Dysregulated Complement Activation as a Common Pathway of Injury in Preeclampsia and Other Pregnancy Complications

Department of Obstetrics and Gynecology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
Placenta (Impact Factor: 2.71). 07/2010; 31(7):561-7. DOI: 10.1016/j.placenta.2010.03.010
Source: PubMed


The complement system protects the host against invading organisms, initiates inflammation and dispose of immune complexes and the products of inflammatory injury. The complement system provides an important link between the innate and adaptive immune systems. Experimental observations suggest that increased complement activation causes and/or perpetuates inflammation during pregnancy. Recent studies suggest a link between complement activation and preeclampsia. Excessive activation or insufficient regulation of complement recruits leukocytes and unleashes potent inflammatory and anti-angiogenic mediators associated with placental insufficiency and maternal endothelial dysfunction characteristic of preeclampsia. We review the animal and human studies that link complement activation and pathogenic events in preeclampsia, present evidence that activation of the complement system is associated with the development of preeclampsia and provides new targets to prevent its complications.

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Available from: Jane E Salmon,
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    • "That a single signaling pathway could account for this vascular phenotype induced by malaria is attractive for the development of therapeutic interventions. These findings may also have broad implications for other pregnancy complications associated with immune activation and placental insufficiency (e.g., preeclampsia), where both C5a and sFlt-1 have been associated with adverse birth outcomes (Lynch and Salmon, 2010). "
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    ABSTRACT: Placental malaria (PM) is a major cause of fetal growth restriction, yet the underlying mechanism is unclear. Complement C5a and C5a receptor levels are increased with PM. C5a is implicated in fetal growth restriction in non-infection-based animal models. In a case-control study of 492 pregnant Malawian women, we find that elevated C5a levels are associated with an increased risk of delivering a small-for-gestational-age infant. C5a was significantly increased in PM and was negatively correlated with the angiogenic factor angiopoietin-1 and positively correlated with angiopoietin-2, soluble endoglin, and vascular endothelial growth factor. Genetic or pharmacological blockade of C5a or its receptor in a mouse model of PM resulted in greater fetoplacental vessel development, reduced placental vascular resistance, and improved fetal growth and survival. These data suggest that C5a drives fetal growth restriction in PM through dysregulation of angiogenic factors essential for placental vascular remodeling resulting in placental vascular insufficiency.
    Cell host & microbe 02/2013; 13(2):215-26. DOI:10.1016/j.chom.2013.01.010 · 12.33 Impact Factor
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    • "The traditional view is that the presence of the aPL leads to activation of the clotting cascade , thereby leading to placental infarction and ensuing fetal demise ( Weiler , 2008 ; Lynch and Salmon , 2010 ; Girardi , 2011 ) . Support for this notion is provided by the clinical use of low molecular weight heparin , which has been shown to be effective in preventing fetal loss in most cases ( Hahn et al . "
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    ABSTRACT: The intention of this review is to provide an overview of the potential role of neutrophil extracellular traps (NETs) in mammalian reproduction. Neutrophil NETs appear to be involved in various stages of the reproductive cycle, starting with fertility and possibly ending with fetal loss. The first suggestion that NETs may play a role in pregnancy-related disorders was in preeclampsia, where vast numbers were detected in the intervillous space of affected placentae. The induction of NETosis involved an auto-inflammatory component, mediated by the increased release of placental micro-debris in preeclampsia. This report was the first indicating that NETs may be associated with a human pathology not involving infection. Subsequently, NETs have since then been implicated in bovine or equine infertility, in that semen may become entrapped in the female reproductive tract during their passage to the oocyte. In this instance interesting species-specific differences are apparent, in that equine sperm evade entrapment via expression of a DNAse-like molecule, whereas highly motile bovine sperm, once free from seminal plasma (SP) that promotes interaction with neutrophils, appear impervious to NETs entrapment. Although still in the realm of speculation it is plausible that NETs may be involved in recurrent fetal loss mediated by anti-phospholipid antibodies, or perhaps even in fetal abortion triggered by infections with microorganisms such as L. monocytogenes or B. abortus.
    Frontiers in Immunology 11/2012; 3:362. DOI:10.3389/fimmu.2012.00362
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    • "We demonstrated a role for complement activation in promoting the growth of transplanted tumors through myeloid-derived suppressor cell (MDSC) recruitment and activation in mice [16], but the role of complement in early oncogenic events remains unknown. Complement proteins are well established as important effectors in pathologic neovascularization in age-related macular degeneration (AMD [17]), diabetic retinopathy, and retinopathy of prematurity [18], as well as in the regulation of the angiogenic factors required for normal placental development [19] [20]. AMD involves a process whereby inappropriate angiogenesis in the choroid causes vascular invasion into the adjacent retina (choroidal neovascularization); preclinical models of AMD directly link complement to this process as complement components C3a and C5a promote choroidal neovascularization [21] and C5a increases vascular endothelial growth factor (VEGF) secretion of human retinal pigment epithelial cells [17]. "
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    ABSTRACT: Complement activation plays a critical role in controlling inflammatory responses. To assess the role of complement during ovarian cancer progression, we crossed two strains of mice with genetic complement deficiencies with transgenic mice that develop epithelial ovarian cancer (TgMISIIR-TAg). TgMISIIR-TAg mice fully or partially deficient for complement factor 3 (C3) (Tg(+)C3(KO) and Tg(+)C3(HET), respectively) or fully deficient for complement factor C5a receptor (C5aR) (Tg(+)C5aR(KO)) develop either no ovarian tumors or tumors that were small and poorly vascularized compared to wild-type littermates (Tg(+)C3(WT), Tg(+)C5aR(WT)). The percentage of tumor infiltrating immune cells in Tg(+)C3(HET) tumors compared to Tg(+)C3(WT) controls was either similar (macrophages, B cells, myeloid-derived suppressor cells), elevated (effector T cells), or decreased (regulatory T cells). Regardless of these ratios, cytokine production by immune cells taken from Tg(+)C3(HET) tumors was reduced on stimulation compared to Tg(+)C3(WT) controls. Interestingly, CD31(+) endothelial cell (EC) function in angiogenesis was significantly impaired in both C3(KO) and C5aR(KO) mice. Further, using the C5aR antagonist PMX53, tube formation of ECs was shown to be C5a-dependent, possibly through interactions with the VEGF(165) but not VEGF(121) isoform. Finally, the mouse VEGF(164) transcript was underexpressed in C3(KO) livers compare to C3(WT) livers. Thus, we conclude that complement inhibition blocks tumor outgrowth by altering EC function and VEGF(165) expression.
    Neoplasia (New York, N.Y.) 11/2012; 14(11):994-1004. DOI:10.1593/neo.121262 · 4.25 Impact Factor
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