Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia

Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a clinical challenge. Alterations in the normal immune adaptations necessary for the maintenance of a healthy pregnancy are central features of preec...

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Published in:	Frontiers in immunology Vol. 10; p. 1305
Main Authors:	Han, Xiaoyuan, Ghaemi, Mohammad S., Ando, Kazuo, Peterson, Laura S., Ganio, Edward A., Tsai, Amy S., Gaudilliere, Dyani K., Stelzer, Ina A., Einhaus, Jakob, Bertrand, Basile, Stanley, Natalie, Culos, Anthony, Tanada, Athena, Hedou, Julien, Tsai, Eileen S., Fallahzadeh, Ramin, Wong, Ronald J., Judy, Amy E., Winn, Virginia D., Druzin, Maurice L., Blumenfeld, Yair J., Hlatky, Mark A., Quaintance, Cecele C., Gibbs, Ronald S., Carvalho, Brendan, Shaw, Gary M., Stevenson, David K., Angst, Martin S., Aghaeepour, Nima, Gaudilliere, Brice
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 11.06.2019
Subjects:	Adaptive Immunity Adult Case-Control Studies Cohort Studies Female Flow Cytometry Humans Immunity, Innate Immunoassay Immunology Inflammation - blood Inflammation - complications Inflammation - immunology mass cytometry Models, Immunological PBMC Pre-Eclampsia - blood Pre-Eclampsia - diagnosis Pre-Eclampsia - immunology preeclampsia pregnancy Pregnancy - blood Pregnancy - immunology Prospective Studies Signal Transduction - immunology T-Lymphocyte Subsets - immunology mass cytometry preeclampsia PBMC immunology pregnancy
ISSN:	1664-3224, 1664-3224
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Abstract	Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a clinical challenge. Alterations in the normal immune adaptations necessary for the maintenance of a healthy pregnancy are central features of preeclampsia. However, prior analyses primarily focused on the static assessment of select immune cell subsets have provided limited information for the prediction of preeclampsia. Here, we used a high-dimensional mass cytometry immunoassay to characterize the dynamic changes of over 370 immune cell features (including cell distribution and functional responses) in maternal blood during healthy and preeclamptic pregnancies. We found a set of eight cell-specific immune features that accurately identified patients well before the clinical diagnosis of preeclampsia (median area under the curve (AUC) 0.91, interquartile range [0.82-0.92]). Several features recapitulated previously known immune dysfunctions in preeclampsia, such as elevated pro-inflammatory innate immune responses early in pregnancy and impaired regulatory T (Treg) cell signaling. The analysis revealed additional novel immune responses that were strongly associated with, and preceded the onset of preeclampsia, notably abnormal STAT5ab signaling dynamics in CD4 T cell subsets (AUC 0.92, = 8.0E-5). These results provide a global readout of the dynamics of the maternal immune system early in pregnancy and lay the groundwork for identifying clinically-relevant immune dysfunctions for the prediction and prevention of preeclampsia.
