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PubMed1983

Complement activation by trichophyton rubrum.

The role of complement in infections by dermatophytes is unknown. Therefore we evaluated the ability of the dermatophyte Trichophyton rubrum to activate complement in vitro. Aliquots of human plasma that had been incubated with T. rubrum were examined for evidence of complement activation. Following incubation, the total hemolytic complement activity of plasma fell 76%. Further, each T. rubrum incubation led to obvious C3 conversion and generation of polymorphonuclear leukocyte (PMN) aggregating activity. Plasma that had complement activity depleted by heat (56 degrees C x 30 min) or 10 mM EDTA failed to develop C3 conversion or PMN aggregating activity. Complement activation was not affected when the classical complement pathway was selectively blocked by MgEGTA. These studies indicate that T. rubrum can activate the complement system by the alternative pathway. The consequent generation of anaphylatoxins, chemotaxins, and opsonins might be important both in host defense against dermatophytic infections and in the inflammatory reactions mediated by them.

Animals↗

PubMed1990

Reduction of complement activation during bypass by prime manipulation.

Complement activation is believed to be of importance in the development of complications arising after cardiopulmonary bypass. The effect on complement activation of priming the extracorporeal circuit with crystalloid alone, crystalloid plus albumin, or crystalloid plus the plasma expander polygeline was assessed in 36 patients undergoing coronary artery operations with cardiopulmonary bypass using a bubble oxygenator. Activation of the alternative and common complement pathways was monitored before, during, and after the bypass period by measuring concentrations of factor B and its fragment Ba and C3 and its fragment C3d. Complement activation occurred in all three groups of patients, with no difference between the crystalloid and crystalloid-albumin groups. In contrast, Ba fragment concentrations were persistently and significantly lower during and after bypass in the polygeline group, denoting reduced complement activation. C3d levels also showed a tendency to be lower in this group. Our results indicate that addition of polygeline to the priming solution reduces complement activation. Because complement activation is associated with morbidity after cardiopulmonary bypass, addition of polygeline to the priming solution may offer an inexpensive method of reducing morbidity after cardiopulmonary bypass.

Albumins↗

PubMed1995

The kinetics and distribution of C9 and SC5b-9 in vivo: effects of complement activation.

Many diseases associated with complement activation are characterized by tissue deposition of components of the terminal complement complex (TCC). The ninth component of complement (C9) plays an important role in the cytolytic effects, and may contribute to the non-lethal cell-regulating functions of the TCC. In this study we examined the behaviour of radiolabelled human C9 and its soluble complexed form SC5b-9 in vivo in order to determine the effects of complement activation on its turnover, distribution and molecular size. In normal rabbits the metabolic parameters of 125I-C9 (median and range) were: plasma half-life (t1/2) 25.9 (20.6-29.5) h, fractional catabolic rate (FCR) 5.7 (5.3-7.0)%/h, and extravascular/intravascular ratio (EV/IV) 0.7 (0.6-1.1). The distribution of radiolabelled C9 amongst body tissues was similar to that observed for rabbit serum albumin (RSA). Activation of the complement cascade with i.v. injection of cobra venom factor (CVF) resulted in rapid disappearance of C9 from the plasma and accumulation of protein-bound radiolabeled in the spleen (exceeding the plasma concentration) and the liver. RSA metabolism and distribution were unaffected by CVF. Fine performance liquid chromatography (FPLC) gel filtration of plasma samples suggested that monomeric C9 was the only major radiolabelled protein present during normal turnovers, whereas CVF administration was accompanied by the prompt appearance of a high mol. wt species consistent in size with SC5b-9. When injected directly, 125I-SC5b-9 disappeared rapidly from the plasma, falling by 50% in 0.7 (0.6-0.8) h, and less than 15% remaining after 4 h with accumulation of protein-bound label in the spleen and liver. These results demonstrate the complexity of C9 metabolism during complement activation.

Animals↗

PubMed1987

Complement activation in IgA nephropathy.

