Mutations in genes encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with systemic lupus erythematosus

Introduction

Inherited deficiencies of several complement components strongly predispose to systemic lupus erythematosus (SLE) while deficiencies of complement inhibitors are found in kidney diseases such as atypical hemolytic uremic syndrome (aHUS).

Methods

The exons of complement inhibitor genes CD46 and CFH (factor H) were fully sequenced using the Sanger method in SLE patients with nephritis originating from two cohorts from southern and mid Sweden (n = 196). All identified mutations and polymorphisms were then analyzed in SLE patients without nephritis (n = 326) and in healthy controls (n = 523).

Results

We found nonsynonymous, heterozygous mutations in CFH in 6.1% patients with nephritis, in comparison with 4.0% and 5.4% in patients without nephritis and controls, respectively. No associations of SLE or nephritis with common variants in CFH (V62I/Y402H/E936D) were found. Furthermore, we found two nonsynonymous heterozygous mutations in CD46 in SLE patients but not in controls. The A353V polymorphism, known to affect function of CD46, was found in 6.6% of nephritis patients versus 4.9% and 6.1% of the non-nephritis SLE patients and controls. The presence of mutations in CD46 and CFH did not predispose to SLE or nephritis but was associated with earlier onset of nephritis. Furthermore, we found weak indications that there is one protective and one risk haplotype predisposing to nephritis composed of several polymorphisms in noncoding regions of CD46, which were previously implicated in aHUS.

Conclusions

SLE nephritis is not associated with frequent mutations in CFH and CD46 as found in aHUS but these may be modifying factors causing earlier onset of nephritis.     

Search for an Association between V249I and T280M CX3CR1 Genetic Polymorphisms,Endothelial Injury and Preeclampsia: The ECLAXIR Study

Background

Preeclampsia and coronary-artery disease share risk factors, suggesting common pathophysiological mechanisms. CX3CR1/CX3CL1 mediates leukocyte migration and adhesion and has been implicated in the pathophysiology of several inflammatory diseases. M280/I249 variants of CX3CR1 are associated with an atheroprotective effect and reduced endothelial dysfunction. The aim of this study was to search for an association between V249I and T280M polymorphisms of CX3CR1, preeclampsia and endothelial dysfunction.

Methodology/Principal Findings

We explored these polymorphisms with real-time polymerase chain reaction in a case-control study (184 white women with preeclampsia and 184 matched normotensive pregnant women). Endothelial dysfunction biomarkers including von Willebrand factor, VCAM-1 and thrombomodulin, as well as the soluble form of CX3CL1 were measured by enzyme-linked immunosorbent assays (ELISA). The I249 and M280 alleles were associated neither with preeclampsia, nor with its more severe form or with endothelial injury. In contrast, we found a trend toward increased CX3CL1 levels in preeclampsia patients, especially in early-onset- preeclampsia as compared to its level in later-onset- preeclampsia.

Conclusions/Significance

This is the first study to characterize the CX3CR1 gene polymorphisms in patients with preeclampsia. We found no differences in genotype or haplotype frequencies between patients with PE and normal pregnancies, suggesting that maternal CX3CR1 V249I and T280M polymorphisms do not increase susceptibility to preeclampsia. Further studies should be performed to directly evaluate the pathophysiological role of CX3CL1, a molecule abundantly expressed in endometrium, which has been shown to stimulate human trophoblast migration.     

NADPH oxidase 2-derived superoxide downregulates endothelial KCa3.1 in preeclampsia