AbstractList	Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a clinical challenge. Alterations in the normal immune adaptations necessary for the maintenance of a healthy pregnancy are central features of preeclampsia. However, prior analyses primarily focused on the static assessment of select immune cell subsets have provided limited information for the prediction of preeclampsia. Here, we used a high-dimensional mass cytometry immunoassay to characterize the dynamic changes of over 370 immune cell features (including cell distribution and functional responses) in maternal blood during healthy and preeclamptic pregnancies. We found a set of eight cell-specific immune features that accurately identified patients well before the clinical diagnosis of preeclampsia (median area under the curve (AUC) 0.91, interquartile range [0.82-0.92]). Several features recapitulated previously known immune dysfunctions in preeclampsia, such as elevated pro-inflammatory innate immune responses early in pregnancy and impaired regulatory T (Treg) cell signaling. The analysis revealed additional novel immune responses that were strongly associated with, and preceded the onset of preeclampsia, notably abnormal STAT5ab signaling dynamics in CD4 T cell subsets (AUC 0.92, = 8.0E-5). These results provide a global readout of the dynamics of the maternal immune system early in pregnancy and lay the groundwork for identifying clinically-relevant immune dysfunctions for the prediction and prevention of preeclampsia. Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a clinical challenge. Alterations in the normal immune adaptations necessary for the maintenance of a healthy pregnancy are central features of preeclampsia. However, prior analyses primarily focused on the static assessment of select immune cell subsets have provided limited information for the prediction of preeclampsia. Here, we used a high-dimensional mass cytometry immunoassay to characterize the dynamic changes of over 370 immune cell features (including cell distribution and functional responses) in maternal blood during healthy and preeclamptic pregnancies. We found a set of eight cell-specific immune features that accurately identified patients well before the clinical diagnosis of preeclampsia (median area under the curve (AUC) 0.91, interquartile range [0.82–0.92]). Several features recapitulated previously known immune dysfunctions in preeclampsia, such as elevated pro-inflammatory innate immune responses early in pregnancy and impaired regulatory T (Treg) cell signaling. The analysis revealed additional novel immune responses that were strongly associated with, and preceded the onset of preeclampsia, notably abnormal STAT5ab signaling dynamics in CD4+T cell subsets (AUC 0.92, p = 8.0E-5). These results provide a global readout of the dynamics of the maternal immune system early in pregnancy and lay the groundwork for identifying clinically-relevant immune dysfunctions for the prediction and prevention of preeclampsia. Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a clinical challenge. Alterations in the normal immune adaptations necessary for the maintenance of a healthy pregnancy are central features of preeclampsia. However, prior analyses primarily focused on the static assessment of select immune cell subsets have provided limited information for the prediction of preeclampsia. Here, we used a high-dimensional mass cytometry immunoassay to characterize the dynamic changes of over 370 immune cell features (including cell distribution and functional responses) in maternal blood during healthy and preeclamptic pregnancies. We found a set of eight cell-specific immune features that accurately identified patients well before the clinical diagnosis of preeclampsia (median area under the curve (AUC) 0.91, interquartile range [0.82-0.92]). Several features recapitulated previously known immune dysfunctions in preeclampsia, such as elevated pro-inflammatory innate immune responses early in pregnancy and impaired regulatory T (Treg) cell signaling. The analysis revealed additional novel immune responses that were strongly associated with, and preceded the onset of preeclampsia, notably abnormal STAT5ab signaling dynamics in CD4+T cell subsets (AUC 0.92, p = 8.0E-5). These results provide a global readout of the dynamics of the maternal immune system early in pregnancy and lay the groundwork for identifying clinically-relevant immune dysfunctions for the prediction and prevention of preeclampsia.Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a clinical challenge. Alterations in the normal immune adaptations necessary for the maintenance of a healthy pregnancy are central features of preeclampsia. However, prior analyses primarily focused on the static assessment of select immune cell subsets have provided limited information for the prediction of preeclampsia. Here, we used a high-dimensional mass cytometry immunoassay to characterize the dynamic changes of over 370 immune cell features (including cell distribution and functional responses) in maternal blood during healthy and preeclamptic pregnancies. We found a set of eight cell-specific immune features that accurately identified patients well before the clinical diagnosis of preeclampsia (median area under the curve (AUC) 0.91, interquartile range [0.82-0.92]). Several features recapitulated previously known immune dysfunctions in preeclampsia, such as elevated pro-inflammatory innate immune responses early in pregnancy and impaired regulatory T (Treg) cell signaling. The analysis revealed additional novel immune responses that were strongly associated with, and preceded the onset of preeclampsia, notably abnormal STAT5ab signaling dynamics in CD4+T cell subsets (AUC 0.92, p = 8.0E-5). These results provide a global readout of the dynamics of the maternal immune system early in pregnancy and lay the groundwork for identifying clinically-relevant immune dysfunctions for the prediction and prevention of preeclampsia.
