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PubMed1986

Complement cleavage products in the phototoxic reaction of porphyria cutanea tarda.

We have measured C3, C4, CH50 and complement cleavage products C3a and C5a in in sera and plasma from PCT patients and normal controls 10 min and 1, 4 and 24 h after UVA irradiation. We found elevated C3a concentrations in PCT patients immediately after UVA irradiation and 24 h later. The same was true for CH50, whereas C3, C4 and C5a did not change significantly. No such changes occurred in normal controls. Our data suggest that activation of the complement cleavage product C3a by porphyrin and UV light triggers a series of events that cause tissue damage.

Adult↗
PubMed1982

Modulation of human lymphocyte function by C3a and C3a(70-77).

Human C3a and the synthetic octapeptide C3a (70-77), which retains the activities of an anaphylatoxin, inhibit in a concentration-dependent manner the generation of leukocyte inhibitory factor (LIF) activity by human mononuclear leukocytes and T lymphocytes cultured with the mitogens phytohemagglutinin (PHA) or concanavalin A (Con A) or the antigen streptokinase-streptodornase (SK-SD). The generation of LIF activity was inhibited by 50% by 10(-8) M C3a or C3a(70-77) with PHA or Con A as the stimulus, whereas a more than 10-fold higher concentration of C3a(70-77) than C3a was required to achieve the same level of suppression with SK-SD as the stimulus. Similar concentrations of C3a(70-77) inhibited to the same extent the migration of T lymphocytes stimulated by alpha-thioglycerol of Con A. Neither C3a nor C3a(70-77) altered significantly the uptake of [3H]thymidine by human mononuclear cells exposed to PHA, Con A, or SK-SD. The capacity of C3a(70-77)-Sepharose,m but not Sepharose alone, to adsorb or inactivate mononuclear leukocytes required for the generation of LIF activity established a direct interaction. Analysis of the lymphocytes in the effluent from C3a(70-77)-Sepharose columns, using monoclonal antibodies to surface antigens, showed a selective depletion of the helper/inducer population of lymphocytes. C3a might represent an important mediator of the functionally selective regulation of human T lymphocyte activities by the complement system.

Cell Division↗
PubMed1993

Characterization of C3a anaphylatoxin receptor on guinea-pig macrophages.

We have characterized a C3a receptor on guinea-pig macrophages by 125I-C3a binding and functional responses. Scatchard analysis applied to the 125I-C3a binding to guinea-pig macrophages revealed the existence of two receptor classes; a high-affinity class with approximately 0.63 x 10(5) binding sites/cell with a Kd = 2.7 nM, and a relatively low-affinity class with approximately 1.2 x 10(5) binding sites/cell with a Kd = 51 nM. The binding of C3a to macrophages was totally blocked when there was an excess of C3a. C3a triggered a transient intracellular Ca2+ ([Ca2+]i) mobilization in macrophages, which was accompanied by homologous desensitization. C3a was also capable of generating O2- from macrophages. The C3a-induced Ca2+ response and O2- generation were not detected in the pertussis toxin-treated macrophages, suggesting that G proteins are coupled with the C3a receptors of macrophages. Although the C3a-induced O2- generation was inhibited by staurosporine, it was more resistant to staurosporine than phorbol 12-myristate-13-acetate (PMA)-induced O2- generation, suggesting that a protein kinase distinct from protein kinase C may be associated with the C3a receptor.

Animals↗
PubMedDate not supplied

Complement activation in patients undergoing mechanical circulatory support.

