Critical Role and Therapeutic Control of the Lectin Pathway of Complement Activation in an Abortion-Prone Mouse Mating. (original) (raw)

Activation of the complement system in normal pregnancy and preeclampsia

Molecular Immunology, 2010

The purpose of this study was to explore the role of the complement system in normal human pregnancy and preeclampsia in a comprehensive manner, measuring circulating levels of complement proteins, their activation fragments and regulatory factors, as well as those of C-reactive protein (CRP). Sixty preeclamptic patients, 60 healthy pregnant women and 59 healthy non-pregnant women were involved in this case-control study. Circulating levels of complement components and CRP were determined with ELISA, radial immunodiffusion and particle enhanced immunoturbidimetric assay. Levels of CRP, C4d, C3a, SC5b9, C3, C9 and factor H antigen were significantly higher, while those of C1-inhibitor were significantly lower in healthy pregnant than non-pregnant women. In addition, preeclamptic patients had significantly higher CRP, C4d, C3a, SC5b9 levels and significantly lower C3 concentrations as compared to healthy pregnant women. Their CRP, C4d, C3a, SC5b9, C4, C3, C9 and factor H antigen levels were significantly higher, while C1-inhibitor concentrations were significantly lower compared with healthy non-pregnant women. However, no significant difference was found in Bb and C4b-binding protein levels among the three study groups. Preeclamptic patients with fetal growth restriction had significantly higher plasma SC5b9 levels than those without IUGR. There was a relative deficiency of C1-inhibitor and C4b-binding protein, and a relative abundance of factor H both in normal pregnancy and preeclampsia. Activation of the classical or lectin pathway (C4d) showed significant positive correlation to C3 activation (C3a) both in healthy pregnant women and preeclamptic patients. However, the correlation between C3 and terminal pathway activation was dominating only in patients with preeclampsia, but not in healthy pregnant women. In conclusion, the complement system is activated through the classical and/or lectin pathways with increased terminal complex formation in the third trimester of normal human pregnancy, and further in preeclampsia, as shown by the elevated amounts of activation markers in the systemic circulation. Excessive activation of the terminal pathway is associated with fetal growth restriction in preeclamptic women. However, additional studies are required to determine the cause and consequence of systemic complement activation in this pregnancy-specific disorder.

The immunology of preeclampsia

Seminars in Perinatology, 1999

The immune maladaptation hypothesis of preeclampsia is concordant with cytokine-mediated oxidative stress, chronology of endothelial activation, lipid changes, adverse effect of changing partners, and the protective effect of sperm exposure. Genetic factors may involve underlying hereditary thrombophilic disorders and hyperhomocysteinemia, essential hypertension and/or obesity, or control of the Thl/Th2 balance and thus affect the maternal response against fetal antigens. Placental ischemia and increased syncytiotrophoblast deportation are probably end-stage disease phenomena.

An immunological insight into the origins of pre-eclampsia

Human Reproduction Update, 2010

† Introduction † Search method † The role of the immune system in the origin of pre-eclampsia † The role of NK cells in pre-eclampsia † The expression and role of MHC molecules on the trophoblast † ILT receptors † The role of IFN-g and other cytokines † The Th1/Th2 paradigm and its relationship with pre-eclampsia † The role of regulatory T lymphocytes † Do Th17 lymphocytes participate in pre-eclampsia? † Negative co-regulatory molecules: their participation in immune control in pregnancy † Immune system modulation by DCs and their relationship with pre-eclampsia † The role of indoleamine 2,3-dioxygenase † Could damage-and pathogen-associated molecular patterns participate in the origins of pre-eclampsia? † Conclusions background: Pre-eclampsia is a syndrome of heterogeneous origin characterized by deficient placentation due to the inability of the cytotrophoblast to acquire an invasive phenotype and to remodel the uterine spiral arteries. One of the main problems observed early in pre-eclampsia is an altered regulation of the immune system, where the shift toward a Th2 cytokine profile observed in normal pregnancies, does not occur. In pre-eclampsia, high interferon (IFN)-g concentrations are present, along with transforming growth factor-b cytokines, which retard migration of cytotrophoblasts. methods: A review of the scientific literature was performed on the immunological factors associated with the origins of pre-eclampsia. The various components of the immune system that may be participating in the aberrant immune activation that pathologically affect early pregnancy events and inhibit cytotrophoblast invasion were identified. results and conclusions: Cells and their signaling and regulatory molecules have been implicated in the immunological alterations found in the placental microenvironment of patients who develop pre-eclampsia. One of the main differences found in pre-eclampsia is a shift toward Th1 responses and the production of IFN-g. The origin of IFN-g is not clearly identified and could be the uterine natural killer cells, the placental dendritic cells modulating Th responses, alterations in synthesis of or response to regulatory molecules, or changes in the function of regulatory T cells in pregnancy. Aberrant immune responses promoting pre-eclampsia may also be due to an altered fetal allorecognition or to inflammatory triggers. Understanding the immunological basis for pre-eclampsia will expand knowledge regarding other adverse pregnancy outcomes.

