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PubMed1983

Fatal complement-induced leukostasis after diatrizoate injection. Principles of clinicopathologic diagnosis.

A case of fatal radiographic contrast medium (RCM)-induced pulmonary granulocyte aggregation (leukostasis) showed massive elevation of the postmortem histamine level. Suspicion of this phenomenon in diverse clinical settings permits clinical and pathological documentation via increased plasma levels of C3a and other means. The existence of effective prophylaxis stimulates a search for predictive tests.

Aged↗
PubMedDate not supplied

Cerebrospinal fluid C3a increases with age, but does not increase further in Alzheimer's disease.

Complement activation is present in the brain in Alzheimer's disease (AD), and C1q concentrations are decreased in AD cerebrospinal fluid (CSF). To determine whether concentrations of other complement proteins are also altered in AD CSF, we measured concentrations of C3a and SC5b-9 in CSF from patients with probable AD (n = 19), normal aged controls (n = 11), and normal younger controls (n = 15). C3a concentrations were similar between AD and aged controls, but threefold higher than in younger controls (p < 0.05 vs. both groups). A similar pattern was found with SC5b-9, though the increase was only twofold and statistically significant only for AD vs. younger controls. These results suggest that an increased generation of complement proteins in localized areas of the AD brain does not result in elevated concentrations of these proteins in CSF, compared with age-matched controls. Increased C3a (and, to a lesser extent, SC5b-9) in aged controls may be due to increased complement activation, increased central nervous system production, and/or blood-brain barrier leakage of these proteins.

Aged↗
PubMed1997

Effect of methylprednisolone on complement activation during heparin neutralization.

During cardiac surgery, steroids are frequently administered before the initiation of cardiopulmonary bypass (CPB), termed "pre-treatment," to reduce "first phase" complement activation during cardiopulmonary bypass (CPB). "Second phase" complement activation also occurs during heparin neutralization with protamine, although the effects of steroid pretreatment on such activation are unknown. This study was performed in patients undergoing coronary artery bypass graft surgery to determine whether high-dose methylprednisolone pretreatment affected complement activation during heparin-protamine interaction after termination of CPB. In eight patients (group MP), methylprednisolone, 30 mg/kg, was administered before CPB commencement, whereas another eight patients received placebo (group C). By using 125I des Arg radioimmunoassay, C3a, C4a, and C5a were measured in the arterial blood samples drawn before and 10 min after administration of protamine. An increase in C3a and C4a was observed in both groups after protamine, suggesting classic pathway activation (delta C3a: group C, 4,484 +/- 3,320; group MP, 1,394 +/- 1,653; delta C4a: group C, 1,810 +/- 731; group MP, 717 +/- 580). C3a and C4a levels were significantly lower in group MP patients after protamine compared with controls [delta C3a, 3,499 +/- 1,826 (p < 0.05); delta C4a, 1,241 +/- 232 (p < 0.05)]. C5a was not detected in any samples. These results demonstrate that the effect of pretreatment persists beyond the period of CPB and that methylprednisolone inhibits second-phase complement activation during heparin-protamine interaction. These findings have implication for patients with severe anaphylactoid reactions to protamine.

Adult↗
PubMed1978

Complement in cystic fibrosis.

Complement components C3, C4, and C3A were estimated in 30 patients with cystic fibrosis aged 1 to 21 years (M:F = 16:14) and were compared with results in 40 healthy, age-matched subjects. The influences of the clinical score, sputum microbiology, and the patients' sex were also investigated. In contrast to most previous communications, this paper shows that, compared to the control group, a significant decrease of C3 (P less than 0.001) and C4 (P less than 0.02) was observed whereas C3A levels were not altered. There were no increases in complement. Shwachman-scores above or below 70 did not influence the complement levels, nor did exacerbations of the disease change the levels. No influence of the patients' sex could be shown. Pseudomonas aer. in the sputum was clearly associated with complement defects (14/18). Alternative-pathway involvement of complement activation could be demonstrated in 32%. The results make complement activation due to pulmonary infection most likely. The defects observed probably represent secondary changes.