Activation of alternative complement pathway is presumed to be important pathogenically in IgA nephropathy since renal biopsies usually exhibit glomerular deposition of C3 and P (properdin). Surprisingly, little is known about plasma complement activation in this disease, and the plasma C3 and C4 concentrations are usually normal or increased. We quantitated C3 activation in 202 plasmas from 81 patients with IgA nephropathy using a sensitive new assay that detects a neoantigen [iC3b-C3d neoantigen) which appears when C3b is inactivated to iC3b, C3dg, or C3d. This assay accurately quantitates small amounts of in vivo C3 activation. The concentration of iC3b-C3d neoantigen in plasma was significantly increased, indicating C3 activation in 37% of the pediatric and 57% of the adult plasmas assayed. When data from serial determinations in the patients were analyzed, 75% of the adult and 57% of the pediatric patients had C3 activation on at least one occasion. Classical pathway activation, quantitated by C4 activation was found in 20% of the adult and 5% of the pediatric plasmas. No association was found between elevated iC3b-C3d neoantigen concentration and history of macroscopic hematuria, chronic renal insufficiency or degree of proteinuria. These studies show that complement activation can frequently be detected in the plasma of IgA nephropathy patients. However, the pathophysiologic significance of this complement activation remains to be determined.

Adult↗

PubMedDate not supplied

Limulus amebocyte lysate reactivity, complement activation, and patients' symptoms. Comparison of dialyzer membranes.

This study was undertaken to clarify the role of Limulus amebocyte lysate reactive material (LAL-RM) in the activation of complement in patients during hemodialysis with cuprophan membranes. The authors measured LAL-RM and complement C3a levels predialysis and at 15 and 60 minutes of dialysis in 16 patients dialyzed for 8 weeks on cuprophan membranes and then for a succeeding 8 weeks on cellulose acetate membranes. Patients' symptoms on dialysis with each membrane were assessed. The LAL-RM levels of these patients were compared to those of six patients dialyzed on cellulose acetate membranes only. The LAL-RM and C3a levels rose significantly in the 16 patients while on dialysis with cuprophan membranes, but there was no correlation between the LAL-RM and C3a levels. C3a levels rose significantly in the 16 patients while on dialysis with cellulose acetate membranes, but there was no rise in LAL-RM levels. C3a levels were significantly lower while the patients were on dialysis with the cellulose acetate membranes. The six patients on dialysis with the cellulose acetate membranes only had no detectable LAL-RM in their blood. Patients' symptoms were less while on dialysis with the cellulose acetate membrane, but the difference did not achieve statistical significance. We conclude that LAL-RM plays a very minor role, if any, in the complement activation caused by cuprophan membranes and that cellulose acetate membranes do not release LAL-RM.

Adult↗

PubMed2001

Complement activation by recombinant adenoviruses.

Recombinant adenoviruses are currently the most important vector system in gene therapy. Adenoviruses frequently cause upper respiratory tract infections in humans and anti-adenoviral antibodies are found in 35-70% of the population. Therefore in the majority of potential patients receiving adenoviral gene therapy, the contact of virus particles and blood will lead to the formation of antigen-antibody complexes. These complexes have the ability to induce inflammatory reactions via an activation of the complement system. We have determined the level of C3a (the most reactive complement component) generated in isolated citrate plasma of healthy individuals after challenge with recombinant and wild-type adenoviruses in amounts corresponding to virus blood levels to be expected in patients during adenoviral gene therapy. All plasma samples containing anti-adenoviral antibodies showed a substantial, dose-dependent generation of C3a. A virus plasma level of about 7.5 x 10(9) particles/ml (which was calculated to be the highest blood level reached during clinical trials in the past) induced an average release of about 3000 ng/ml C3a (baseline levels <140 ng/ml). Analyzing the nature of anti-adenoviral antibodies showed, that not only antibodies with neutralizing properties (anti-Ad5), but also non-neutralizing anti-adenoviral antibodies are capable of complement activation. This study suggests that complement activation can be ignored in local low-dose applications of recombinant adenoviruses, but warrants attention after systemic application of large viral quantities. In clinical protocols aiming at systemic virus application, measures for monitoring and controlling the complement system should be included on a regular basis.

Adenoviridae↗

PubMed1999

Complement activation and expression of membrane regulators in the middle ear mucosa in otitis media with effusion.