Activation of Leukocytes During the Uteroplacental Passage in Preeclampsia

Hypertension, 2002

Endothelial dysfunction and inflammation appear to play a major role in the pathogenesis of preeclampsia. We hypothesize that a chronic inflammation in the decidua and placenta during preeclampsia may lead to a local leukocyte activation in this compartment. Venous blood was sampled simultaneously from antecubital and uterine veins during cesarean sections in 30 women with preeclampsia, 29 with uncomplicated pregnancies, and from 17 nonpregnant women. The expression of adhesion molecules and complement-related markers on neutrophils and monocytes was analyzed by flow cytometry. In patients with preeclampsia, neutrophil expression of the integrins CD11a, CD11b, and CD11c and of the complement related markers CD35 and CD59 was significantly higher in samples from uterine than from antecubital veins . No differences were found in nonpregnant women. On monocytes the expression of the Sialyl Lewis x antigen, the integrins CD11a, CD11c, and CD49d, and the complement-related markers CD46 a...

A leading role for the immune system in the pathophysiology of preeclampsia

Journal of Leukocyte Biology, 2013

Preeclampsia syndrome is characterized by inadequate placentation, because of deficient trophoblastic invasion of the uterine spiral arteries, leading to placental hypoxia, secretion of proinflammatory cytokines, the release of angiogenic and antiangiogenic factors and miRNAs. Although immune-system alterations are associated with the origin of preeclampsia, other factors, including proinflammatory cytokines, neutrophil activation, and endothelial dysfunction, are also related to the pathophysiology of this syndrome. The pathophysiology of preeclampsia may involve several factors, including persistent hypoxia at the placental level and the release of high amounts of STBMs. DAMP molecules released under hypoxic conditions and STBMs, which bind TLRs, may activate monocytes, DCs, NK cells, and neutrophils, promoting persistent inflammatory conditions in this syndrome. The development of hypertension in preeclamptic women is also associated with endothelial dysfunction, which may be mediated by various mechanisms, including neutrophil activation and NET formation. Furthermore, preeclamptic women have higher levels of nonclassic and intermediate monocytes and lower levels of lymphoid BDCA-2 ϩ DCs. The cytokines secreted by these cells may contribute to the inflammatory process and to changes in adaptive-immune system cells, which are also modulated in preeclampsia. The changes in T cell subsets that may be seen in preeclampsia include low Treg activity, a shift toward Th1 responses, and the presence of Th17 lymphocytes. B cells can participate in the pathophysiology of preeclampsia by producing autoantibodies against adrenoreceptors and au-toantibodies that bind the AT1-R.

