PBMC-derived RNA signatures show impaired ability to regulate immune responses in women developing preeclampsia†.

Preeclampsia is a serious pregnancy complication with unclear etiology, making early detection challenging but imperative to improve prognosis. We here examine the potential roles of protein-coding and long non-coding (lnc) RNA from peripheral blood mononuclear cells (PBMCs) in the development of preeclampsia by examining women during pregnancy and 5 years following pregnancy. We isolated PBMCs from women with preeclampsia (N = 37) and normal pregnant controls (N = 215) at 22-24 and 36-38 weeks of gestation, and 5-year follow-up. We performed RNA sequencing at all time points for N = 7 normal pregnant controls and N = 9 women with preeclampsia and explored data manually and using bioinformatics analyses. Spearman correlation was used between lncRNA and preeclampsia-associated markers, while Notch-related RNAs were measured by qPCR. We found dysregulated RNAs at all time points, mostly at 36-38 weeks (491 upregulated, 155 downregulated). Most downregulated RNAs were lncRNA and these correlated positively with P-selectin and negatively with sFlt-1 and myeloperoxidase from the maternal circulation. Overrepresentation analyses and manual data exploration at 36-38 weeks revealed increased activation of adaptive immune functions and dampening of innate immune response, including Notch signaling. NOTCH2NLA/B/C was decreased at 22-24 weeks in the total cohort. In conclusion, circulating protein-coding and lncRNA from women developing preeclampsia broadly indicate enhanced adaptive immune cell activation but dampened innate immune responses. The association of downregulated lncRNAs with markers of endothelial dysfunction and platelet activation may support impaired immune regulation in these women. The function of circulating lncRNAs in women with preeclampsia warrants further study.