Endothelial dysfunction is associated with K_Ca3.1 dysfunction and contributes to the development of hypertension in preeclampsia. However, evidence of endothelial K_Ca3.1 dysfunction in the vascular system from women with preeclampsia is still lacking. Therefore, we examined whether endothelial K_Ca3.1 dysfunction occurs in vessels from women with preeclampsia. We compared K_Ca3.1 and NADPH oxidase (NOX) expression in umbilical vessels and primary cultured human umbilical vein endothelial cells (HUVECs) from normal (NP; n=17) and preeclamptic pregnancy (PE; n=19) and examined the effects of plasma from NP or PE on K_Ca3.1 and NOX2 expression in primary cultured HUVECs from NP or human uterine microvascular endothelial cells. The endothelial K_Ca3.1 was downregulated, and NOX2 was upregulated, in umbilical vessels and HUVECs from PE, compared with those from NP. In addition, HUVECs from PE showed a significant decrease in K_Ca3.1 current. Plasma from PE induced K_Ca3.1 down regulation, NOX2 upregulation, phosphorylated-p38 mitogen-activated protein kinase downregulation, and superoxide generation, and these effects were prevented by antioxidants (tempol or tiron), NOX2 inhibition, or anti-lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1) antibody. Oxidized LDL and the superoxide donor xanthine/xanthine oxidase mixture induced K_Ca3.1 downregulation. In contrast, plasma from PE did not generate hydrogen peroxide, and the hydrogen peroxide donor tert-butylhydroperoxide induced K_Ca3.1 upregulation. These results provide the first evidence that plasma from PE generates superoxide via a LOX1–NOX2-mediated pathway and downregulates endothelial K_Ca3.1, which may contribute to endothelial dysfunction and vasculopathy in preeclampsia. This suggests K_Ca3.1as a novel target for patients with preeclampsia.     

Missing links in preeclampsia cell model systems of endothelial dysfunction

Preeclampsia, one of the main hypertensive disorders of pregnancy, is associated with circulating factors released by the ischemic placenta accompanied by systemic endothelial dysfunction. The etiology of preeclampsia remains poorly understood although it is associated with high maternal and fetal mortality and increased cardiovascular disease risk. Most cell model systems used for studying endothelial dysfunction have not taken into account hemodynamic physical factors such as shear-stress forces which may prevent extrapolation of cell data to in vivo settings. We overview the role of hemodynamic forces in modulating endothelial cell function and discuss strategies to reproduce this biological characteristic in vitro to improve our understanding of endothelial dysfunction associated with preeclampsia.     

Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort

Background

Pregnancy in women with systemic lupus erythematosus (SLE) or antiphospholipid antibodies (APL Ab)—autoimmune conditions characterized by complement-mediated injury—is associated with increased risk of preeclampsia and miscarriage. Our previous studies in mice indicate that complement activation targeted to the placenta drives angiogenic imbalance and placental insufficiency.

Methods and Findings

We use PROMISSE, a prospective study of 250 pregnant patients with SLE and/or APL Ab, to test the hypothesis in humans that impaired capacity to limit complement activation predisposes to preeclampsia. We sequenced genes encoding three complement regulatory proteins—membrane cofactor protein (MCP), complement factor I (CFI), and complement factor H (CFH)—in 40 patients who had preeclampsia and found heterozygous mutations in seven (18%). Five of these patients had risk variants in MCP or CFI that were previously identified in atypical hemolytic uremic syndrome, a disease characterized by endothelial damage. One had a novel mutation in MCP that impairs regulation of C4b. These findings constitute, to our knowledge, the first genetic defects associated with preeclampsia in SLE and/or APL Ab. We confirmed the association of hypomorphic variants of MCP and CFI in a cohort of non-autoimmune preeclampsia patients in which five of 59 were heterozygous for mutations.

Conclusion

The presence of risk variants in complement regulatory proteins in patients with SLE and/or APL Ab who develop preeclampsia, as well as in preeclampsia patients lacking autoimmune disease, links complement activation to disease pathogenesis and suggests new targets for treatment of this important public health problem.

Study Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00198068","term_id":"NCT00198068"}}NCT00198068 Please see later in the article for the Editors'' Summary     

Endothelium Dependent Vasomotion and In Vitro Markers of Endothelial Repair in Patients with Severe Sepsis: An Observational Study

Background

Outcome in sepsis is mainly defined by the degree of organ failure, for which endothelial dysfunction at the macro- and microvascular level is an important determinant. In this study we evaluated endothelial function in patients with severe sepsis using cellular endothelial markers and in vivo assessment of reactive hyperaemia.

Materials and Methods

Patients with severe sepsis (n = 30) and 15 age- and gender- matched healthy volunteers were included in this study. Using flow cytometry, CD34+/KDR+ endothelial progenitor cells (EPC), CD31+ T-cells, and CD31+/CD42b- endothelial microparticles (EMP) were enumerated. Migratory capacity of cultured circulating angiogenic cells (CAC) was assessed in vitro. Endothelial function was determined using peripheral arterial tonometry at the fingertip.

