Immune activation by nucleic acids: A role in pregnancy complications

Abstract

Cell-free self-DNA or RNA may induce an immune response by activating specific sensing receptors. During pregnancy, placental nucleic acids present in the maternal circulation further activate these receptors due to the presence of unmethylated CpG islands. A higher concentration of cell-free foetal DNA is associated with pregnancy complications and a higher risk for foetal rejection. Cell-free foetal DNA originates from placental trophoblasts. It appears in different forms: free, bound to histones in nucleosomes, in neutrophil extracellular traps (NETs) and in extracellular vesicles (EVs). In several pregnancy complications, cell-free foetal DNA triggers the production of proinflammatory cytokines, and this production results in a cellular and humoral immune response. This review discusses preeclampsia, systemic lupus erythematosus, foetal growth restriction, gestational diabetes, rheumatoid arthritis and obesity in pregnancy from an immunological point of view and closely examines the different pathways that result in maternal inflammation. Understanding the role of cell-free nucleic acids, as well as the biogenesis of NETs and EVs, will help us to specify their functions or targets, which seem to be important in pregnancy complications. It is still not clear whether higher concentrations of cell-free nucleic acids in the maternal circulation are the cause or consequence of various complications. Therefore, further clinical studies and, even more importantly, animal experiments that focus on the involved immunological pathways are needed.

DNA in extracellular vesicles: biological and clinical aspects

“…During pregnancy, immunomodulation may result from EVs released from the placental trophoblast into the maternal circulation. EVs contribute to the amount of total fetal cfDNA, which in turn plays a role in pregnancy complications and fetal rejection, and possibly spontaneous abortion and preterm delivery as well [86,87]. There is increasing evidence that EVs play an important role in the pathogenesis of systemic lupus erythematosus and rheumatoid arthritis in pregnant women.…”

Mechanisms of Key Innate Immune Cells in Early- and Late-Onset Preeclampsia

“…Neutrophil extracellular traps (NETs) have been found in the intervillous spaces of placentae in women with preeclampsia (25). The formation of these web-like chromatin structures is induced by STB microparticles (STBMs) released from the placenta and ROS (91). Neutrophils, in addition to causing inflammation, represent the first wave of leukocytes responding to inflammation (5,83).…”

Role of the NLRP3 Inflammasome in Preeclampsia

“…During pregnancy, the amount of total cfDNA and cf-fetal DNA (cffDNA) is significantly increased in the maternal blood depending on the stage of pregnancy (98). There are also significant associations between elevated cfDNA and cffDNA with pregnancy complications such as PE and FGR (98)(99)(100)(101)(102)(103)(104). We recently showed that expression levels of TLR9 and the amount of cffDNA from the placenta were higher in PE patients compared with that in women with normal placenta (NP), and PE-derived cffDNA stimulated levels of inflammatory cytokine, including IL-1β and sEng secretion depend on TLR9 signaling, compared with NP-derived cffDNA (105).…”