Adolescent↗
PubMed2003

Infusion of plasma-derived mannan-binding lectin (MBL) into MBL-deficient humans.

Our first experience of mannan-binding lectin (MBL)-replacement therapy was with a patient experiencing recurrent erythema multiforme associated with reactivation of herpes simplex virus; his erythematous eruptions could be controlled with infusions of fresh frozen plasma containing MBL, but not with plasma lacking MBL. Some years later, we treated a young girl with recurrent, debilitating infections with purified MBL; this was also followed by a dramatic clinical improvement. We have now carried out a phase I clinical trial on 20 MBL-deficient, but healthy, adult volunteers. The MBL was prepared by the State Serum Institute in Copenhagen, Denmark, from blood donor plasma. Each volunteer received a total of 18 mg of MBL in three 6-mg doses given intravenously once a week over 3 weeks. The volunteers were monitored closely after each infusion and no adverse clinical or laboratory effects were observed. Laboratory parameters included C-reactive protein, various complement components, and antibodies to MBL, HIV and hepatitis viruses. C3a (the anaphylotoxin derived from complement component C3) was monitored for signs of complement activation, but no significant infusion-associated fluctuations were observed. Serum levels of MBL after each 6-mg infusion ranged between 1200 and 2500 ng/ml. The half-life of the infused MBL was about 70 h, or 3 days. It was concluded that infusion of purified MBL manufactured by the Danish State Serum Institute is a safe procedure. However, adults may have to be given 6 mg or more at least twice weekly to maintain protective plasma MBL levels in MBL-deficient individuals.

Clinical Trials, Phase I as Topic↗
PubMed1985

Bioactive complement fragments in immunoregulation.

Several fragments derived from complement components have been identified as potent effector substances in in vitro assays that measure cell proliferation and antibody synthesis. The anaphylatoxin C3a suppresses the immune response but fails to influence T- or B-cell proliferation. The factor C5a augments both antibody production and antigen-induced, but not mitogen-induced, T-cell proliferation. C3a-mediated suppression occurs through the activation of a suppressor T-cell cascade with macrophage collaboration. C5a-mediated enhancement, depending upon the in vitro system studied, acts at the level of the helper T cell and/or macrophage. A fragment generated from treating iC3b with kallikrein (c3d-K) has aided in defining a structural region of the C3b molecule that can influence the level of circulating leukocytes. The factor C3d-K is also capable of suppressing both specific and non-specific T-cell proliferative responses and mitogen-induced B cell growth. The mechanism of C3d-K action is defined as a direct effect on "activated" T cells, even though IL-2 synthesis of treated cells is diminished. The effect of C3d-K is long lasting, non-reversible and requires only a short exposure to the target cell.

Animals↗
PubMed2006

APT070 inhibits complement activation during in vitro cardiopulmonary bypass.

BACKGROUND: The proteins of the complement cascade play an important role in inflammation and the immune response. They have been shown to be activated during cardiopulmonary bypass (CPB), and may be responsible for the inflammatory response to CPB. We looked at the effect of APT070, an anti-complement agent, on human blood during in vitro CPB. MATERIALS AND METHODS: Four hundred millilitres of blood was venesected from healthy human volunteers and heparinised. To the blood was added either APT070 to a concentration of 50 microg/ml (n=5) or vehicle control (n=4). The blood was entered into an in vitro CPB circuit and circulated for 90 min. RESULTS: Our results showed that after 90 min of in vitro bypass APT070 significantly inhibited the activation of compliment as demonstrated by C3a (p=0.03) and sC5b-9 (p=0.01) levels, and reduced neutrophil stimulation as measured by CD11b expression (p=0.04 at 90 min). CONCLUSION: APT070 significantly inhibits complement and neutrophil activation. This result may have considerable implications, especially if it can be shown to decrease the inflammatory sequelae of CPB.