Results

In patients with severe sepsis, a lower number of EPC, CD31+ T-cells and a decreased migratory capacity of CAC coincided with a blunted reactive hyperaemia response compared to healthy subjects. The number of EMP, on the other hand, did not differ. The presence of organ failure at admission (SOFA score) was inversely related with the number of CD31+ T-cells. Furthermore, the number of EPC at admission was decreased in patients with progressive organ failure within the first week.

Conclusion

In patients with severe sepsis, in vivo measured endothelial dysfunction coincides with lower numbers and reduced function of circulating cells implicated in endothelial repair. Our results suggest that cellular markers of endothelial repair might be valuable in the assessment and evolution of organ dysfunction.     

High levels of urinary vascular endothelial growth factor in women with severe preeclampsia

Elevated plasma VEGF concentrations in preeclampsia are associated with local placental ischemia and endothelial dysfunction. We investigated the urinary VEGF excretion in women with severe preeclampsia (n=37) and its relation with proteinuria compared to that in healthy pregnant (n=32) and non-pregnant women (n=30). In women with severe preeclampsia VEGF levels were 54.0 (19.9-192.4) ng/mmol creatinine, significantly (p<0.0001) higher than levels in pregnant controls (28.2 (6.7-63.0) ng/mmol creatinine) and non-pregnant controls (29.5 (10.1-59.1) ng/mmol creatinine). Proteinuria was not significantly correlated with urinary VEGF levels. In conclusion, high urinary VEGF concentrations in severe preeclampsia might reflect increased renal production of VEGF rather than elevated VEGF levels in the systemic circulation.     

Severe anaemia is associated with a higher risk for preeclampsia and poor perinatal outcomes in Kassala hospital,eastern Sudan

Background

Anaemia during pregnancy is major health problem. There is conflicting literature regarding the association between anaemia and its severity and maternal and perinatal outcomes.

Methods

This is a retrospective case-control study conducted at Kassala hospital, eastern Sudan. Medical files of pregnant women with severe anaemia (haemoglobin (Hb) < 7 g/dl, n = 303) who delivered from January 2008 to December 2010 were reviewed. Socio-demographic and obstetric data were analysed and compared with a similar number of women with mild/moderate anaemia (Hb = 7-10.9 g/dl, n = 303) and with no anaemia (Hb > 11 g/dl, n = 303). Logistic regression analysis was performed separately for each of the outcome measures: preeclampsia, eclampsia, preterm birth, low birth weight (LBW) and stillbirth.

Results

There were 9578 deliveries at Kassala hospital, 4012 (41.8%) women had anaemia and 303 (3.2%) had severe anaemia. The corrected risk for preeclampsia increased only in severe anaemia (OR = 3.6, 95% CI: 1.4-9.1, P = 0.007). Compared with women with no anaemia, the risk of LBW was 2.5 times higher in women with mild/moderate anaemia (95% CI: 1.1-5.7), and 8.0 times higher in women with severe anaemia (95% CI: 3.8-16.0). The risk of preterm delivery increased significantly with the severity of anaemia (OR = 3.2 for women with mild/moderate anaemia and OR = 6.6 for women with severe anaemia, compared with women with no anaemia). The corrected risk for stillbirth increased only in severe anaemia (OR = 4.3, 95% CI: 1.9-9.1, P < 0.001).

Conclusions

The greater the severity of the anaemia during pregnancy, the greater the risk of preeclampsia, preterm delivery, LBW and stillbirth. Preventive measures should be undertaken to decrease the prevalence of anaemia in pregnancy.

     

Immunohistochemical expression of von Willebrand factor in the preeclamptic placenta