The aetiopathogenesis of chronic otitis media with effusion (OME) in children is not yet fully understood. OME is characterized by metaplasia of the epithelium and accumulation of sticky, glue-like effusion in the middle ear containing different mediators of inflammation, including activation fragments of the complement system. Here we examined whether the fluid phase complement activation is reflected in the middle ear mucosa and how the mucosa is protected against the cytolytic activity of complement. Mucosal biopsies from 18 middle ears of children with a history of chronic OME were taken. The biopsies were analysed by immunofluorescence microscopy after staining for complement fragments iC3b/C3c, C3d and C9, and regulators membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF; CD55) and protectin (CD59). There was a strong staining for iC3b/C3c, and a weaker one for C3d and C9 on the surface of the middle ear epithelial cells of OME patients but not in controls without OME. MCP was expressed on the hyperplastic three to four outer cell layers of the epithelium, while CD59 was expressed throughout the middle ear mucosa. The results suggest a strong ongoing complement activation and consequent inflammation in the middle ear cavity. Unrestricted complement damage of the epithelial lining is prevented by the strong expression of MCP and CD59.

Antigens, CD↗

PubMed1994

Effects of systemic complement activation on renal circulation of rats.

In a variety of immunopathological diseases activation of the complement cascade occurs either systemically or localized in the kidney. To elucidate the functional impact of complement activation upon the renal microcirculation, we administered cobra venom factor of Naja naja kaouthia (CVF) i.v. into thiobarbital anaesthetized female rats. CVF is a potent activator of the alternative pathway of complement by forming the C3-convertase CVF, Bb which cannot be downregulated by the natural inhibitor factors H and I and thereby leads to generation of the anaphylatoxins C3a and C5a and formation of the membrane attack complex (MAC). We utilized creatinine clearance and flowmeter measurements in the normal kidney and intravital microscopy of the split hydronephrotic rat kidney model to observe the microvascular changes. Bolus injection of CVF (100 U kg-1) resulted in an immediate reduction of RBF (-68% after 10 min), which remained decreased during the entire experiment (90 min). Systemic blood pressure was significantly reduced only in the early period (-23% of control: 126 mmHg after 10 min). After an initial anuric phase of 30 min duration, the glomerular filtration rate was significantly diminished by 47%. White cell count was decreased by about 50% after the experiments. Application of the competitive thromboxane A2-antagonist, BM 13505, reversed all renal and systemic CVF-effects. Continuous infusion of the competitive leukotriene D4-antagonist, ICI 198615, attenuated the late renal CVF-effects (i.e. 30 min after injection of CVF). Depletion of polymorphonuclear cells (PMN) attenuated the CVF-effects similar to BM 13505. Intravenous administration of CVF in the hydronephrotic kidney model resulted in a massive constriction of the interlobar and arcuate artery, with a fall in glomerular blood flow comparable to the reduction of RBF in the normal kidney. Diameters of the afferent arterioles--most sensitive to many vasoconstricting agents--were not significantly altered. Our results suggest that injection of CVF and the liberation of high amounts of the anaphylatoxins, C3a and C5a, induces the release of TXA2, which contributes to the early renal effects and the formation of cysteinyl-leukotrienes which play an important role in the late phase of systemic complement activation. Utilizing the split hydronephrotic kidney model we demonstrated the predominant action of complement activation on the large preglomerular vessels for the first time. PMN are seemingly involved in the liberation of secondary mediators which appear to reduce renal blood flow and glomerular filtration.

Animals↗

PubMed1987

Assessment of complement activation during extracorporeal circulation by measurement of complement split C3d.

The present report summarizes our previous experience with the effect of various dialyzer membranes on leukocyte count, plasma C3d and C5a/C5ades-Arg, and total hemolytic complement. A relationship between the formation of C5a/C5ades-Arg within the dialyzer and hemodialysis leukopenia was demonstrated by comparing different membranes. Arterial plasma C3d was found to be a useful cumulative marker of complement activation during hemodialysis. C3d was shown to be generated in the artificial kidney with kinetics resembling the formation of C5a/C5ades-Arg. Total hemolytic complement transitorily decreased with all membranes, but did not reflect dialyzer biocompatibility. It is suggested that determination of complement-split C3d outdates previous more elaborate estimates of complement activation during hemodialysis.

Complement Activation↗

PubMed1991

Local complement activation in inflammatory bowel disease.

