Four Pathways Involving Innate Immunity in the Pathogenesis of Preeclampsia

Abstract

The maternal innate immune system plays an important role both in normal pregnancy as well as hypertensive disorders of pregnancy including preeclampsia (PE). We propose four pathways that involve excessive innate immunity that lead to most forms of PE. Pre-existing endothelial dysfunction plus pregnancy leads to an excessive innate immune response resulting in widespread inflammation, placental and renal dysfunction, vasoconstriction, and PE. Placental dysfunction due to shallow trophoblast invasion, inadequate spiral artery remodeling, and/or low placental perfusion initiates an innate immune response leading to excessive inflammation, endothelial and renal dysfunction, and PE. A heightened innate immune system due to pre-existing or acquired infections plus the presence of a paternally derived placenta and semi-allogeneic fetus cause an excessive innate immune response which manifests as PE. Lastly, an abnormal and excessive maternal immune response to pregnancy leads to widespread inflammation, organ dysfunction, and PE. We discuss the potential role of innate immunity in each of these scenarios, as well as the overlap, and how targeting the innate immune system might lead to therapies for the treatment of PE.

Preeclampsia and health risks later in life: an immunological link

“…Interestingly, our published and unpublished observations strongly suggest that dNK cells have the potential to turn into foes to pregnancy in response to inflammatory triggers. In experimental models, LPS and poly IC treatment of pregnant mice can induce alterations in the phenotype and functional characteristics of dNK cells by stimulating production of inflammatory cytokines such as TNF-α and IFN-γ [44][45][46]. In humans, it is possible that defective regulatory activation of dNK cells combined with local inflammation or intrauterine infection may program poor placentation and associated pathologies.…”

Human placenta-derived stromal cells decrease inflammation, placental injury and blood pressure in hypertensive pregnant mice

“…In addition, there have been reports that women with abnormal immune responses to endogenous (autoimmunity) and exogenous (paternally derived) antigens are highly vulnerable to developing PE during the physiological stress of pregnancy [10,11]. Although all four of these scenarios originate from different initiators, they all involve the innate immune system [12].…”

Increased serum levels of high mobility group protein B1 and calprotectin in pre‐eclampsia

“…Potential etiological factors for this complication of pregnancy include poor placentation, excessive maternal inflammation and immune response, and endothelial dysfunction . Several studies have reported that an exaggerated inflammatory response and an imbalanced immune response together play important roles in the development of pre‐eclampsia …”

“…2 Several studies have reported that an exaggerated inflammatory response and an imbalanced immune response together play important roles in the development of pre-eclampsia. [3][4][5] Among women with high-risk pregnancies, both damage- immunologic response and promote persistent inflammatory conditions by activating pattern-recognition receptors. 6 DAMPs are self-molecules primarily released as a result of non-programmed cell death in the first few hours of an injury.…”