CD11b Antigen↗
PubMed1987

The ischaemic leg as a source of complement activation.

Complement activation before and after surgical resection was studied in 40 patients with ischaemic legs (17 with acute and 23 with chronic ischaemia). Plasma anaphylatoxin concentrations (C3a and C5a) and anaphylatoxin inhibitor (AI) activity were studied pre-operatively, and 1 h, 24 h and 1 week postoperatively. Increased plasma anaphylatoxin concentrations were found pre-operatively. Anaphylatoxin levels in plasma had returned to normal one week postoperatively. Patients with acute ischaemia had higher plasma C3a and C5a pre-operatively and during the first 24 h postoperatively than patients with chronic ischaemia. Anaphylatoxins increase vascular permeability, smooth muscle contraction and histamine release from mast cells. Their enhanced activity might be one of the explanations for respiratory, hepatic and renal insufficiency before surgical resection in patients with extensive ischaemia.

Aged↗
PubMed1999

Expression of cytokines by human astrocytomas following stimulation by C3a and C5a anaphylatoxins: specific increase in interleukin-6 mRNA expression.

C3a and C5a anaphylatoxins are two proinflammatory peptides generated during complement activation that act through distinct Gi protein-coupled receptors named C3aR and C5aR, respectively. We have demonstrated previously that human astrocytes expressed C3aR and C5aR constitutively and were able to produce a functional complement. In this study, we examined the effect of an anaphylatoxin stimulation on cytokine expression by human astrocyte cell lines. Interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, and transforming growth factor-beta mRNA expression was studied by quantitative RT-PCR. Whereas IL-1beta, tumor necrosis factor-alpha, and transforming growth factor-beta mRNA levels remained unchanged, stimulation of astrocytoma cells (T98G, CB193, U118MG) by C3a, C5a, and peptidic C3aR and C5aR agonists induced an increase in the IL-6 mRNA level. The amount of IL-6 was markedly increased at 3 and 6 h and returned to the basal level at 9 h of stimulation. This response was specific, because pretreatment of cells with pertussis toxin or with polyclonal anti-C3aR or anti-C5aR antibodies completely blocked the IL-6 mRNA increase. The IL-6 response was also investigated at the protein level, but IL-6 protein was detected neither in cell lysates nor in supernatants of stimulated cells. The anaphylatoxin-mediated transcriptional activation of IL-6 gene suggests that C3a and C5a could play a role in priming glial cells during the inflammatory process in the brain.

Anaphylatoxins↗
PubMed1992

A recombinant hybrid anaphylatoxin with dual C3a/C5a activity.

By site-directed mutagenesis of a human complement factor C5a cDNA clone, we have designed a hybrid anaphylatoxin in which three amino acid residues in the C-terminal sequence of human C5a were exchanged to create the native C-terminal human C3a (hC3a) sequence Leu-Gly-Leu-Ala-Arg. This hybrid anaphylatoxin rC5a-(1-69)-LGLAR exhibited true C3a and C5a activity when tested in the guinea pig ileum contraction assay. Quantitative measurements of ATP release from guinea pig platelets revealed about 1% intrinsic C3a activity for this hybrid, while the C5a activity was essentially unchanged. Competitive binding assays confirmed that the rC5a-(1-69)-LGLAR mutant was able to displace radioiodinated rhC5a with a KI of approx. 40 nM and hC3a with a KI of approx. 3.7 microM from guinea pig platelets. Since the C-termini of both human C3a and C5a anaphylatoxins are known to interact with their respective receptors, we conclude that the same peptidic sequence, LGLAR, is able to bind to and activate two different receptors, the C3a receptor as well as the C5a receptor. This clone provides a novel tool for the identification of further receptor-binding residues in both anaphylatoxins, since any mutants may be tested for altered C3a and C5a activity simultaneously.

Adenosine Triphosphate↗
PubMed1986

Helical conformation at the carboxy-terminal portion of human C3a is required for full activity.

