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

doi:10.1016/j.placenta.2010.03.010

Placenta

Volume 31, Issue 7, July 2010, Pages 561-567

https://doi.org/10.1016/j.placenta.2010.03.010 Get rights and content

Abstract

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.

Section snippets

Angiogenic and immune dysregulation in preeclampsia

Preeclampsia is a complex multisystem disease that contributes significantly to maternal and neonatal mortality and morbidity [1], [2], [3]. The classical clinical manifestations, de novo hypertension and proteinuria, occur late in pregnancy, in the setting of maternal endothelial cell activation [4] and excessive systemic inflammation [5].

Preeclampsia has been called the “disease of theories” as its cause is unclear [2]. The pathologic process originates in the placenta, with inadequate

The complement system and tissue injury

The complement system, composed of over 30 proteins that act in concert to protect the host against invading organisms, initiates inflammation and tissue injury (Fig. 2) (described in [45], [46], [47]). Like the clotting cascade, the complement cascade contains a potent amplification mechanism based on sequential cleavage of inactive zymogen forms of proteins by serine protease mechanisms. Complement activation promotes chemotaxis of inflammatory cells and generates proteolytic fragments that

Models of the antiphospholipid antibody syndrome and other adverse pregnancy outcomes

That appropriate complement inhibition is an absolute requirement for normal pregnancy has been demonstrated by the finding that deficiency of Crry (a membrane-bound intrinsic complement regulatory protein in mice, like DAF and MCP, that blocks classical and alternative pathway activation of C3 [62]) leads to embryonic lethality in mice; Crry^−/− embryos are surrounded by activated C3 fragments and PMN [63]. Importantly, embryos are rescued when C3 deficiency or factor B deficiency is introduced

Complement and human pregnancy

Little information is available about complement activation in normal and abnormal human pregnancy [73]. During normal gestation, serum levels of C3, C4, and total hemolytic complement (CH50) gradually increase 10–50% [74], likely reflecting increased synthesis, and levels of complement split products increase, suggesting low grade classical pathway activation [75]. Studies performed nearly 20 years ago showed marked elevations in levels of Bb, C3a, C4d, and soluble C5b-9 in preeclampsia,

Complement activation in preeclampsia patients

In 2005, inspired by novel research in the animal model of APS [65], [90], [91], Lynch et al conducted a prospective study in human pregnancy (n = 701) to investigate whether elevated levels of complement activation fragments Bb (reflecting alternative complement pathway activation) at a single point in early pregnancy (less than 20 weeks gestation) were predictive of preeclampsia later in pregnancy [92]. This was the first large prospective study to examine the relationship between Bb levels in

Conclusion

The complement system provides a link between the innate and adaptive immune systems, recognizing and responding to danger. In preeclampsia, perhaps related to immune maladaptation or oxidative stress, there is increased complement activation at the maternal–fetal interface. 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

Acknowledgements

This research was supported in part by NIH AR49772 (JES), AR38889 (JES) and K23 HD049684 (AML), the Mary Kirkland Center for Lupus Research (JES), American Heart Association (AML), the Center for Women’s Health Research and the List Family Foundation at University of Colorado Denver (AML) and Newborn Hope Colorado (AML).

