Abstract
BackgroundAltered maternal inflammatory responses play a role in the development of preeclampsia and the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. We examined whether allelic variants of the innate immune receptors Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 2 (NOD2), that impair the inflammatory response to endotoxin, are related to preeclampsia and HELLP syndrome.Methods and FindingsWe determined five common mutations in TLR4 (D299G and T399I) and NOD2 (R702W, G908R and L1007fs) in 340 primiparous women with a history of early-onset preeclampsia, of whom 177 women developed HELLP syndrome and in 113 women with a history of only uneventful pregnancies as controls. In addition, we assessed plasma levels of pro-inflammatory biomarkers C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, fibrinogen and von Willebrand factor in a subset of 214 women included at least six months after delivery. After adjustment for maternal age and chronic hypertension, attenuating allelic variants of TLR4 were more common in women with a history of early-onset preeclampsia than in controls (OR 2.9 [95% CI 1.2–6.7]). Highest frequencies for TLR4 variants were observed in women who developed HELLP syndrome (adjusted OR 4.1 [95% CI 1.7–9.8]). In addition, high levels of interleukin-6 and fibrinogen were associated with a history of early-onset preeclampsia. Combined positivity for any of the TLR4 and NOD2 allelic variants and high levels of interleukin-6 was 6.9-fold more common in women with a history of early-onset preeclampsia (95% CI 2.1–23.2) compared to controls.ConclusionsWe observed an association of common TLR4 and NOD2 gene variants, and pro-inflammatory phenotype with a history of early-onset preeclampsia and HELLP syndrome. These findings suggest involvement of the maternal innate immune system in severe hypertensive disorders of pregnancy.
Highlights
Preeclampsia is a complex multi-system disease of unknown origin, characterized by hypertension and proteinuria in the second half of pregnancy, with potentially life-threatening consequences for both mother and baby [1]
We observed an association of common Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 2 (NOD2) gene variants, and pro-inflammatory phenotype with a history of early-onset preeclampsia and HELLP syndrome
In this study we examined the contribution of two common allelic variants of the TLR4 (D299G and T399I) and three common allelic variants of NOD2 (R702W, G908R and L1007fs) to the pathogenesis of early-onset preeclampsia and HELLP syndrome
Summary
Preeclampsia is a complex multi-system disease of unknown origin, characterized by hypertension and proteinuria in the second half of pregnancy, with potentially life-threatening consequences for both mother and baby [1]. LPS leads to release of pro-inflammatory cytokines through activation of two major pattern recognition receptors (PRRs) present on innate immune cells (macrophages, NK cells and dendritic cells), i.e. the extracellular Toll-like receptor 4 (TLR4), and the intracellular nucleotide oligomerization domain 2 (NOD2) protein, known as the caspase-activating recruitment domain 15 (CARD15). We examined whether allelic variants of the innate immune receptors Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain 2 (NOD2), that impair the inflammatory response to endotoxin, are related to preeclampsia and HELLP syndrome
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