Evidence Of Complement Activation Research Articles

Prevalence, Course and Impact of HLA Donor-Specific Antibodies in Liver Transplantation in the First Year

The presence of preformed donor-specific HLA antibodies (DSA) in liver transplant recipients is increasingly recognized; however, the prevalence of DSA and their impact on early allograft function remains unknown. We prospectively followed serum DSA levels of 90 consecutive liver transplant recipients from baseline to 4 months. Twenty recipients (22.2%) had preformed DSA. No antibody-targeting treatments were undertaken. Seven days after transplantation, DSA levels decreased markedly in all but three patients. Day 7 protocol biopsies showed diffuse C4d deposition along the portal stroma, central vein, subendothelial and stromal space in the patients with persistent high DSA levels. The rate of acute cellular rejection was not significantly different in patients with DSA. The transaminase and bilirubin levels remained comparable during the first year despite the presence of DSA. The three patients with persistently high DSA levels continue to have normal allograft function. We conclude that in most cases, DSA disappear after liver transplant, however in rare instances where they persist, there is evidence of complement activation in the liver allograft, without significant clinical impact in the first year.

Guidelines on the investigation and management of antiphospholipid syndrome

This guidance updates and replaces the previous guideline on the investigation and management of antiphospholipid syndrome (APS) published in 2000 (Greaves et al, 2000), though where there have not been changes we refer back to them when appropriate. The guidance is updated with reference to relevant publications since 2000. Publications known to the writing group were supplemented with additional papers identified by searching PubMed for publications in the last 11 years using the key words: lupus anticoagulant, anticardiolipin, antiphospholipid, b2–glycoprotein I, antiprothrombin and limits (clinical trial, randomized control trial, meta-analysis, humans, core clinical journals, English language). The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the Royal College of Obstetricians and Gynaecologists (RCOG), and the British Committee for Standards in Haematology (BCSH) Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMEN DATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with antiphospholipid syndrome though individual patient circumstances may dictate an alternative approach.

Innate and adaptive immunity in amyotrophic lateral sclerosis: Evidence of complement activation

Increasing evidence suggests a role for the immune system in amyotrophic lateral sclerosis (ALS). To determine the extent of the immune activation in ALS we analyzed the expression and cellular distribution of components of innate and adaptive immunity in spinal cord (SC) and motor cortex (MCx) from patients with rapid and slow sporadic ALS and controls. High levels of mRNA and protein of classical complement pathway, C1q and C4, as well as the downstream complement components C3 and C5b-9 were found in all ALS samples. Furthermore, we found higher numbers of activated microglia, reactive astrocytes, dendritic cells (DCs) and CD8+ T-cells in ALS than in control tissue. Rapid ALS cases had more dendritic cells than slow ALS cases, whereas slow ALS cases had more activated microglia than rapid cases.Our findings demonstrate a persistent and prominent activation of both innate and adaptive immunity in ALS. We propose a complement-driven immune response which may contribute to the progression of the inflammation and ultimately lead to even more motor neuron injury.

Abstract C169: Intermittent dosing of Imetelstat Sodium, a telomerase inhibitor, induces drug exposure consistent with in vivo tumor growth inhibition