To trace sites for local complement activation in inflammatory bowel disease, an indirect two-colour immunofluorescence method was applied on prewashed and directly ethanol-fixed mucosal specimens from patients with ulcerative colitis, Crohn's colitis, or terminal ileitis. Monoclonal antibodies to the IgG subclasses and to neoepitopes of activated complement C3b and the terminal complement complex (TCC) were used in combination with rabbit antiserum to immunoglobulins and various complement components. Deposits of activated C3b were found on the luminal face of the surface epithelium in the most affected ulcerative colitis specimens from 91% of 23 studied patients, together with cytolytic TCC in 81%. Furthermore, there was a selective deposition of the immunoglobulin G subclass 1 (IgG1) within the epithelial immune complexes in 63% of 11 studied patients. These results suggested that IgG1 autoantibodies to brush-border antigen(s) induce a complement-mediated attack on the epithelium in ulcerative colitis. The epithelial complement deposition seen in Crohn's disease tended to be more granular and was observed in 5 of 10 patients with colitis and in 4 of 10 with ileitis. No co-localization of IgG was observed, suggesting that complement activation had been induced by the alternative pathway. Type III immune reaction may, in addition, take place in both diseases since there was evidence of continuous vascular complement activation in submucosal blood vessels.

Blood Vessels↗

PubMed1985

Steroids reduce complement activation in rheumatoid arthritis.

Patients with seropositive, classical rheumatoid arthritis (RA) with severe active disease have raised plasma concentrations of the complement C3 split product C3d. These values display little diurnal or circadian variation in the individual patient. During a 3-month period the variation was within 10 mU/l in 45 patients (ref. range 20-52 mU/l, RA patients up to 120 mU/l.) Six RA patients were treated with steroids on clinical indication, and the plasma C3d, Ritchie index and pain score before and during the treatment (30 mg prednisolone per day) were measured. The variables showed a steady decrease during the next 14 days. Plasma C3d fell 2/3 of the total fall within the first 48 hours, while the serum total haemolytic complement activity, complement C3 and C4 did not change significantly. This shows that the anti-inflammatory effect of steroids is accompanied by a reduction of complement activation.

Arthritis, Rheumatoid↗

PubMed1983

The absence of detectable complement activation in aspirin-sensitive asthmatic patients during aspirin challenge.

Activation of complement was sought by two independent assay methods, total hemolytic complement (CH50) and C4 activation by rocket immunoelectrophoresis for C4d and C4 in plasma samples obtained from 16 aspirin-sensitive asthmatic patients and four control subjects during provocative oral aspirin challenges. No consistent evidence of significant complement activation was detected in either the asthmatic or control groups when serial measurements were performed. The measurements of CH50 and C4 activation did not change in either arterial or venous samples. These findings indicate that oral aspirin given in dosages that provoke bronchospasm did not activate C4 or significantly decrease serum complement activity.

Adult↗

PubMed1991

Complement activation and antibody binding by pneumolysin via a region of the toxin homologous to a human acute-phase protein.

Pneumolysin, a membrane-damaging toxin, is known to activate the classical complement pathway. We have shown that 1 microgram ml-1 of pneumolysin can activate complement, which is a much lower level than observed previously. We have identified two distinct regions of pneumolysin which show homology with a contiguous sequence within acute-phase proteins, including human C-reactive protein (CRP). Site-directed mutagenesis of the pneumolysin gene was used to change residues common to pneumolysin and CRP. Some of the modified toxins had a reduced ability both to activate complement and bind antibody. We suggest that the ability of pneumolysin to activate complement is related to its ability to bind the Fc portion of immunoglobulin G.

Amino Acid Sequence↗

PubMed1987

Complement activation following multiple injuries.

Complement activation was evaluated by assay of plasma C3dg and the terminal complement complex (TCC) in 19 patients with multiple injuries. In the nine patients with thoracic involvement, statistically significant increase of plasma TCC was found at first sampling (average 90 min post-trauma), and of C3dg after 24 hours. Such increase was not found in the ten patients without thoracic involvement. Heightened granulocyte elastase activity was found in bronchial lavage fluid 90 min after the trauma in three patients with thoracic injury. Pulmonary insufficiency (pO2/FiO2 less than 16 kPa on intermittent positive-pressure ventilation) arose in four patients. All four had raised plasma levels of TCC or C3dg on arrival at the hospital. Six patients with complement activation did not show pulmonary insufficiency. Although the series was relatively small, the results indicate that thoracic injury is particularly associated with complement activation, and that complement activation alone does not suffice to produce post-traumatic pulmonary insufficiency.