Human C3a, a 77-residue fragment released during complement activation, is a potent spasmogen that contracts smooth muscle, enhances vascular permeability, and suppresses humoral immune responses. Studies with synthetic peptides have shown that the active site of this anaphylatoxin resides in the COOH-terminal portion of C3a; the minimal peptide structure capable of expressing activity contains residues 73-77, Leu-Gly-Leu-Ala-Arg (C3a-73-77). Longer synthetic C3a analogue peptides, e.g., C3a-57-77 containing the 21 COOH-terminal amino acids, exhibit activity nearly equivalent to that of intact C3a. Circular dichroism spectra of peptide C3a-57-77 in aqueous buffer containing 25% (v/v) trifluoroethanol indicated helical structure (41% helix), and analysis of the sequence suggested an amphipathic surface. We have synthesized several 21-residue peptide analogues of the natural C3a sequence containing residues 57-77 that were designed to enhance helix and to accentuate amphipathy. Syntheses were designed to include strategic placement of the helix-promoting residues 2-aminobutyric acid (beta-methylalanine) and 2-aminoisobutyric acid (alpha-methylalanine). Two 21-residue C3a analogue peptides that were designed to enhance helical content were shown to exhibit greater biological activity than either the native factor C3a or C3a-57-77. Moreover, activity was abrogated by the appropriate placement of helix-breaking residues, e.g., proline, suggesting that a conformational requirement for activity is genuine. These observations suggest that a helical conformation is requisite for optimal C3a activity and that in intact C3a the NH2-terminal portion (residues 1-21) and the disulfide-linked core (residues 22-57) function primarily to stabilize ordered conformation at the COOH-terminal region of the molecule.

Amino Acids↗
PubMed1990

Hypersensitivity reactions during haemodialysis: role of complement fragments and ethylene oxide antibodies.

IgE-antibodies against ethylene oxide (EtO) and activation of the complement system have been suspected as causative factors for acute hypersensitivity reactions at the onset of haemodialysis. The present study was conducted to determine which of the two mechanisms is mainly responsible for the occurrence of reactions. According to clinical criteria, 13 of the 129 patients studied were identified as having suffered from at least one episode of acute hypersensitivity. Seven of them experienced severe symptoms, including five with elevated circulating serum EtO antibodies. Of the remaining six patients who experienced moderate symptoms, only one had elevated serum EtO antibodies, and of the 114 patients not exhibiting symptoms, two had enhanced serum concentrations of EtO antibodies. In-vivo complement activation was determined during haemodialysis by measurement of both C3adesarg and C5adesarg fragments. No differences in the onset levels and the degree of complement activation were found between patients suffering from severe, moderate, or no hypersensitivity reactions. In-vitro activation of the complement cascade by zymosan, measured in plasma samples obtained from patients prior to dialysis, revealed no differences in the extent of C3adesarg generation. Finally, we determined the activity of the C3a- and C5a-inactivating enzyme, carboxypeptidase N1 (CN1), in plasma samples of patients both with and without hypersensitivity reactions. No difference in the CN1 activity between the two groups of patients was found. These data lead us to conclude that sensitisation to ethylene oxide is responsible for the majority of severe hypersensitivity reactions in haemodialysis patients. However, a small subgroup of patients having anaphylactoid reactions displayed neither elevated serum EtO antibodies with excessive complement activation nor a tendency towards reduced inactivation of anaphylatoxins.

Adolescent↗
PubMed1986

Evaluation and tolerance of a new polycarbonate membrane in elderly patients. Preliminary results.

We studied the performance and tolerance of a new capillary hemodialyzer using a polycarbonate membrane (Gambrane PCD 1000) in a group of 5 elderly patients (mean age 68 years). The ultrafiltration coefficient is 6 (justifying the monitoring control of weight loss) and clearances for small molecules are comparable with cellulosic membranes. A good tolerance during 300 sessions was observed; nevertheless, an important neutropenia was noted in 2 out of 5 patients. The complement activation measured by the dosage of the C3a Desarg fraction existed in all the patients, reaching an average 6 times the initial level compared to 40 times for Cuprophan. Complement activation and neutropenia are considerably reduced by the reuse of the hemodialyzer as it was described for the cellulosic membranes.