Abstract Background: Telomerase maintains telomere length (TL) of dividing cells, and is essential for cell immortalization. Telomerase is upregulated in tumors, particularly in cancer progenitor cells. Imetelstat (GRN163L), the first targeted telomerase inhibitor in clinical trials, is a 13-mer lipidated oligonucleotide that binds to the template RNA strand of telomerase. With weekly dosing, thrombocytopenia was dose limiting and MTD was 4.8 mg/kg. To increase drug exposure and maintain tolerability, we tested an intermittent dosing schedule of imetelstat. Methods: Patients (pts) with advanced solid cancers were given imetelstat as a single agent by 2 hr. i.v. infusions on D1 and D8 of 21-Day cycles (Cy), starting at 4.8 mg/kg. A 3+3 dose escalation was used. Pre-treatment granulocyte TL (PMN TL), a surrogate of hematopoietic progenitor TL, was measured by Flow-FISH. Results: 31 pts have been treated, with 4 currently on study. Mean number of prior cytotoxic regimens reported for 26 pts was 3.6 and 16 pts had prior irradiation. Dose escalation proceeded to 11.7 mg/kg, which was judged to be in excess of the MTD due to cytopenias. Three pts had been previously treated with 9.4 mg/kg without DLT, and the 9.4 mg/kg cohort was subsequently expanded to 12 pts, maintaining q21 D dosing. To date, severe myelosuppression has been observed in only 1 pt, and all 12 completed Cy 1. Three pts had doses held in Cy 2 for thrombocytopenia. Eight pts discontinued treatment after completing 1 to 4 Cy, 6 for PD, 1 for a hypersensitivity reaction and 1 for an unrelated SAE. Four pts are currently on treatment and have completed 2 to 3 Cy. Hypersensitivity reactions were observed in 5 of 31 pts dosed to date and were associated with biochemical evidence of complement activation; one was managed with secondary prophylaxis with steroids and antihistamines, and routine primary prophylaxis was subsequently instituted for all patients. Transient (<24hr) prolongation of aPTT occurs without clinical sequelae. Other AEs were non-specific, mild to moderate and of dubious causality. Mean ± SD (N) imetelstat AUC-inf from pts treated with 7.5, 9.4 and 11.7 mg/kg were 1036 ± 359 (3), 1219 ± 109 (2) and 1408 ± 812 (6), respectively. By comparison, antitumor effects were noted in xenograft models with AUC-inf of 819. Preliminary analysis of pre- and post-treatment hair follicle samples for pharmacodynamic activity suggests a trend for telomerase inhibition. As previously noted*, thrombocytopenia correlated with short baseline PMN TL among 17 pts. Conclusions: Intermittent dosing of imetelstat at 9.4 mg/kg was well tolerated for multiple cycles. Drug exposures were in a range associated with antitumor activity in preclinical models and preliminary evidence of a pharmacodynamic effect has been observed. Hematologic toxicity is doselimiting, and may be mechanism-based. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C169.

Evidence for complement activation in the amniotic fluid of women with spontaneous preterm labor and intra-amniotic infection

Objective. The complement system plays an important role in host defense against infection. Concentrations of complement split products or anaphylatoxins (C3a, C4a, and C5a) in biological fluids are considered to reflect complement activation. The purpose of this study was to determine if term and preterm parturition are associated with evidence of complement activation in the amniotic fluid.Study design. Amniotic fluid (AF) samples were collected from 270 women in the following groups: (1) normal pregnant women in midtrimester (n = 70), (2) term not in labor (n = 23), (3) term in labor (n = 48), and (4) preterm labor (PTL) (n = 129). PTL was categorized into: (a) PTL without microbial invasion of the amniotic cavity (MIAC) who delivered at term (n = 42), (b) PTL who delivered preterm without MIAC (n = 57), and (c) PTL with MIAC (n = 30). C5a, C4a, and C3a concentrations in amniotic fluid were determined by ELISA. Nonparametric tests were used for statistical analysis.Results. (1) The median AF C5a concentration was higher in women at term than that of those in the midtrimester (p = 0.02); (2) Spontaneous labor at term was not associated with changes in AF concentrations of anaphylatoxins C3a, C4a, and C5a (all p > 0.05); (3) Among patients with PTL who delivered preterm, those with MIAC had higher AF C4a and C5a concentrations than those without infection (p < 0.01); and (4) AF C3a, C4a, and C5a concentrations were higher in patients with PTL with MIAC than in those with PTL without MIAC who delivered at term.Conclusion. Patients with spontaneous preterm labor and intact membranes with microbial invasion of the amniotic cavity had higher median amniotic fluid concentration of complement split products C3a, C4a, and C5a than patients without intra-amniotic infection. These findings suggest that preterm labor in the context of infection is associated with activation of the complement system.

Correlation of Donor-Specific Antibodies, Complement and Its Regulators with Graft Dysfunction in Cardiac Antibody-Mediated Rejection

Antibody-mediated rejection (AMR) is an immunopathologic process in which activation of complement often results in allograft injury. This study correlates C4d and C3d with HLA serology and graft function as diagnostic criteria for AMR. Immunofluorescence staining for C4d and C3d was performed on 1511 biopsies from 330 patients as part of routine diagnostic work-up of rejection. Donor-specific antibodies were detected in 95% of those with C4d+C3d+ biopsies versus 35% in the C4d+C3d- group (p = 0.002). Allograft dysfunction was present in 84% in the C4d+ C3d+ group versus 5% in the C4d+C3d- group (p < 0.0001). Combined C4d and C3d positivity had a sensitivity of 100% and specificity of 99% for the pathologic diagnosis of AMR and a mortality of 37%. Since activation of complement does not always result in allograft dysfunction, we correlated the expression pattern of the complement regulators CD55 and CD59 in patients with and without complement deposition. The proportion of patients with CD55 and/or CD59 staining was highest in C4d+C3d- patients without allograft dysfunction (p = 0.03). We conclude that a panel of C4d and C3d is diagnostically more useful than C4d alone in the evaluation of AMR. CD55 and CD59 may play a protective role in patients with evidence of complement activation.