Contact of blood with artificial surfaces activates pro-inflammatory responses and the complement cascade. This may have broad implications on the post implantation fate of patients needing mechanical circulatory support. Therefore, we investigated the course and prognostic value of complement factors C3a and C5a in 66 patients supported with pulsatile ventricular assist devices. All patients were in severe cardiogenic shock, i.e., catecholamine dependent and in the intensive care unit, before implementation of mechanical circulatory support. Isolated left ventricular support (Novacor [Oakland, CA] or Thermo Cardiosystems, Inc. [TCI; Woburn, MA]) was used in 28 patients, and biventricular support (Berlin Heart [Mediport, Berlin, Germany]) in 38 patients. Before initiation of mechanical circulatory support, no statistically significant differences in C3a or C5a between surviving and nonsurviving patients with left ventricular assist devices (LVADs) were found. Patients with biventricular assist devices (BVADs) had significantly higher C3a (804 +/- 364 ng/L) levels than patients with LVADs (536 +/- 204 ng/L, p = 0.02) before mechanical circulatory support. Only C5a, only in the BVAD group, was able to predict patients' post implantation course before implantation of a ventricular assist device (p = 0.02). Three weeks after initiation of mechanical circulatory support, complement factors remained increased in all groups. There was no difference, however, in complement activation between patients with LVADs and those with BVADs. Patients not reaching transplantation had significantly higher C3a levels at this point than those successfully supported (p = 0.007). The degree of complement activation mainly depends on the severity of cardiogenic shock before initiation of mechanical circulatory support, and not on the device used. Patients with extremely high levels of complement activation before implantation of the device could be saved with BVAD rather than LVAD support. Patients who continued to have highly elevated complement levels 3 weeks after initiation of mechanical circulatory support had unfavorable prognoses. Complement activation indicates the severity of cardiogenic shock before implementation of mechanical circulatory support and the degree of recovery from secondary organ dysfunction while on the device. It is fairly independent of the system used for mechanical circulatory support, and therefore can be applied to predict patients' post implantation course and outcome.

Adolescent↗
PubMed1996

Role of atheroma liposomes and malondialdehyde-modified low-density lipoproteins in complement activation.

We investigated the ability of atheroma-associated liposomes and malondialdehyde (MDA)-modified low-density lipoproteins (MDA-LDL) to activate complement. Complement activation markers C3a, Bb, C4d and SC5b-9 were measured in both normal and complement-deficient sera. We found that MDA-LDL was able to generate C3a and SC5b-9, predominantly by the alternative pathway. High-density lipoproteins modified with MDA were also capable of C3a generation although to a lesser degree. The presence of atheroma-associated liposomes did not result in detectable levels of complement activation markers. We conclude that MDA-modified lipoproteins may represent a possible source for complement activation within atherosclerotic lesions.

Aortic Diseases↗
PubMed1993

Proteins separated from human IgG molecules.

Immunoglobulin G binding proteins were separated from human IgG molecules using 1 N acetic acid followed by 5 M guanidinium chloride in 0.1 M acetic acid. The proteins thus obtained were heterogeneous as demonstrated by SDS-PAGE and reverse-phase HPLC. The isolated proteins consisted of two types: the C3a and C4a complement fragments (anaphylatoxins) and immunoglobulin peptide chain fragments V kappa I and C gamma 3. Both anaphylatoxins immobilized on cellulose nitrate membranes could reassociate with intact IgG molecules. The ubiquitous presence of C3a in IgG preparations was demonstrated using monoclonal antibodies specific for C3a. Nearly all of the bound anaphylatoxin molecules were found in the Fab fragment. These findings suggest that IgG molecules can eliminate anaphylatoxins from the circulation, and thus prevent harmful effects due to these active complement components.

Amino Acid Sequence↗
PubMed1992

C3a and C5a anaphylatoxins bind to heparin-based sorbent in low density lipoprotein apheresis: in vitro and in vivo investigations.

Plasmasorption on a heparin-based sorbent was performed in vitro. It demonstrated affinity of the C3a and C5a anaphylatoxins for the sorbent: C3a was removed almost completely (97%), and the C5a concentration decreased on average by 55%. The plasma level of C3a and C5a complement components was also monitored during the procedure of clinical extracorporeal low density lipoprotein (LDL) apheresis on the sorbent in patients with familial hypercholesterolemia. A two- to threefold increase in C3a (up to 1,500 ng/ml) was observed after plasma separation by the IBM 2997 cell sorter. Subsequent processing of the plasma through the column led to the low level of C3a detected (less than 50 ng/ml), demonstrating significant uptake of C3a by the sorbent column. The removed C3a was found in the eluate obtained after regeneration of the sorbent with 2 M NaCl solution. No significant increase in C5a was found during the procedure. Nevertheless, some C5a was detected in the eluate from the sorbent. The content of C3a and C5a in patients blood after the treatment was approximately the same as it was initially, 200-500 ng/ml for C3a and less than 10 ng/ml for C5a. The removal of C3a and C5a anaphylatoxins by heparin-based sorbent should be regarded as an advantage of this type of plasmasorbent.

