obstetrics and Gynaecology, University of Debrecen, Debrecen, Hungary
- Amanda Demeter
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
- Anett Szecsi
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
- Eva Hunyadi-Gulyas
- 5Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary
- Zsuzsanna Darula
- 5Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Szeged, Hungary
- Attila Simor
- 1Laboratory of Proteomics, Department of Physiology and Neurobiology, ELTE Eotvos Lorand University, Budapest, Hungary
- Katalin Eder
- 6Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
- Szilvia Szabo
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
- Szilvia Szabo
- 7Department of Morphology and Physiology, Semmelweis University, Budapest, Hungary
- Vanessa Topping
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Vanessa Topping
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Haidy El-Azzamy
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Haidy El-Azzamy
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Christopher LaJeunesse
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Christopher LaJeunesse
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Andrea Balogh
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Andrea Balogh
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Andrea Balogh
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
- Gabor Szalai
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Gabor Szalai
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Gabor Szalai
- Systems Biology of Reproduction Lendulet Research Group, Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
- Susan Land
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States
- Olga Torok
- 4Department of Obstetrics and Gynaecology, University of Debrecen, Debrecen, Hungary
- Zhong Dong
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Zhong Dong
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Ilona Kovalszky
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
- Andras Falus
- 6Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
- Hamutal Meiri
- 8TeleMarpe Ltd, Tel Aviv, Israel
- Sorin Draghici
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, United States
- Sorin Draghici
- 9Department of Clinical and Translational Science, Wayne State University, Detroit, MI, United States
- Sonia S. Hassan
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Sonia S. Hassan
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Sonia S. Hassan
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States
- Sonia S. Hassan
- 0Department of Physiology, Wayne State University School of Medicine, Detroit, MI, United States
- Tinnakorn Chaiworapongsa
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Tinnakorn Chaiworapongsa
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Tinnakorn Chaiworapongsa
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States
- Manuel Krispin
- 3Zymo Research Corporation, Irvine, CA, United States
- Martin Knöfler
- 1Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
- Offer Erez
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Offer Erez
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Offer Erez
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, United States
- Offer Erez
- 2Department of Obstetrics and Gynecology, Soroka University Medical Center School of Medicine, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
- Graham J. Burton
- 3Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
- Chong Jai Kim
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, United States
- Chong Jai Kim
- Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Detroit, MI, United States
- Chong Jai Kim
- 4Department of Pathology, Wayne State University School of Medicine, Detroit, MI, United States
- Chong Jai Kim
- 5Department of Pathology, Asan Medical Center, University of Ulsan, Seoul, South Korea
- Gabor Juhasz
- 1Laboratory of Proteomics, Department of Physiology and Neurobiology, ELTE Eotvos Lorand University, Budapest, Hungary
- Zoltan Papp
- Maternity Private Department, Kutvolgyi Clinical Block, Semmelweis University, Budapest, Hungary
- DOI
- https://doi.org/10.3389/fimmu.2018.01661
- Journal volume & issue
-
Vol. 9
Abstract
Preeclampsia is a disease of the mother, fetus, and placenta, and the gaps in our understanding of the complex interactions among their respective disease pathways preclude successful treatment and prevention. The placenta has a key role in the pathogenesis of the terminal pathway characterized by exaggerated maternal systemic inflammation, generalized endothelial damage, hypertension, and proteinuria. This sine qua non of preeclampsia may be triggered by distinct underlying mechanisms that occur at early stages of pregnancy and induce different phenotypes. To gain insights into these molecular pathways, we employed a systems biology approach and integrated different “omics,” clinical, placental, and functional data from patients with distinct phenotypes of preeclampsia. First trimester maternal blood proteomics uncovered an altered abundance of proteins of the renin-angiotensin and immune systems, complement, and coagulation cascades in patients with term or preterm preeclampsia. Moreover, first trimester maternal blood from preterm preeclamptic patients in vitro dysregulated trophoblastic gene expression. Placental transcriptomics of women with preterm preeclampsia identified distinct gene modules associated with maternal or fetal disease. Placental “virtual” liquid biopsy showed that the dysregulation of these disease gene modules originates during the first trimester. In vitro experiments on hub transcription factors of these gene modules demonstrated that DNA hypermethylation in the regulatory region of ZNF554 leads to gene down-regulation and impaired trophoblast invasion, while BCL6 and ARNT2 up-regulation sensitizes the trophoblast to ischemia, hallmarks of preterm preeclampsia. In summary, our data suggest that there are distinct maternal and placental disease pathways, and their interaction influences the clinical presentation of preeclampsia. The activation of maternal disease pathways can be detected in all phenotypes of preeclampsia earlier and upstream of placental dysfunction, not only downstream as described before, and distinct placental disease pathways are superimposed on these maternal pathways. This is a paradigm shift, which, in agreement with epidemiological studies, warrants for the central pathologic role of preexisting maternal diseases or perturbed maternal–fetal–placental immune interactions in preeclampsia. The description of these novel pathways in the “molecular phase” of preeclampsia and the identification of their hub molecules may enable timely molecular characterization of patients with distinct preeclampsia phenotypes.
Keywords