Attenuation of IgG immune complex‐induced acute lung injury by silencing C5aR in lung epithelial cells

Acute lung injury (ALI) in mouse lung occurs after distal airway deposition of IgG immune complexes (IgGICs), resulting in a breakdown of the vascular-airway barrier, causing intrapulmonary edema, hemorrhage, and accumulation of neutrophils [polymorphonuclear leukocytes (PMNs)] in the alveolar compartment, these changes being complement (C5a) and C5a receptor (C5aR) dependent. In this ALI model, C5aR expression (protein) was found to occur on upper (bronchial) and lower (alveolar) airway epithelial cells. An adenovirus construct (siRNA) was used to silence mRNA for C5aR in the lung. Under such conditions, C5aR protein was markedly reduced on lung epithelial cells, resulting in much reduced leakage of albumin into the lung, diminished buildup of PMNs, and lower levels of proinflammatory mediators in bronchoalveolar lavage fluids. These studies indicate that bronchial and alveolar epithelial cell C5aR is up-regulated and greatly contributes to inflammation and injury in the lung. The use of siRNA administered into the airways avoids systemic suppression of C5aR, which might compromise innate immunity. It is possible that such an intervention might be employed in humans with ALI or acute respiratory distress syndrome as well as in upper-airway inflammatory diseases, such as chronic obstructive pulmonary disease and asthma, where there is evidence for complement activation and buildup of PMNs.

Fragment Bb in amniotic fluid: evidence for complement activation by the alternative pathway in women with intra-amniotic infection/inflammation

Objective. Fragment Bb is an activator of the alternative pathway of the complement system. Recently, increased first trimester maternal plasma concentrations of this fragment were reported in patients destined to have a spontaneous preterm delivery before 34 weeks of gestation. The aim of this study was to determine whether the amniotic fluid (AF) concentrations of fragment Bb change with gestational age, spontaneous labor (term and preterm) and in the presence of intra-amniotic infection/inflammation (IAI).Study design. This cross-sectional study included patients in the following groups: (1) mid-trimester (n = 64); (2) term in spontaneous labor (n = 70); (3) term not in labor (n = 43); (4) spontaneous preterm labor (PTL) who delivered at term (n = 76); (5) PTL without IAI who delivered preterm (n = 73); (6) PTL with IAI (n = 76); (7) preterm prelabor rupture of membranes (PROM) without IAI (n = 71); and (8) preterm PROM with IAI (n = 71). Fragment Bb concentration in AF was determined by an enzyme-linked immunoassay. Non-parametric statistics were used for analyses.Results. (1) Fragment Bb was detected in all AF samples (n = 544); (2) The median AF concentration of fragment Bb in patients at term not in labor was significantly higher than that of those in the mid-trimester [2.42 μg/ml, interquartile range (IQR) 1.78–3.22 vs. 1.64 μg/ml, IQR 1.06–3.49; p < 0.001]; (3) Among patients with PTL, those with IAI had a higher median AF fragment Bb concentration than that of woman without IAI, who delivered preterm (4.82 μg/ml, IQR 3.32–6.08 vs. 3.67 μg/ml, IQR 2.35–4.57; p < 0.001) and than that of women with an episode of PTL, who delivered at term (3.21 μg/ml, IQR 2.39–4.16; p < 0.001); (4) Similarly, among patients with preterm PROM, the median AF fragment Bb concentration was higher in individuals with IAI than in those without IAI (4.24 μg/ml, IQR 2.58–5.79 vs. 2.79 μg/ml, IQR 2.09–3.89; p < 0.001). (5) Among patients at term, the median AF fragment Bb concentration did not differ between women with spontaneous labor and those without labor (term in labor: 2.47 μg/ml, IQR 1.86–3.22; p = 0.97).Conclusions. (1) Fragment Bb, an activator of the alternative complement pathway, is a physiologic constituent of the AF, and its concentration increases with advancing gestational age; (2) AF concentrations of fragment Bb are higher in pregnancies complicated with IAI; and (3) labor at term is not associated with changes in the AF concentrations of fragment Bb. These findings suggest a role for fragment Bb in the host immune response against IAI.