Preeclampsia is a high-prevalence systemic pregnancy disorder associated with maternal and foetal mortality. Its pathogenesis is unknown, but it is thought that oxidative stress and endothelial dysfunction may play a fundamental role. Von Willebrand factor (vWF), a marker of endothelial cell injury, can be found in different cells and zones of the placenta. To determine the differential immunoexpression of vWF at different tissue types of preeclamptic placenta and endothelial dysfunction markers at maternal serum of preeclamptic pregnancies. A case–control study was performed on a population of pregnant women with preeclampsia (n = 14), and normal pregnancies (n = 8). Placental and blood plasma samples were withdrawn at delivery. Immunohistochemical vWF expression in the placental tissue was determined. Endothelial dysfunction was assessed through plasminogen activator inhibitor (PAI) 1 and 2 ratio and vWF concentration in maternal plasma. P values less than 0.05 were considered statistically significant. Preeclamptic women showed increased plasma PAI-1/PAI-2 ratio (P < 0.05). There was diminished placental vWF expression in syncytiotrophoblast and increased in the intervillous space of preeclamptic placentas (P < 0.05). No significant differences in vWF expression were found in the villous endothelium and stroma, but it was significantly higher in maternal plasma (P < 0.05). In preeclampsia occurs endothelial damage and placental cell injury. Cell damage in syncytiotrophoblast that occurs in preeclampsia could liberate vWF from syncytiotrophoblast to the placental intervillous space, and this may have pathogenic implications.     

Lead Accumulation as Possible Risk Factor for Primary Open-Angle Glaucoma

The objective of this study was to investigate the relationship between preeclampsia and iodine levels and magnesium concentration in the blood of subjects in the northeast Anatolia region where iodine deficiency is common. Blood specimens were obtained from 24 preeclamptic and 16 healthy pregnant women. Iodine levels in blood were determined by the Foss method based on the Sandell–Kolthoff reaction. Serum protein-bound iodine (PBI) levels and magnesium concentration in maternal blood were lower in patients with severe preeclampsia compared to normal pregnant women (8.46?±?1.22 vs. 11.46?±?1.71 μg/dL, p?<?0.001, 1.63?±?0.05 vs. 1.86?±?0.05 mg/dL, p?<?0.001, respectively). Serum PBI levels and magnesium concentration in umbilical cord blood were higher in patients with severe preeclampsia than in normal pregnant women (8.84?±?1.9 vs. 7.33?±?1.07 μg/dL, p?<?0.05, 2.48?±?0.03 vs. 2.02?±?0.01 mg/dL, p?<?0.001, respectively). There was a positive correlation between the serum PBI levels in maternal blood and magnesium concentration in maternal blood in patients with severe preeclampsia (r?=?0.41, p?<?0.05). Thus, iodine may be one factor contributing to the pathophysiology of preeclampsia. Iodine supplementation may be effective therapy in preeclamptic in pregnant women.     

Highly Significant Association between Two Common Single Nucleotide Polymorphisms in CORIN Gene and Preeclampsia in Caucasian Women

Preeclampsia is a frequent medical complication during pregnancy. Corin, a serine protease which activates pro-atrial natriuretic peptide, has recently been shown to be involved in the pathophysiology of preeclampsia. The aim of this study was to search for CORIN gene variations and their association to preeclampsia in Caucasian and African women. Our study population was composed of 571 pregnant women (295 with preeclampsia and 276 normotensive controls) matched for maternal and gestational age, and ethnic origin. The 22 exons of the CORIN gene were sequenced in a discovery sample (n = 260), where 31 single nucleotide polymorphisms were identified. In a replication sample (n = 311), 4 single nucleotide polymorphisms were tested. Two minor alleles (C for rs2271036 and G for rs2271037) were significantly associated to preeclampsia. Adjusted odds ratios [95% confidence interval] were 2.5 [1.2–3.8] (p = 0.007) and 2.3 [1.5–3.5] (p = 1.3×10⁻⁴), respectively. These associations were ethnic-specific, as only found in the Caucasian of subjects (odds ratio = 3.5 [1.8–6.6], p = 1.1×10⁻⁴; odds ratio = 3.1 [1.7–5.8], p = 2.1×10⁻⁴, for each single nucleotide polymorphism, respectively). The two single nucleotide polymorphisms are in almost perfect linkage disequilibrium (r² = 0.93). No specific association was found with severe preeclampsia, early-onset preeclampsia nor fetal growth retardation. In conclusion, this is the first report of a highly significant association between these two single nucleotide polymorphisms in CORIN gene and preeclampsia. Our findings further support the probability of a critical role of corin in preeclamspia pathophysiology at the uteroplacental interface.     