Adsorption↗
PubMed1997

Leishmania, macrophages and complement: a tale of subversion and exploitation.

Leishmania are intracellular protozoan parasites which reside primarily, if not exclusively, in host mononuclear phagocytes. Several studies have demonstrated that infectious promastigotes rapidly and efficiently fix complement when they encounter serum components during their transmission to the mammalian host. Activation of the complement system by a microorganism can have 3 distinct biological effects. First, fixation of the terminal complement components can result in complement-mediated lysis. Second, fixation of the 3rd component of complement can lead to opsonization of the organism for uptake by phagocytic cells. Finally, the elaboration of the complement anaphylotoxins, C3a and C5a, can lead to inflammation. In the present chapter, we discuss the interaction of leishmania promastigotes with the complement system. We show that infectious promastigotes avoid the lytic effects of complement and resist fixation of the terminal complement components. At the same time, however, these organisms depend on fixation of opsonic complement to invade host mononuclear phagocytes efficiently. We discuss the mechanisms which allow metacyclic leishmania promastigotes to exploit the opsonic properties of complement and the receptors on macrophages involved in leishmania recognition. The role of complement mediated inflammatory processes in the host response to leishmania infection is an area which requires additional study.

Animals↗
PubMed1991

Biocompatibility of four plasmapheresis membranes in patients treated for hypercholesterolemia.

Membrane plasma separation uses artificial polymers which might interact with blood components during treatment. In 7 patients treated for familial hypercholesterolemia with heparin-induced extracorporeal LDL precipitation (HELP), we studied 4 different synthetic plasma separation materials. The effect of membranes made from polyethylene, polymethylmethacrylate (PMMA), polypropylene and polysulfone on complement activation (C3a), granulocyte elastase release and granulocyte count were measured repeatedly during the treatment. Polyethylene and PMMA induced high levels of plasma elastase and marked granulocytopenia after 60 min of treatment, much later than during hemodialysis, where granulocyte nadir is known to occur already after 15 min. Polysulfone and polypropylene did not change granulocyte counts and caused only modest levels of elastase during plasmapheresis. Complement activation was present in all 4 membranes but with polyethylene, very high concentrations of C3a were detected. These data indicate that irritation of immune system components as granulocytes or the complement system do occur during plasmapheresis to different degrees depending on the membrane material used. Reinfusion of plasma after processing increases the amount of plasmatic activation products infused into the patient. This was the case, although the plasma processing procedure itself did not add activation products to the plasma. Activation patterns during plasma separation differ from those known to occur during hemodialysis despite use of the same polymer. Immunocompromised patients treated with plasmapheresis may react differently than these otherwise healthy subjects with familial hypercholesterolemia.

Biocompatible Materials↗
PubMed2000

Heparin-coated cardiopulmonary bypass circuits reduce circulating complement factors and interleukin-6 in paediatric heart surgery.

Children are sensitive to the inflammatory side effects of cardiopulmonary bypass (CPB). Our intention was to investigate if the biocompatibility benefits of heparin-coated CPB circuits apply to children. In 20 operations, 19 children were randomized to heparin-coated (group HC, n = 10) or standard (group C, n = 10) bypass circuits. Plasma levels of acute phase reactants, interleukins, granulocytic proteins and complement factors were measured. All were significantly elevated after CPB. Levels of complement factor C3a (851 (791-959)ng/ml [median with quartiles] in group C, 497 (476-573)ng/ml in group HC, p < 0.001), Terminal Complement Complex (114 (71-130) AU/ml in group C, 35.5 (28.9-51.4) AU/ml in group HC, p < 0.001), and interleukin-6 (570 (203-743) pg/ml in group C, 168 (111-206)pg/ml in group HC, p = 0.005), were significantly reduced in group HC. Heparin-coated CPB circuits improve the biocompatibility of CPB during heart surgery in the paediatric patient population, as reflected by significantly reduced levels of circulating complement factors and interleukin-6.