Evidence for complement activation in the amniotic fluid of women with spontaneous preterm labor and intra-amniotic infection

Evidence for complement activation in the amniotic fluid of women with spontaneous preterm labor and intra-amniotic infection

An early complement-dependent and TLR-4–independent phase in the pathogenesis of ethanol-induced liver injury in mice #

The innate immune system has been implicated in the pathogenesis of alcoholic liver disease. Although innate immunity is usually considered an early response to injury, previous work implicating innate immunity in ethanol-induced liver injury focuses primarily on long-term ethanol exposure. We investigated the early period of ethanol exposure to determine whether there were temporal associations between activation of innate immune responses and known correlates of liver injury. Female C57BL/6 mice were allowed free access to an ethanol-containing Lieber-DeCarli diet or were pair-fed a control diet. Within 4 days of ethanol exposure, we observed a striking spike in expression of hepatic proinflammatory cytokines-including tumor necrosis factor alpha (TNF-alpha), interleukin-6, and interferon-gamma-prior to hepatic triglyceride accumulation or increased plasma alanine aminotransferase activities, as well as before the induction of cytochrome P450 2E1 or oxidative stress. This early spike in inflammatory cytokines coincided with deposition of C3b-iC3b/C3c (C3b) in the liver. This deposition, resulting from the cleavage of the third component of the complement system (C3), is evidence for activation of complement in response to ethanol. C3(-/-) mice were protected from the early, ethanol-induced increase in hepatic TNF-alpha expression. Ethanol increased C3b deposition in mice deficient in C3a receptor or C5a receptor, as well as in wild-type mice depleted of hepatic macrophages; however, there was no increase in hepatic TNF-alpha in the absence of C3a receptor, C5a receptor, or hepatic macrophages. In contrast, the absence of Toll-like receptor 4 (TLR-4) had no effect on the early, ethanol-induced increase in either C3b or TNF-alpha. We have identified a complement- and macrophage-dependent, but TLR-4 independent, phase in the pathogenesis of ethanol-induced liver injury.

Why do patients develop reactions to streptokinase?

Minor reactions to streptokinase are not uncommon, although the etiology is unknown. It is widely presumed, however, that these, like the more serious immune reactions, are antibody-mediated. We measured specific anti-streptokinase IgG, subclasses IgG1, IgG2, IgG3, IgG4 and IgE by ELISAs, haemagglutination, indirect Coombs' test and immunoblotting in six patients who developed reactions to streptokinase. Evidence of complement activation by streptokinase was sought by a haemolytic complement assay and by measurement of C3, C4 and C3d. The patients who reacted to streptokinase presented with low titres of anti-streptokinase IgG (median = 5; range 0-32) and IgG1 (median = 3; range 0-14). No evidence of any other IgG subclass was found, nor of specific anti-streptokinase IgE. Anti-streptokinase IgG1 was found to fix complement; patients who reacted to streptokinase were found to have low levels of total complement 1 year post reaction. Probable aggregates and fragments of human albumin (added stabilizer) were found in the streptokinase preparation and proved to be antigenic in some patients, but were not found to be related to the development of reactions. The findings suggest that patients who develop reactions to streptokinase cannot be predicted on the basis of antibody titres at presentation. Minor reactions to streptokinase would not appear to be antibody-mediated, although complement activation may be involved.

Nonfouling biomaterials based on polyethylene oxide‐containing amphiphilic triblock copolymers as surface modifying additives: Adsorption of proteins from human plasma to copolymer/polyurethane blends

Three polyethylene oxide-polyurethane-polyethylene oxide (PEO-PU-PEO) block copolymers of variable PEO block size (MW 550, 2000, and 5000) were used to modify the surface of a conventional segmented polyurethane (PU) with the objective of inhibiting interactions with proteins. The surface-active copolymers were blended with the PU by solution methods. Protein adsorption from human plasma to the modified materials was investigated using radiolabeling and immunoblotting methods. From the radiolabeling experiments, it was found that fibrinogen adsorption from plasma to all of the modified surfaces was much lower than to the unmodified PU matrix. For blends of low copolymer content, resistance to adsorption was greatest on the copolymer 1 (PEO550)-modified materials, and increased with increasing copolymer content for all three blend types. At high copolymer content inhibition of adsorption was very strong and independent of PEO block size. The immunoblotting experiments showed that on materials of high copolymer content (20 wt %), the proteins investigated (fibrinogen, albumin, complement C3, and apolipoprotein A-I) were undetectable. At low copolymer content (< or = 5 wt %), the blends of copolymer 1, with the shortest PEO block, exhibited greater protein resistance than those of copolymers 2 and 3 (PEO blocks of MW 2000 and 5000, respectively), and resistance decreased with decreasing protein size. Evidence of complement activation was seen for the blends of low copolymer content. Adsorption of C3 and complement activation decreased with increasing content of the copolymers. It was concluded that surface density of PEO is more important than chain length for protein resistance in contact with plasma.