Alterations in Adhesion Molecules,Pro-Inflammatory Cytokines and Cell-Derived Microparticles Contribute to Intima-Media Thickness and Symptoms in Postmenopausal Women

Menopause, the cessation of menses, occurs with estrogens decline, low-grade inflammation, and impaired endothelial function, contributing to atherosclerotic risk. Intima-media thickness (IMT) is an early subclinical biomarker of atherosclerosis. Inflammation may have a role on symptoms: hot flashes, anxiety, and depressive mood, which also are related to endothelial dysfunction, increased IMT and cardiovascular risk. In this study we compared several inflammatory markers in early vs. late postmenopausal women and studied the association of IMT and symptoms with these markers in the full sample. In a cross-sectional design including 60 women (53.1±4.4 years old) at early and late postmenopause, we evaluated the expression of CD62L, ICAM-1, PSGL-1, CD11b, CD11c, and IL-8R on PBMC by flow cytometry. Serum soluble ICAM-1, sVCAM-1, sCD62E, sCD62P, CXCL8, IL-1β, IL-6, and TNF-α levels were quantified by ELISA. Plasma levels of microparticles (MPs) were determined by FACS. Finally, carotid intima-media thickness (IMT) was measured by ultrasound. We observed that ICAM-1 expression by lymphocytes and serum sVCAM-1 levels were augmented at late postmenopause. Late postmenopause women with severe hot flashes had increased expression of CD62L and IL-8R on neutrophils. By multivariate analysis, the carotid IMT was strongly associated with membrane-bound TNF-α, CD11b expression, Annexin V⁺ CD3⁺ MPs, LPS-induced NO production, HDL-cholesterol and age. Depressive mood was associated negatively with PSGL-1 and positively with LPS-induced NO. Finally, Log(AMH) levels were associated with carotid IMT, IL-8R expression and time since menopause. IMT and depressive mood were the main clinical features related to vascular inflammation. Aging, hormonal changes and obesity were also related to endothelial dysfunction. These findings provide further evidence for a link between estrogen deficiency and low-grade inflammation in endothelial impairment in mature women.     

Preeclampsia Does Not Alter Vascular Growth and Expression of CD31 and Vascular Endothelial Cadherin in Human Placentas

Preeclampsia is characterized by maternal endothelial dysfunction (e.g., increased maternal vascular permeability caused by the disassembly of endothelial junction proteins). However, it is unclear if preeclampsia is associated with impaired vascular growth and expression of endothelial junction proteins in human placentas. Herein, we examined vascular growth in placentas from women with normal term (NT) and preeclamptic (PE) pregnancies using two endothelial junction proteins as endothelial markers: CD31 and vascular endothelial-cadherin (VE-Cad). We also compared protein and mRNA expression of CD31 and VE-Cad between NT and PE placentas, and determined the alternatively spliced expression of CD31 using PCR. We found that CD31 and VE-Cad were immunolocalized predominantly in villous endothelial cells. However, capillary number density (total capillary number per unit villous area) and capillary area density (total capillary lumen area per unit villous area) as well as CD31 and VE-Cad protein and mRNA levels were similar between NT and PE placentas. PCR in combination with sequence analysis revealed a single, full-length CD31, suggesting that there are no alternatively spliced isoform of CD31 expressed in placentas. These data indicate that preeclampsia does not significantly affect vascular growth or the expression of endothelial junction proteins in human placentas.     

Association of the sEH gene promoter polymorphisms and haplotypes with preeclampsia

BackgroundThe epoxyeicosatrienoic acids (EETs) have antihypertensive, anti-inflammatory, and organ protective properties and their circulation levels are related to hypertension, diabetes mellitus, cardiovascular diseases, and preeclampsia. Soluble epoxide hydrolase (sEH) catalyses the degradation of EETs to less biologically active dihydroxyeicosatrienoic acids. Here, we sequenced the promoter region of EPHX2 to investigate the association between promoter sequence alterations that we thought to affect the expression levels of the enzyme and preeclampsia (PE).MethodsNucleotide sequencing of the promoter region of the EPHX2, spanning from position -671 to +30, was performed on 100 pregnant women with PE and, 20 or more weeks pregnant normotensive, healthy women (n=100).ResultsPregnant women who carry rs4149235, rs4149232, rs73227309, and rs62504268 polymorphisms have 4.4, 2.4, 2.3, and 2.8 times significantly increased risk of PE, respectively. CCGG (OR: 3.11; 95% CI: 1.12-8.62) and CCCA (OR: 0.45; 95% CI: 0.36-0.55) haplotypes were associated with an increased and decreased risk of PE, respectively.ConclusionsFour SNPs (rs4149232, rs4149235, rs73227309, and rs62504268) in the promoter region of the EPHX2, and CCGG and CCCA haplotypes of these 4 SNPs were significantly associated with PE. These SNPs in the promoter region may affect sEH expression and thus enzyme activity and may play a role in PE pathogenesis by causing individual differences in EET levels. However, future studies are needed to confirm our findings and examine the effect of these SNPs on the sEH expression and/or enzyme activity.     