Anticoagulants↗
PubMed1990

Biocompatibility of blood tubings.

We studied hemocompatibility of various blood tubings with C3a anaphylatoxin measurement and comparative electron scanning microscopy. The following tubing materials were tested: polyvinylchloride (PVC) plasticised with phthalate (PVC), pvc plasticised with phthalate coextruded with polyurethane (PIV), and two phthalate-free lines: pvc plasticised with trimellitate coextruded with polyurethane (TRI) and pvc plasticised with LT 360 (LTP). Results of C3a generation rate showed a significant activation by all blood tubings, with a reduced rate with PIV when compared to all others. Electron scanning microscopy showed marked alterations of PIV surface on tubings stored for 6 months. Protein deposits on internal surfaces after dialysis were similar whatever tubing material was tested, but adhesive cell number was greater with TRI when compared to PVC and LTP. Hemocompatibility is unchanged with phthalate-free tubings when compared to phthalate plasticised ones. In contrast with phthalate plasticised PVC there is no beneficial effect of polyurethane coextrusion with trimellitate plasticised PVC in regard to C3a generation.

Anaphylatoxins↗
PubMed1996

Complement activation by a B cell superantigen.

Staphylococcal protein A (SpA), acting as a B cell superantigen, binds to the Fab region of human VH3+ Igs. Using SpA abrogated of its IgG Fc binding activity (Mod SpA) as a model B cell superantigen, we determined whether such an interaction causes complement activation. Addition of Mod SpA to human serum led to complement consumption and the generation of C3a. To determine whether this complement activation 1) was due to an interaction between VH3+ Igs and the Fab binding site of SpA and 2) proceeded via the classical complement pathway, we tested a panel of monoclonal IgM proteins for the ability to hind C1q following interaction with SpA. C1q binding was restricted to SpA-reactive, VH3+ IgM proteins. To formally determine whether the binding of SpA to the reactive VH3+ IgM proteins led to complement activation, we reconstituted the serum from a hypogammaglobulinemic patient with monoclonal IgM proteins and measured complement consumption and C3a generation following the addition of Mod SpA. We observed complement consumption and C3a production only in Mod SpA-treated serum reconstituted with a VH3+, SpA-binding, IgM protein. Taken together, these results provide compelling evidence that the interaction of the Fab binding site of SpA and VH3+ Igs can lead to complement activation via the classical pathway. This novel interaction may have significant implications for the in vivo properties of a B cell superantigen.

Adult↗
PubMed1989

Quantitation of the anaphylatoxin C3a in the presence of C3 by a novel sandwich ELISA using monoclonal antibody to a C3a neoepitope.

C3a levels in plasma are usually measured by a competitive inhibition radioimmunoassay (RIA) using 125I-labelled C3a-desArg and antibodies to C3a capable of detecting C3a determinants which are also present on the native C3. Therefore, prior to the assay native, non-cleaved C3 has to be removed completely from the C3a-containing sample by precipitation. We developed a new rapid two-site sandwich ELISA system for the quantitation of C3a-desArg in plasma. This immunoassay uses a monoclonal antibody (mAb H466) reacting with C3a-desArg but not with C3. The reactivity of mAb H466 with a neoantigenic determinant of C3a-desArg permitted the direct quantitation of C3a-desArg without removal of C3 from the sample. The mAb H466 was used as a capture antibody and bound C3a-desArg was detected with a second peroxidase-labelled anti-C3a mAb. The lower limit of detection of C3a-desArg in this ELISA was 1 ng/ml. The C3a-desArg levels measured in the plasma samples of various patients were found to differ over a wide range. A good correlation was observed between the results obtained in the RIA and those obtained in the ELISA (r = 0.95). High levels of C3a-desArg were detected in plasma from patients with multiple trauma and patients undergoing haemodialysis. The C3a-desArg assay described should facilitate the routine quantitation of C3a in samples of plasma.