Author	Tsai, Amy S. Einhaus, Jakob Blumenfeld, Yair J. Winn, Virginia D. Aghaeepour, Nima Gaudilliere, Brice Ganio, Edward A. Fallahzadeh, Ramin Culos, Anthony Gaudilliere, Dyani K. Angst, Martin S. Ghaemi, Mohammad S. Quaintance, Cecele C. Druzin, Maurice L. Judy, Amy E. Wong, Ronald J. Stelzer, Ina A. Hlatky, Mark A. Hedou, Julien Gibbs, Ronald S. Carvalho, Brendan Ando, Kazuo Peterson, Laura S. Bertrand, Basile Tsai, Eileen S. Stevenson, David K. Tanada, Athena Stanley, Natalie Shaw, Gary M. Han, Xiaoyuan
AuthorAffiliation	4 March of Dimes Prematurity Research Center, School of Medicine, Stanford University , Palo Alto, CA , United States 2 Department of Pediatrics, School of Medicine, Stanford University , Palo Alto, CA , United States 3 Department of Surgery, School of Medicine, Stanford University , Palo Alto, CA , United States 5 Department of Obstetrics and Gynecology, School of Medicine, Stanford University , Palo Alto, CA , United States 6 Department of Health Research and Policy, School of Medicine, Stanford University , Palo Alto, CA , United States 1 Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University , Palo Alto, CA , United States
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Copyright	Copyright © 2019 Han, Ghaemi, Ando, Peterson, Ganio, Tsai, Gaudilliere, Stelzer, Einhaus, Bertrand, Stanley, Culos, Tanada, Hedou, Tsai, Fallahzadeh, Wong, Judy, Winn, Druzin, Blumenfeld, Hlatky, Quaintance, Gibbs, Carvalho, Shaw, Stevenson, Angst, Aghaeepour and Gaudilliere. 2019 Han, Ghaemi, Ando, Peterson, Ganio, Tsai, Gaudilliere, Stelzer, Einhaus, Bertrand, Stanley, Culos, Tanada, Hedou, Tsai, Fallahzadeh, Wong, Judy, Winn, Druzin, Blumenfeld, Hlatky, Quaintance, Gibbs, Carvalho, Shaw, Stevenson, Angst, Aghaeepour and Gaudilliere
Copyright_xml	– notice: Copyright © 2019 Han, Ghaemi, Ando, Peterson, Ganio, Tsai, Gaudilliere, Stelzer, Einhaus, Bertrand, Stanley, Culos, Tanada, Hedou, Tsai, Fallahzadeh, Wong, Judy, Winn, Druzin, Blumenfeld, Hlatky, Quaintance, Gibbs, Carvalho, Shaw, Stevenson, Angst, Aghaeepour and Gaudilliere. 2019 Han, Ghaemi, Ando, Peterson, Ganio, Tsai, Gaudilliere, Stelzer, Einhaus, Bertrand, Stanley, Culos, Tanada, Hedou, Tsai, Fallahzadeh, Wong, Judy, Winn, Druzin, Blumenfeld, Hlatky, Quaintance, Gibbs, Carvalho, Shaw, Stevenson, Angst, Aghaeepour and Gaudilliere
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Keywords	mass cytometry preeclampsia PBMC immunology pregnancy
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 This article was submitted to Immunological Tolerance and Regulation, a section of the journal Frontiers in Immunology Edited by: Helen Marie McGuire, University of Sydney, Australia These authors have contributed equally to this work Reviewed by: Frederic Sierro, Australian Nuclear Science and Technology Organisation, Australia; Peter Hsu, Children's Hospital at Westmead, Australia
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Snippet	Preeclampsia is one of the most severe pregnancy complications and a leading cause of maternal death. However, early diagnosis of preeclampsia remains a...
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SubjectTerms	Adaptive Immunity Adult Case-Control Studies Cohort Studies Female Flow Cytometry Humans Immunity, Innate Immunoassay Immunology Inflammation - blood Inflammation - complications Inflammation - immunology mass cytometry Models, Immunological PBMC Pre-Eclampsia - blood Pre-Eclampsia - diagnosis Pre-Eclampsia - immunology preeclampsia pregnancy Pregnancy - blood Pregnancy - immunology Prospective Studies Signal Transduction - immunology T-Lymphocyte Subsets - immunology
Title	Differential Dynamics of the Maternal Immune System in Healthy Pregnancy and Preeclampsia
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