Age Factors↗
PubMed2001

C3A binds to the seven transmembrane anaphylatoxin receptor expressed by epithelial cells and triggers the production of IL-8.

The complement (C) plays an important role in many acute inflammatory processes. C3a is an inflammatory polypeptide named anaphylatoxin, generated during C activation and which acts through a specific receptor C3aR. In this study, we demonstrated that the epithelial cell line ECV 304 constitutively expressed C3aR (by flow cytometry and immunofluorescence) and that binding of purified C3a to epithelial cells resulted in a time- and dose-dependent upregulation of interleukin-8 (IL-8). Pre-treatment of ECV 304 with pertussis toxin inhibited IL-8 response induced by C3a, indicating that the action of C3a was mediated by a G protein coupled pathway.

Anaphylatoxins↗
PubMed2005

Anaphylatoxins in preterm and term labor.

OBJECTIVE: The complement system plays a central role in the first line of defense against invading pathogens, and its activation involves the release of potent pro-inflammatory mediators such as anaphylatoxins C3a, C4a and C5a. The aim of this study was to determine whether differences existed in maternal plasma anaphylatoxin concentrations between patients with term and preterm parturition. STUDY DESIGN: A cross-sectional study was designed to determine the plasma anaphylatoxin concentrations in 296 pregnant women in the following groups: 1) normal pregnancy between 20-36 6/7 weeks (n=64); 2) term not in labor (n=70); 3) term in labor (n=60); and 4) preterm labor with intact membranes (n=102). Women with preterm labor were classified into: a) term delivery (n=24); b) preterm delivery without intra-amniotic infection (IAI) (n=62); and c) preterm delivery with IAI (n=16). Concentrations of C3a, C4a and C5a were determined by ELISAs. Statistical analysis was conducted with non-parametric methods. RESULTS: 1) The median plasma C5a concentration was lower in women at term in labor than in those not in labor (P<0.001). In contrast, there were no differences in plasma C3a and C4a concentrations between the two groups (P>0.05). 2) Among patients with preterm labor, those with IAI had a higher median plasma C5a concentration than those without IAI and those who delivered at term (post-hoc tests P<0.001 and P=0.01, respectively). When comparing the preterm labor subgroups with normal pregnancy, only women with preterm delivery and IAI had a median plasma C5a concentration higher than that of normal pregnant women (Kruskal-Wallis P<0.001, post hoc test P<0.001). There was no difference in the plasma C4a concentration among patients with preterm labor. The median plasma C3a concentration in patients with preterm labor with IAI was higher than in those without IAI (Kruskal-Wallis P=0.01, and post-hoc test P=0.005). There was no difference in the plasma C3a concentrations between women with preterm labor who delivered at term and those with preterm delivery, with or without IAI. In addition, no differences were observed in the median plasma C3a concentration between women with normal pregnancy and those in each of the preterm labor subgroups. CONCLUSIONS: The maternal plasma concentration of anaphylatoxin C5a is increased in women with preterm labor and IAI, but not in spontaneous labor at term.

Adolescent↗
PubMed1984

Effect of C3a and C5a anaphylatoxins on guinea-pig isolated blood vessels.