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There are few early biomarkers to identify pregnancies at risk of preeclampsia (PE) and abnormal placental function. In this cross-sectional study, we utilized targeted ultra-performance liquid chromatography-ESI MS/MS and a linear regression model to identify specific bioactive lipids that serve as early predictors of PE. Plasma samples were collected from 57 pregnant women prior to 24-weeks of gestation with outcomes of either PE (n = 26) or uncomplicated term pregnancies (n = 31), and the profiles of eicosanoids and sphingolipids were evaluated. Significant differences were revealed in the eicosanoid, (±)11,12 DHET, as well as multiple classes of sphingolipids; ceramides, ceramide-1-phosphate, sphingomyelin, and monohexosylceramides; all of which were associated with the subsequent development of PE regardless of aspirin therapy. Profiles of these bioactive lipids were found to vary based on self-designated race. Additional analyses demonstrated that PE patients can be stratified based on the lipid profile as to PE with a preterm birth linked to significant differences in the levels of 12-HETE, 15-HETE, and resolvin D1. Furthermore, subjects referred to a high-risk OB/GYN clinic had higher levels of 20-HETE, arachidonic acid, and Resolvin D1 versus subjects recruited from a routine, general OB/GYN clinic. Overall, this study shows that quantitative changes in plasma bioactive lipids detected by ultra-performance liquid chromatography-ESI-MS/MS can serve as an early predictor of PE and stratify pregnant people for PE type and risk.
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Hypertensive disorders are the most common medical conditions during pregnancy and are a leading cause of maternal and perinatal morbidity and mortality worldwide. Hypertension complicates 6% to 10% of pregnancies and, of 4 million women giving birth in the United States each year, an estimated 240,000 are affected by hypertension. Of concern, hypertension is the most important risk factor for stroke, and there has been an overall rise in the incidence of pregnancy-related stroke and subsequent morbidity in the past 20 years. Although maternal mortality rates are considerably lower in developed nations compared with developing nations, hypertension still accounts for 15% of maternal deaths in the United States, mostly as a result of intracerebral hemorrhage. Although the obstetrician manages most cases of hypertension during pregnancy, the internist, cardiologist, or nephrologist may be consulted if hypertension precedes conception, if end organ damage is present, or when accelerated hypertension occurs. This chapter assumes a medical perspective focusing on nonobstetric diagnostic and therapeutic issues in the care of pregnant women with hypertension.
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We aimed to define the relationships between the serum concentrations of complement factors B and H in mid-pregnancy and the risk of preeclampsia (PE) in patients with gestational diabetes mellitus (GDM).
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The incidence of PE was 5.96 %. The serum concentrations of triacylglycerol (TG), FB, and FH of women with GDM who developed PE (GDM-PE group) in mid-pregnancy were significantly higher than those of the GDM group [TG: 3.60 (2.94–4.63) vs 2.54 (2.14–3.01) mmol/L, p < 0.001; FB: 346 (314–378) vs 284 (263–323) mg/L, p < 0.001; FH: 417 ± 45 vs 379 ± 47 mg/L, p = 0.003]. Multivariate regression analysis showed that high serum concentrations of TG and FB in mid-pregnancy were related to the risk of patients with GDM developing PE [TG: odds ratio (OR) 2.035 (95 % confidence interval (CI) 1.032–4.013); FB: OR 1.018 (95 % CI 1.001–1.035)]. The area under the curve (AUC) of FB for the prediction of PE was 0.821 (95 % CI 0.722–0.921) and that for a combination of TG, FB, and FH was 0.857 (95 % CI 0.770–0.944).
High serum FB concentration during mid-pregnancy is a potential predictor of the risk of PE in patients with GDM, and the combination of FB, FH, and TG increased this predictive value.
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Citation Excerpt :
These mice spontaneously have fetal growth restriction, abnormal placentation, and defects in maternal decidual arteries [76,77]. These issues lead to inflammation and activation of the complement pathway, which has been shown to be associated with adverse pregnancy outcomes [78–80]. Complement inhibition using a fusion protein (CR2-Crry) between a pan-C3 convertase inhibitor, Crry, and a targeting protein that binds to C3 degradation products, CR2, was able to increase placental weight, normalize junctional zone and spiral artery morphology, increase placental vascular endothelial growth factor (VEGF) concentration, and reduce neutrophil recruitment to the placenta without altering the numbers of uterine natural killer cells or macrophages [81].
Maternal mortality rates in the United States have steadily increased since 1987 to the current rate of over 16 deaths per 100,000 live births. Whereas most of these deaths are related to an underlying condition, such as cardiovascular disease, many pregnant women die from diseases that emerge as a consequence of pregnancy. Both pre-existing and emergent diseases and conditions are difficult to treat in pregnant women because of the potential harmful effects of the treatment on the developing fetus. Often the health of the woman and the health of the baby are at odds and must be weighed against each other when medical treatment is needed, frequently leading to iatrogenic preterm birth. However, the use of engineered nanomedicines has the potential to fill the treatment gap for pregnant women. This review describes several conditions that may afflict pregnant women and fetuses and introduces how engineered nanomedicines may be used to treat these illnesses. Although the field of maternal-fetal nanomedicine is in its infancy, with additional research and development, engineered nanotherapeutics may greatly improve outcomes for pregnant women and their offspring in the future.
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2021, Chesley’s Hypertensive Disorders in Pregnancy
Case reports describing familial clustering of eclampsia were first reported in the late 1800s, but Chesley was one of the first to perform a true genetic analysis. Chesley's first edition text summarized his early investigations in hundreds of mother–daughter pairs. He reported that among daughters of women with eclampsia, 26% had preeclampsia in their first pregnancies. By contrast, the daughters-in-law control group had only an 8% rate of first-pregnancy preeclampsia. This comprehensively updated chapter will “fast-forward” the reader into the postgenomic era. As molecular analyses become less expensive and bioinformatic tools become more powerful, we are gaining new appreciation for the complexity of the etiologies, management strategies, and prevention of this syndrome.
Evidence for regulation of the complement system during pregnancy being ancient and conserved in mammals
2020, Developmental and Comparative Immunology
Here we demonstrate that regulation of the Complement (C′) components of the immune system is an ancient and conserved feature of mammalian pregnancy. Transcript levels were reduced for complement components C3 and C4 throughout pregnancy in a marsupial, Monodelphis domestica. Downstream C′ component transcripts were significantly less abundant relative to non-pregnant controls at the start of pregnancy but increased during late pregnancy, in some cases peaking close to parturition. These results are consistent with observations in human pregnancy that deposition of C5 through C9 on fetal membranes is associated with labor and parturition. Complement regulators CD46 and CD59 are present at the fetomaternal interface during M. domestica pregnancy as well, implying regulation of C′ effector mechanisms is necessary for maintenance of normal marsupial pregnancy. Collectively these results support regulating the complement system may have contributed to the transition from oviparity to viviparity in mammals over 165 million years ago.