Antibodies, Monoclonal↗
PubMed1988

Gene synthesis by serial cloning of oligonucleotides.

A rapid and simple method of gene synthesis is presented. A gene is constructed by serial additions of individual gene fragments in the 5'----3' direction. The vector used as the synthesis vehicle contains a unique Bsm I site at the amino terminus of the lacZ gene. Plasmid linearized with Bsm I is recircularized in vivo by oligonucleotide-directed double-strand break repair. The synthetic oligonucleotide used to "bridge" the double-strand break carries a 70- to 100-nucleotide insert which constitutes a portion of the gene along with a BsmI site at the 3' end that regenerates the site and allows for another consecutive round of mutagenesis to extend the gene sequence. The process is repeated until the entire gene is assembled. The method uses the beta-galactosidase color assay as a means of screening for correct insert lengths. The only in vitro enzymatic step necessary is a single Bsm I restriction digest of plasmid DNA. No ligation reactions are required. Only one strand of a gene sequence needs to be synthesized chemically. The gene synthesis method presented here was used to construct the human anaphylatoxin complement factor C3a gene.

Amino Acid Sequence↗
PubMed2001

In-vitro activation of complement system by lactic acidosis in newborn and adults.

INTRODUCTION: Complement activation occurs secondary to a variety of external stimuli. Lactic acidosis has been previously shown to activate the complement factors C3a and C5a. In the present investigation we examined the differential effect of lactic acidosis on anaphylatoxin levels in cord and adult blood. Furthermore we aimed to determine if the entire complement cascade could be activated by lactic acidosis. METHODS: Cord and adult blood samples (n = 20 each) were collected and incubated for one hour in either untreated condition or with the addition of lactate in two concentrations (5.5 mmol/l vs. 22 mmol/l). Following incubation, levels of C3a, C5a and sC5b-9, and blood gas parameters were determined. RESULTS: Anaphylatoxin (C3a and C5a) and sC5b-9 levels increased with the addition of lactate in a dose-dependent manner in cord and adult blood (C3a: 1 h, 5.5 mmo/l, 22 mmol/l: 418/498/622 microg/l in cord blood; 1010/1056/1381 microg/l in adult blood, p<0,05; similar results were found for C5a and sC5b-9). CONCLUSION: Lactic acidosis leads to an activation of the entire complement system in neonates and in adults. This activation is dose-dependent and more pronounced in adults as compared to neonates.

Acidosis, Lactic↗
PubMed1987

Ex vivo biocompatibility evaluation of a new modified cellulose membrane.

To evaluate membrane biocompatibility, an open loop ex vivo model was designed simulating the hemodialysis procedure. Blood was withdrawn continuously from healthy nonuremic donors, heparinized, and pumped through a module containing the membrane to be studied. C3a generation in the module was determined at various time points comparing the cuprammonium cellulose (CC) membrane and four types of modified cellulose (MC) membrane, each with a different degree of hydroxyl (OH-) group substitution. In other studies, C3a generation in the ex vivo mode was compared with that during in vivo dialysis. In the ex vivo model, C3a generation with MC membranes was reduced by 70% compared with CC. However, within the MC group, the degree of C3a generation did not correlate with the degree of OH-group substitution. In vivo studies confirmed the reduced degree of C3a generation with the MC membrane compared with CC. Additionally, validation studies using the CC membrane showed excellent agreement between C3a generation during ex vivo perfusion and in vivo dialysis. The results suggest that a group of new MC membranes causes substantially less complement activation than the CC membrane but that the degree of complement activation with various subtypes of MC membranes is not related to the degree of OH-group substitution.

Anaphylaxis↗