Disruption in the Regulation of Immune Responses in the Placental Subtype of Preeclampsia

Abstract

Preeclampsia is a pregnancy-specific disorder, of which one of its major subtypes, the placental subtype is considered a response to an ischemic placental environment, impacting fetal growth and pregnancy outcome. Inflammatory immune responses have been linked to metabolic and inflammatory disorders as well as reproductive failures. In healthy pregnancy, immune regulatory mechanisms prevent excessive systemic inflammation. However, in preeclampsia, the regulation of immune responses is disrupted as a result of aberrant activation of innate immune cells and imbalanced differentiation of T-helper cell subsets creating a cytotoxic environment in utero. Recognition events that facilitate immune interaction between maternal decidual T cells, NK cells, and cytotrophoblasts are considered an indirect cause of the incomplete remodeling of spiral arteries in preeclampsia. The mechanisms involved include the activation of immune cells and the subsequent secretion of cytokines and placental growth factors affecting trophoblast invasion, angiogenesis, and eventually placentation. In this review, we focus on the role of excessive systemic inflammation as the result of a dysregulated immune system in the development of preeclampsia. These include insufficient control of inflammation, failure of tolerance toward paternal antigens at the fetal–maternal interface, and subsequent over- or insufficient activation of immune mediators. It is also possible that external stimuli, such as bacterial endotoxin, may contribute to the excessive systemic inflammation in preeclampsia by stimulating the release of pro-inflammatory cytokines. In conclusion, a disrupted immune system might be a predisposing factor or result of placental oxidative stress or excessive inflammation in preeclampsia. Preeclampsia can thus be considered a hyperinflammatory state associated with defective regulation of the immune system proposed as a key element in the pathological events of the placental subtype of this disorder.

Use of antimalarial drugs is associated with a lower risk of preeclampsia in lupus pregnancy: A prospective cohort study

“…29 On the other hand, active disease before and during pregnancy is associated with an increased risk of developing preeclampsia, as it has been previously reported. 32,[34][35][36][37][38][39] In fact some of these angiogenic factors are potential biomarkers for predicting preeclampsia in patients with SLE and APS, such as endoglin, sFlt-1 and PIGF, because these factors are progressively elevated in patients who are complicated with preeclampsia. 38,39 In addition, it has been found that type I interferon can generate an antiangiogenic environment, so that high levels of this cytokine may contribute to the pathogenesis of preeclampsia in some patients with SLE.…”

Markers of Endothelial Injury and Dysfunction in Early- and Late-Onset Preeclampsia

“…Activation and dysregulation of maternal immune system constitutes the second most probable mechanism of endothelial damage and dysfunction in patients with PE [ 15 , 16 ]. The activation of immune system in patients with PE leads to a proinflammatory status, including intravascular inflammation [ 17 ].…”

“…One mechanism leading to the activation of immune cells in women with PE may be the increased shedding of syncytiotrophoblast microparticles (STBM) into maternal circulation following the increased apoptosis of trophoblast cells in the placenta [ 16 ]. Interestingly, the primary dysfunction of immune system in mother may predispose to that by negatively affecting the proper trophoblast invasion in the first half of pregnancy [ 15 ].…”

Impact of pregravid obesity on maternal and fetal immunity: Fertile grounds for reprogramming

“…[128][129][130] For instance, studies have reported decreased IL-35 and IL-9 levels and concurrent drop in CD11c+ myleloid cells and regulatory T cell populations over the course of gestation. 128 Local changes in frequencies, phenotype, and functions of immune cells in the decidua and villi have been attributed in the pathogenesis of several obstetric complications such as preterm labor, 131 PE, [132][133][134] and chorioamnionitis. 135 Indeed, first trimester placentas from women with obesity show reduced uterine NK cell numbers, which normally comprise ∼70% of the leukocyte population in early human decidua and play a central role in uterine artery remodeling and altered expression of genes in pathways associated with matrix remodeling and growth factor signaling 136 (Fig.…”