The Common Variant rs11646213 Is Associated with Preeclampsia in Han Chinese Women

Background

Preeclampsia, characterized by hypertension and proteinuria, is a multifactorial disease caused by complex interactions between environmental and genetic factors. A recent genome-wide association study of blood pressure reported an association between hypertension and rs11646213. This study evaluated the association between preeclampsia and rs11646213.

Methods

A total of 454 cases and 460 controls were recruited to participate in this study. The single nucleotide polymorphism (SNP) rs11646213 was genotyped by polymerase chain reaction (PCR) and direct sequencing.

Results

The allele frequency of rs11646213 was significantly different between the preeclampsia and control groups (P = 0.017, OR = 1.36, 95% CI = 1.06–1.76). Differences were particularly significant in the severe preeclampsia subgroup (P = 0.002, OR = 1.54, 95% CI = 1.17–2.03) and the early-onset preeclampsia subgroup (P = 0.004, OR = 1.57, 95% CI = 1.16–2.13). Genotyping analysis showed that the T allele of rs11646213 could confer a risk for preeclampsia, severe preeclampsia and early-onset preeclampsia.

Conclusions

Rs11646213 upstream of the CDH13 gene is associated with preeclampsia in Han Chinese women.     

Plasma l-arginine is markedly reduced in pregnant women affected by preeclampsia

The objective of this study was to determine the concentration of free l-amino acids and in particular of l-arginine in the plasma of pregnant women affected by preeclampsia compared to healthy pregnant women in order to know if an alteration in the concentrations of these amino acids occurs in preeclamspia. Twelve pregnant women affected by preeclampsia and twelve pregnant control women, ages 28–35 years old and at the 35–36 weeks of pregnancy were studied. The blood analysis of free amino acids was carried out by using a high performance liquid chromatographic (HPLC) fluorometric method and OPA-NAC as derivatizing agent for the amino acid determination. In the blood of women affected by preeclampsia l-arginine is markedly reduced compared to controls (about five-fold lower, P<0.01). The other amino acids also are significantly reduced, but to lesser extents (about 1.5 times lower, P<0.05). Thus, the determination of l-arginine in the blood of pregnant women could potentially constitute an additional marker for the early diagnosis of preeclampsia.     

Maternal plasma VEGF, sVEGF-R1, and PlGF concentrations in preeclamptic and normotensive pregnant Zimbabwean women

Vascular endothelial growth factor (VEGF), a disulphide-linked homodimeric glycoprotein that is selectively mitogenic for endothelial cells, plays an important role in vasculogenesis and angiogenesis. Preeclampsia, a relatively common complication of pregnancy that is characterized by diffuse endothelial dysfunction possibly secondary to impaired trophoblast invasion of the spiral arteries during implantation, has recently been associated with alterations in maternal serum/plasma concentrations of VEGF, and other related growth factors and their receptors. We examined the relationship of maternal plasma VEGF, sVEGF-R1 and PlGF levels to the risk of preeclampsia among women delivering at Harare Maternity Hospital, Zimbabwe. 131 pregnant women with preeclampsia and 175 controls were included in a case-control study. Maternal plasma concentrations of each biomarker were measured using enzymatic methods. We used logistic regression to calculate odds ratios (OR) and 95 % confidence intervals (CI). Preeclampsia risk was inversely related with quartiles of plasma VEGF (OR: 1.0, 1.0, 0.7, and 0.5, with the lowest quartile as reference; p for trend=0.06). We noted a strong positive association between preeclampsia risk and sVEGF-R1 concentrations (OR: 1.0, 6.5, 9.7, 31.6, with the first quartile as the referent group; p for trend<0.001). After adjusting for confounders, we noted that women with sVEGF-R1 concentrations in the highest quartile (>or=496 pg/ml), as compared with those in the lowest quartile (<62 pg/ml) had a 31.6-fold increased risk of preeclampsia (OR=31.6, 95 % CI 7.7-128.9). There was no clear evidence of a linear relation in risk of preeclampsia with PlGF concentrations. In conclusion, plasma VEGF, sVEGF-R1 and PlGF concentrations (measured at delivery) were altered among Zimbabwean women with preeclampsia as compared with normotensive women. Our results are consistent with some, though not all, previous reports. Prospective studies are needed to: 1) identify modifiable determinants of maternal plasma concentrations VEGF, sVEGF-R1, and PlGF; and 2) evaluate the temporal relationship between observed alterations of these biological markers in preeclamptic pregnancies.     