Adolescent↗

PubMed1987

Neutrophil lysosomal enzyme release and complement activation during cardiopulmonary bypass.

Complement activation and neutrophil degranulation were concomitantly studied during uncomplicated cardiopulmonary bypass (CPB). Plasma concentrations of complement factor C4, complement split product C3d, the neutrophil lysosomal enzyme elastase complexed with alpha 1-proteinase inhibitor (PI) and fibronectin were measured in 12 patients, C3d and elastase/PI increased significantly during CPB (volume-corrected results). The C3d rise was almost linear, whereas elastase/PI showed exponential increase. Mean elastase/PI and mean C3d concentrations at different times during CPB covaried closely. The study showed that during CPB neutrophil lysosomal enzyme release is intimately related to complement activation, although activation of the two systems may be caused by a common third activator within the extracorporeal circuit.

Adult↗

PubMed2001

Deposition of C3b/iC3b leads to the concealment of antigens, immunoglobulins and bound C1q in complement-activating immune complexes.

Complement activation by bound IgG in serum at physiological concentrations is reflected in the deposition of C3b/iC3b in the absence of antigenic expression of the IgG or of any bound C1q on the target. The aim of this study was to investigate the functional requirements for this phenomenon and to establish its relationship to a release or concealment of the antigens. Microtiter wells coated with IgG by direct adsorption or by binding of IgG antibodies to pre-adsorbed homologous antigen were incubated with serum or serum reagents at 37 degrees C. The complement reaction was analyzed by ELISA to quantitate bound or released reaction products, and the release of IgG from the coated microtiter wells was gauged radiometrically. In the presence of serum, rapid binding of C1q and C3b occurred and was soon followed by a rapid loss of C1q expression; C3b binding remained high. Loss of IgG paralleled that of C1q. The functional requirement for the reaction was restricted to the activation and deposition of C3b/iC3b but was dependent of the combined function of the classical and alternative complement pathways. The loss of the IgG antigen was solely the result of antigen concealment, whereas the loss of C1q was only partly so. In biological terms, the concealment of bound IgG and C1q may reflect mechanisms by which complement down-regulates leukocyte responses stimulated by ligand-cell membrane receptor interactions.

Antigen-Antibody Complex↗

PubMed2000

Cutting edge: complement-activating complex of ficolin and mannose-binding lectin-associated serine protease.

Both ficolins and mannose-binding lectin (MBL) are lectins characterized by the presence of collagen-like and carbohydrate-binding domains in a subunit, although their carbohydrate-binding moieties are quite different. A fibrinogen-like domain is in ficolins, and a carbohydrate recognition domain is in MBL. On binding to pathogens, human MBL activates the complement system via the lectin pathway in association with two types of MBL-associated serine proteases (MASP), MASP-1 and MASP-2 and its truncated form, small MBL-associated protein (sMAP, also called MAp19). We report here that ficolin/P35, a human serum ficolin, was found to copurify with MASPs and sMAP. MASPs that were complexed with ficolin/P35 exhibited proteolytic activities against complement components C4, C2, and C3. The ficolin/P35-MASPs-sMAP complex that was bound to Salmonella typhimurium activated complement. These findings indicate that ficolin/P35 is a second collagenous lectin capable of activating the lectin pathway and thus plays a role in innate immunity.

Biopolymers↗

PubMed1989

Complement activation and endotoxin levels in systemic meningococcal disease.

The activation state of the complement system in 39 consecutively admitted patients with systemic meningococcal disease was studied prospectively using two monoclonal antibodies reacting with neoepitopes exposed during complement activation. The fluid-phase C3 activation products and SC5b-9 (terminal complement complex) were strongly correlated to the levels of endotoxin (lipooligosaccharides, LOS) in plasma on admission (r = .79, P less than .0001 and r = .76, P less than .0001, respectively) and to fatality. Maximum complement activation in survivors occurred 7h (median; range 0-44 h) after initiation of antibiotic treatment. The most severely ill patients had the capacity to activate the whole complement cascade. In nonsurvivors, high-grade activation often continued until the patients died. The results suggest that LOS are important activators of complement in systemic meningococcal disease and that complement-activating products, in concert with other mediators, may contribute to the multiple organ failure and death occurring in the most severe cases.

Complement Activation↗