Abstract
Preeclampsia is one of the leading causes of maternal and neonatal mortality and morbidity worldwide, affecting 2–8% of all pregnancies. Studies suggest a link between complement activation and preeclampsia. The complement system plays an essential role in the innate immunity, leading to opsonization, inflammation, and elimination of potential pathogens. The complement system also provides a link between innate and adaptive immunity and clearance of immune complexes and apoptotic cells. During pregnancy there is increased activity of the complement system systemically. However, locally at the placenta, complement inhibition is crucial for the maintenance of a normal pregnancy. Inappropriate or excessive activation of the complement system at the placenta is likely involved in placental dysfunction, and is in turn associated with pregnancy complications like preeclampsia. Therefore, modulation of the complement system could be a potential therapeutic target to prevent pregnancy complications such as preeclampsia. This review, based on a systematic literature search, gives an overview of the complement system and its activation locally in the placenta and systemically during healthy pregnancies and during complicated pregnancies, with a focus on preeclampsia. Furthermore, this review describes results of animal and human studies with a focus on the complement system in pregnancy, and the role of the complement system in placental dysfunction. Various clinical and animal studies provide evidence that dysregulation of the complement system is associated with placental dysfunction and therefore with preeclampsia. Several drugs are used for prevention and treatment of preeclampsia in humans and animal models, and some of these drugs work through complement modulation. Therefore, this review further discusses these studies examining pharmaceutical interventions as treatment for preeclampsia. These observations will help direct research to generate new target options for prevention and treatment of preeclampsia, which include direct and indirect modulation of the complement system.
Highlights
In pregnancy, protection of mother and fetus against potential pathogens is essential, a functional immune system is required (1)
For this review we aimed to provide an overview of the complement system, and its activation locally in the placenta, and systemically during normal healthy pregnancy, and complicated pregnancies, focusing on preeclampsia
We undertook a systematic search of the published literature on animal and human studies, which investigated the role of the complement system in placental dysfunction, as it occurs in preeclampsia
Summary
Protection of mother and fetus against potential pathogens is essential, a functional immune system is required (1). The endothelial cells of the spiral arteries are partly substituted by endovascular (extravillous) trophoblasts (2). A healthy pregnancy is associated with immunological changes, especially locally at the feto-maternal interface, characterized by the presence of uterine NK cells, and the induction of regulatory T cells both essential for spiral artery remodeling, normal placental development, and preventing fetal tissue rejections (4). The complement system plays an important role in these processes (1). It recruits and activates immune cells which leads to opsonization, inflammation, and lysis of potential pathogens (1, 2). Control of complement activation at the feto-maternal interface is important for a successful pregnancy, and may otherwise lead to adverse pregnancy outcomes including preeclampsia (3)
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