The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice

Age-related macular degeneration (AMD) is the most common cause of vision loss in developed countries. A defining characteristic of this disorder is the accumulation of material between Bruch's membrane and the retinal pigment epithelium (RPE), first as microscopic basal deposits and later as clinically evident drusen. The pathogenesis of these deposits remains to be defined. Biochemical and genetic studies have suggested that inflammation and complement activation may play roles in AMD. Several lines of evidence also suggest that alterations to the extracellular matrix (ECM) of the RPE and choroid contribute to the development of AMD. The inherited macular degeneration Doyne honeycomb retinal dystrophy/Malattia Leventinese is thought to be caused by an R345W mutation in the EFEMP1 gene (also called fibulin-3). The pathogenicity of this mutation has been questioned because all individuals identified to date with the R345W mutation have shared a common haplotype. We investigated the pathogenicity of this mutation in families with early-onset macular degeneration and by generating Efemp1-R345W knockin mice. Genetic studies show that one of the identified families with the R345W mutation has a novel haplotype. The mutant Efemp1-R345W mice develop deposits of material between Bruch's membrane and the RPE, which resemble basal deposits in patients with AMD. These basal deposits contain Efemp1 and Timp3, an Efemp1 interacting protein. Evidence of complement activation was detected in the RPE and Bruch's membrane of the mutant mice. These results confirm that the R345W mutation in EFEMP1 is pathogenic. Further, they suggest that alterations in the ECM may stimulate complement activation, demonstrating a potential connection between these two etiologic factors in macular degeneration.

Evidence for complement activation in premature labor associated with intra-amniotic infection

Evidence for complement activation in premature labor associated with intra-amniotic infection

G.P.7 02 Amyloid myopathy presenting with rhabdomyolysis: Evidence of complement activation

At age of 57 years, a man experienced an episode of rhabdomyolysis. On that occasion muscle biopsy was not performed, however monoclonal gammopathy of undetermined significance (MGUS) was diagnosed. Further, he developed a moderate proximal muscle weakness with CK level persistently elevated (1000–1200 U/l). When he came to our observation, at age 67, a muscle biopsy revealed an amyloid myopathy and multiple myeloma was at the same time disclosed. Terminal complement complex C5b9 (membrane attack complex) deposits were found in the vessel walls and muscle fibers surface depicted by amyloid. Our case suggests to keep in mind the possibility that amyloid myopathy may begin as an isolated episode of rhabdomyolysis. The detection of complement complex C5b9 suggests that complement cascade is implicated in the muscular damage of amyloid myopathy.

Amyloid myopathy presenting with rhabdomyolysis: Evidence of complement activation

At age of 57 years, a man experienced an episode of rhabdomyolysis. On that occasion muscle biopsy was not performed, however monoclonal gammopathy of undetermined significance (MGUS) was diagnosed. Further he developed a moderate proximal muscle weakness with CK level persistently elevated (1000–1200 U/l). When he came to our observation, at age 67, a muscle biopsy revealed an amyloid myopathy and multiple myeloma was at the same time disclosed. Terminal complement complex C5b9 (membrane attack complex) deposits were found in the vessel walls and muscle fibers surface depicted by amyloid. Our case suggests to keep in mind the possibility that amyloid myopathy may begin as an isolate episode of rhabdomyolysis. The detection of complement complex C5b9 suggests that complement cascade is implicated in the muscular damage of amyloid myopathy.

Plasma fibronectin and complement in surgical patients.

Plasma fibronectin and a fragment of the third component of complement (C3b) are both opsonins of the reticulo-endothelial system. Twenty patients undergoing uncomplicated gastro-intestinal surgery were studied. There was a significant reduction in plasma fibronectin and total haemolytic complement, but not C3, in the early postoperative period (days 1 to 3). In six surgical patients critically ill with severe sepsis both plasma fibronectin concentrations and C3 concentration were reduced significantly when compared with the early postoperative period of uncomplicated surgery. In addition, in the critically ill patients, direct evidence of complement activation was demonstrated. These studies show a transient reduction of humoral host defence mechanisms following surgery which may be permissive to bacteraemia and complement activation.