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

Abstract

Section snippets

Angiogenic and immune dysregulation in preeclampsia

The complement system and tissue injury

Models of the antiphospholipid antibody syndrome and other adverse pregnancy outcomes

Complement and human pregnancy

Complement activation in preeclampsia patients

Conclusion

Acknowledgements

Semin Perinatol

Am J Obstet Gynecol

Semin Fetal Neonatal Med

Lancet

Am J Pathol

Placenta

J Reprod Immunol

J Reprod Immunol

Eur J Obstet Gynecol Reprod Biol

Am J Obstet Gynecol

Blood

J Thromb Haemost

Am J Kidney Dis

Am J Obstet Gynecol

Trends Immunol

Baillieres Clin Obstet Gynaecol

Curr Biol

Cell

J Reprod Immunol

Clin Immunol Immunopathol

Immunol Today

Blood

Adv Immunol

Immunity

Blood

Obstet Gynecol

J Reprod Immunol

Placenta

Am J Obstet Gynecol

Am J Med

Blood

Mol Immunol

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Blood

Blood

Blood

Severe maternal morbidity associated with hypertensive disorders in pregnancy in the United States

Hypertens Pregnancy

Endothelial dysfunction in preeclampsia

Semin Reprod Endocrinol

Gabor Than Award Lecture 2008: pre-eclampsia – from placental oxidative stress to maternal endothelial dysfunction

Placenta

NK cells and trophoblasts: partners in pregnancy

J Exp Med

Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation

J Clin Invest

Placental oxidative stress: from miscarriage to preeclampsia

J Soc Gynecol Investig

Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia

Placenta

Complement activation induces dysregulation of angiogenic factors and causes fetal rejection and growth restriction

J Exp Med

Circulating angiogenic factors and the risk of preeclampsia

N Engl J Med

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia

J Clin Invest

Placental stress and pre-eclampsia: a revised view

Placenta

The two stage model of preeclampsia: variations on the theme

Placenta

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