Four major guinea-pig blood vessels were isolated and studied in vitro for their contractile responses to anaphylatoxins C3a and C5a. Both peptides were assayed in the 10(-9) to 10(-7) M range and their effects were parallel, although C3a was less potent and more tachyphylactic than C5a. The most responsive blood vessel, relative to a histamine maximal response, was the portal vein, followed by the pulmonary artery and the thoracic aorta. The abdominal vena cava did not respond to either C3a or C5a. Participation of secondary mediators in the vasoconstrictor effect of C3a and C5a was assessed by exposing portal veins and pulmonary arteries to specific inhibitors. The four drugs were: indomethacin, a cyclooxygenase inhibitor; pyrilamine, an antagonist of H1 receptors for histamine; FPL55712, an antagonist of the leukotriene component of slow-reacting substance of anaphylaxis; and phentolamine, an alpha adrenergic blocker. This pharmacological analysis suggests that prostaglandin-like substances mediate most of the anaphylatoxin vasoconstrictor effects, with a biologically significant participation of leukotrienes in the case of C3a and histamine in the case of C5a. High variability between individual tissue responses to the anaphylatoxins was investigated in terms of previous exposure to activated complement. Cobra venom factor (200 micrograms) was injected i.v. in five guinea pigs 2 hr before sacrifice. This treatment reduced the serum concentration of C3 and C5 to 9 and 32%, respectively, as compared with saline-treated animals. The portal vein excised from the cobra venom factor-treated animals exhibited reduced sensitivities to C3a, but showed normal response to C5a. The selective desensitization to C3a after complement activation in vivo is presumably related to the highly tachyphylactic effect of C3a on blood vessels.

Anaphylatoxins↗
PubMed1996

Regulation of alternative pathway activation and C3a production by adipose cells.

Adipose tissue is a major source of adpisin/factor D of the alternative pathway of complement. Adipose tissue also expresses the two other complement components which are involved in the first activation step of the alternative pathway, factor B and C3, and this step is activated in adipose tissue, producing C3a/Acylation Stimulating Protein (C3a/ASP), a stimulator of triglyceride synthesis. Complement activation is a highly regulated process, however, nothing is known about regulation of complement activation in adipose tissue. To gain insight into the nature of adipose complement activation and its regulation, we have now examined the expression of several complement activation regulatory genes, and analyzed the production of C3a/ASP in lean vs. obese, adpisin-deficient mice. We found that undifferentiated preadipocytes expressed the mRNAs encoding the negative regulatory proteins Crry and factor H, but expression of both genes was decreased upon differentiation. The positive regulator properdin, as well as Crry and factor H, were found in adipose tissue. None of these genes was regulated in murine genetic obesity. To investigate the relative levels of complement activation in lean vs. adpisin-deficient obese mice, we developed a radioimmunoassay for measurement of murine C3a/ASP in plasma. We report that there was no significant difference in the level of C3a in lean vs. obese plasma; however, we found a positive correlation between C3a and plasma triglyceride levels in normal lean mice.

Adipose Tissue↗
PubMed1997

Suppression of alternative complement pathway activity by radiographic contrast media.

The authors examined the effect of four different kinds of contrast media (ionic/non-ionic, monomer/dimer) on the activation of the complement (C) system (haemolytic activity and anaphylatoxin generation) in vitro. In addition, the authors compared the effect of contrast media on inulin-mediated generation of the anaphylatoxin derivative C3a des Arg in sera from urticarial reactors and their non-reacting controls. It was observed that the incubation of commercial iohexol, ioxaglate, iodixanol and meglumin amidotriz solutions in normal human serum (NHS) resulted in a dose-dependent decrease in the haemolytic activity of the alternative C pathway. Contrary to expectations the contrast media did not activate C in NHS. Instead, inulin-induced generation of C3a des Arg was inhibited by all the four contrast media. The strongest inhibitor was ioxaglate, an ionic dimer. No significant difference between the urticarial reactors and non-reactors in the inhibition of C3a des Arg generation was observed. In analyzing the mechanism of C inhibition we found that the contrast media solutions, particularly the ionic ones, prevented formation of the alternative pathway C3 convertase, C3bBb, by inhibiting the binding of factor B to surface-associated C3b molecules. The results suggest that the previously observed decrease in haemolytic C titres by contrast media is due to direct suppression of C activity rather than activation-induced consumption.

Complement C3-C5 Convertases↗