Normal pregnancy is characterized by systemic activation of the complement system

Background. The complement system, a major component of innate immunity, has recently been implicated in the mechanisms of fetal loss and placental inflammation in the anti-phospholipid antibody syndrome. Inhibition of complement has been proposed as an absolute requirement for normal pregnancy. Yet, pregnancy is characterized by a generalized activation of the innate immune system. This study was conducted to determine whether or not normal pregnancy is associated with complement activation in the maternal circulation.Methods. Anaphylatoxins (C3a, C4a and C5a) were determined in the plasma of normal pregnant (20–42 wks; n = 134) and non-pregnant women (n = 40). These complement split products (C3a, C4a and C5a) were measured using specific immunoassays. Non-parametric statistics were used for analysis.Results. 1) The median plasma concentrations of C3a, C4a and C5a were significantly higher in normal pregnant women than in non-pregnant women (all p < 0.001); 2) the concentration of C3a, C4a and C5a did not change with gestational age (p > 0.05); and 3) the median plasma concentration of C3a had a positive correlation with the plasma C4a and C5a concentrations (r = 0.36, p < 0.001 and r = 0.35, p < 0.001, respectively).Conclusion. 1) Normal human pregnancy is associated with evidence of complement activation, as determined by higher concentrations of the anaphylatoxins C3a, C4a and C5a in the maternal circulation; and 2) we propose that physiologic activation of the complement system during pregnancy is a compensatory mechanism aimed at protecting the host against infection.

Unexplained intrauterine fetal death is accompanied by activation of complement

Activation of the complement system has recently been implicated in the mechanisms of fetal loss in the antiphospholipid syndrome. It is, however, possible that complement activation is also involved in other causes of fetal death in the second and third trimesters of pregnancy. We therefore conducted a study to determine whether fetal death is associated with changes in the maternal plasma concentrations of complement split products or anaphylatoxins (C3a, C4a and C5a). A cross-sectional study was designed to include normal pregnant women (n=60) and patients with fetal death (n=60). Patients with fetal death were classified according to the cause of fetal demise into: a) unexplained (n=44); b) associated with preeclampsia (n=8); and c) associated with chromosomal abnormalities or major congenital fetal anomalies (n=8). The plasma concentrations of C3a, C4a and C5a were measured using sensitive and specific ELISAs. Non-parametric statistics were used for analysis. A P value of <0.05 was considered significant. 1) The median plasma concentration of C5a was higher in patients with fetal death than in normal pregnant women [median 16 ng/mL (range 4.5-402.5) vs. median 11.6 ng/mL (range 1.2-87.1), respectively; P<0.001]; 2) patients with an unexplained fetal death and those associated with preeclampsia had a higher median plasma C5a concentration than normal pregnant women (P=0.002 and P<0.001, respectively); 3) no differences were observed in the maternal plasma concentrations of C3a and C4a among the study groups. Unexplained fetal death is associated with evidence of complement activation.

IgE-Dependent Activation of T cells by Allergen in Atopic Dermatitis: Pathophysiologic Relevance

The importance of interactions between allergen and IgE in allergen-mediated activation of T lymphocytes from patients with atopic dermatitis (AD) is unclear. A role for this interaction is implied by past evidence for IgE-facilitated presentation of allergen to T cells, but this phenomenon has only been demonstrated in specific in vitro systems biased to maximize the effect. It is therefore not known whether the process is relevant in patients. We now show that the responses to allergen of unmodified peripheral blood mononuclear cells (PBMC) from individual AD patients are significantly greater in the presence of fresh, unheated, IgE-containing autologous serum than the same serum heated under IgE-denaturing conditions or specifically depleted of IgE by immunoprecipitation. In six independent experiments, 59%-67% of the maximal in vitro PBMC response to allergen was found to be dependent upon the presence of IgE in autologous serum used at 5% final concentration. These data provide the first evidence that sufficient amounts of allergen-specific IgE and allergen-reactive T cells occur concomitantly in the blood of individual AD patients to allow IgE-enhanced T cell responses to allergen. We conclude that IgE-enhanced T cell responses are pathophysiologically relevant and a therapeutic target in AD.