Preeclampsia inactivates glucose-6-phosphate dehydrogenase and impairs the redox status of erythrocytes and fetal endothelial cells

Inactivation of glucose-6-phosphate dehydrogenase (G6PD) may contribute to vascular dysfunction in preeclampsia, and oxidative stress has been implicated in the pathogenesis of this disease. We have compared the susceptibility of erythrocytes and human umbilical vein endothelial cells (HUVEC) to oxidative stress in women with normotensive or preeclamptic pregnancies. The redox status of erythrocytes was also correlated with neutrophil-mediated superoxide (O₂⁻) production in women recruited to the “Vitamins in Preeclampsia” (VIP) trial. Erythrocytes and HUVEC from women with preeclampsia demonstrated impaired redox regulation and diminished response to glucose, detectable at 14–20 weeks gestation prior to onset of the clinical disease. Hexokinase and G6PD activities were decreased in erythrocytes and G6PD activity was decreased in HUVEC from preeclamptic pregnancies. Phorbol-ester-stimulated O₂⁻ was enhanced in preeclamptic neutrophils. Impaired redox regulation in erythrocytes and HUVEC in preeclampsia may be due to diminished hexokinase and G6PD activities resulting from increased release of reactive oxygen species from activated neutrophils. Our findings provide the first evidence that decreased G6PD activity in preeclampsia is associated with impaired redox regulation in erythrocytes and fetal endothelial cells. The deficiency in G6PD in preeclampsia potentially accounts for the lack of protection against oxidative stress afforded by antioxidant vitamin C/E supplementation in the VIP trial.     

CD46 protects against chronic obstructive pulmonary disease

Background

Chronic obstructive pulmonary disease and emphysema develops in 15% of ex-smokers despite sustained quitting, while 10% are free of emphysema or severe lung obstruction. The cause of the incapacity of the immune system to clear the inflammation in the first group remains unclear.

Methods and Findings

We searched genes that were protecting ex-smokers without emphysema, using microarrays on portions of human lungs surgically removed; we found that loss of lung function in patients with chronic obstructive pulmonary disease and emphysema was associated with a lower expression of CD46 and verified this finding by qRT-PCR and flow cytometry. Also, there was a significant association among decreased CD46⁺ cells with decreased CD4⁺T cells, apoptosis mediator CD95 and increased CD8⁺T cells that were protecting patients without emphysema or severe chronic obstructive pulmonary disease. CD46 not only regulates the production of T regulatory cells, which suppresses CD8⁺T cell proliferation, but also the complement cascade by degradation of C3b. These results were replicated in the murine smoking model, which showed increased C5a (produced by C3b) that suppressed IL12 mediated bias to T helper 1 cells and elastin co-precipitation with C3b, suggesting that elastin could be presented as an antigen. Thus, using ELISA from elastin peptides, we verified that 43% of the patients with severe early onset of chronic obstructive pulmonary disease tested positive for IgG to elastin in their serum compared to healthy controls.

Conclusions

These data suggest that higher expression of CD46 in the lungs of ex-smoker protects them from emphysema and chronic obstructive pulmonary disease by clearing the inflammation impeding the proliferation of CD8⁺ T cells and necrosis, achieved by production of T regulatory cells and degradation of C3b; restraining the complement cascade favors apoptosis over necrosis, protecting them from autoimmunity and chronic inflammation.