Cytokines and C-reactive protein in moderate and severe preeclampsia

Perinatal Journal, 2015

Orta ve ileri derece preeklampside sitokinler ve C-reaktif protein Amaç: Bu çal›flman›n amac›, gebeli¤in üçüncü trimesterinde orta ve ileri derece preeklampside pro-enflamatuar (IL-1β, IL-8) ve anti-enflamatuar (IL-10) sitokin ve C-reaktif protein (CRP) üretimi ile tümör nekroz faktörünü (TNF) de¤erlendirmektir. Yöntem: Preeklampsi komplikasyonlu 50 gebe ve normotensif 50 gebe, gebeliklerinin üçüncü trimesterinde de¤erlendirildi. IL-1β, IL-8, IL-10 ve TNF-α seviyeleri, kat› fazl› enzim immunoassay yard›m›yla ölçüldü. ‹statistiksel veriler, SPSS Windows 13 yaz›l›m› kullan›larak ifllendi. Analiz edilen de¤iflkenlerin da¤›l›m›n› aç›klamak üzere tan›mlay›c› yöntemler (ortalama, medyan, minimum ve maksimum) kullan›ld›. Bulgular: ‹leri derece preeklampside IL-10'un afla¤› yönde bir e¤ilimi bulunurken, IL-8 görece stabil bir parametredir ve CRP, preeklampsi gelifltirme riski bulunan kad›nlarda daha yüksek olma e¤ilimindedir. 28-40 haftal›k gebeliklerde artan seviyelerde TNF-α ve IL-β'n›n, preeklampsi geliflimi yönünden prognostik bir belirteç olabilece¤i düflünülmektedir. Sonuç: Preeklampsi komplikasyonlu gebeli¤in üçüncü trimesterinde sitokinlerin analizi yararl›d›r. Orta faz›n, en fonksiyonel homeostatik sistem belirtisiyle ilgili olarak preeklampside kritik bir aflama oldu¤u düflünülebilir.

The Complement System and Preeclampsia

Current Hypertension Reports, 2017

Purpose of review-Preeclampsia affects 3-4% of pregnancies with few treatment options to reduce maternal and fetal harm. Recent evidence that targeting the complement system may be an effective therapeutic strategy in prevention or treatment of preeclampsia will be reviewed. Recent findings-Studies in humans confirm the safety and efficacy of C5 blockade in complement-mediated disorders of pregnancy, including preeclampsia. Animal models mimic the placental abnormalities, and/or the maternal symptoms, which characterize preeclampsia. These models in mouse and rat have defined a role for complement and its regulators in placental dysfunction, hypertension, proteinuria, endothelial dysfunction, fetal growth restriction and angiogenic imbalance, thus informing future human studies. Summary-Targeting excessive complement activation, particularly the terminal complement complex (C5b-9) and C5a may be an effective strategy to prolong pregnancy in women with preeclampsia. Continued research is needed to identify the initiator(s) of activation, the pathways involved and the key component(s) in the pathophysiology to allow development of safe and effective therapeutics to target complement without compromising its role in homeostasis and host defense.

The complement system in the pathophysiology of pregnancy

Molecular Immunology, 2006

A fully active complement system deriving from the maternal circulation as well as from local production by various cell source is present in the placenta. The role of this system at the placental level, as in any other tissue in the body, is to protect both the fetus and the mother against infectious and other toxic agents. As fetal tissues are semi-allogeneic and alloantibodies commonly develop in the mother, the placenta is potentially subject to complement-mediated immune attack at the feto-maternal interface with the potential risk of fetal loss. Uncontrolled complement activation is prevented in successful pregnancy by the three regulatory proteins DAF, MCP and CD59 positioned on the surface of trophoblasts. The critical role played by these complement regulators is supported by the embryonic lethality observed in mice deficient in the complement regulator Crry.

Immune complexes in preeclampsia and normal pregnancy

American Journal of Obstetrics and Gynecology, 1985

We determined in normal nonpregnant (group I) and normal pregnant (group II) women and in patients with preeclampsia (group Ill): (1) immunoglobulins and complement C3b associated with polymorphonuclear leukocytes and platelet surfaces in an attempt to evaluate the interaction in vivo of immune complexes with the membranes of these cells; (2) the occurrence of circulating immune complexes; (3) the serum levels of immunoglobulins, C3, and C4; and (4) the plasma levels of complement C3d. In patients with preeclampsia (group Ill), the percentages of polymorphonuclear leukocytes and platelets positive for membrane-bound lgG, lgM, lgA, and C3 were significantly higher than the percentages in groups I and II. In group Ill, there also was a significant increase in circulating immune complexes, as compared to groups I and II. However, circulating immune complexes were also present in significant amounts in normal pregnancy (group II). The plasma levels of complement C3d were markedly increased in the most severe cases of preeclampsia.