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

Xiaoyuan Han, Mohammad S Ghaemi, Kazuo Ando, Laura Peterson, Edward A Ganio, Amy S Tsai, Dyani K Gaudilliere, Jakob Einhaus, Basile Bertrand, Natalie Stanley, Anthony Culos, Athena Taneda, Eileen S Tsai, Ramin Rallahzadeh, Ronald James Wong, Amy E Judy, Virginia D Winn, Druzin L Maurice, Yair J Blumenfeld, Mark A Hlatky, Cecele C Quaintance, Ronald S Gibbs, Brendan Carvalho, Gary M Shaw, David K Stevenson, Martin S Angst, Nima Aghaeepour, Brice Gaudilliere

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, 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.

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