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Results for “Complement Pathway, Classical”

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PubMed1983

Activation of the complement system and accumulation of hemoglobin-haptoglobin complexes in plasma during an adverse reaction to penicillin treatment.

A patient treated with penicillin intravenously developed a serum sickness-like reaction. Classical pathway complement (C) activation was indicated by quantitation of the split products C3c and C3d as well as demonstration of C4 conversion. Circulating immune complexes could, however, not be detected by the solid-phase Clq and PEG-precipitation methods. A concomitant accumulation of circulating hemoglobin-haptoglobin complexes and a marked fall in serum-fibronectin concentrations suggested saturation of the reticuloendothelial system. The plasma became a deep-red color, and a diffuse intravascular coagulation followed. The patient recovered completely upon discontinuation of penicillin administration.

Antigen-Antibody Complex↗

PubMed1993

Inhibitory effect of FUT-175 on complement activation and its application for glomerulonephritis with hypocomplementemia.

FUT-175 (6-amidino-2-naphthyl p-guanidinobenzoate dimethane-sulphonate), a potent serine protease inhibitor, has been reported to inhibit complement activity in vitro, and especially the classical complement pathway effectively. In the present study, we examined the inhibitory effect of FUT-175 on the classical complement pathway components by hemolytic assay using purified human complement components. As a result, 50% inhibition of the C1 protease activity for classical C3 convertase formation and for C2 was obtained with 3.0 x 10(-8) M and 7.0 x 10(-8) M of FUT-175, respectively. FUT-175 did not inhibit the C2 protease activity at all. We then administered FUT-175 to 5 glomerulonephritic patients with hypocomplementemia and proteinuria in order to assess the clinical effectiveness of this drug. When FUT-175 was administered intravenously and continuously at a rate of 0.1 to 0.2 mg/kg/hr for 2 weeks, the urinary protein excretion decreased significantly from 2.9 +/- 0.8 to 1.4 +/- 0.5 g/day (P < 0.025). In these patients, some of the serum complement markers (serum C3, C4 level and the hemolytic activity via the classical complement pathway (CH50)) were increased after FUT-175 administration. The above findings suggests that FUT-175 can exert beneficial effects on glomerulonephritis with hypocomplementemia by inhibiting complement activation.

Adult↗

PubMed1990

Complement activation and white cell sequestration in postischemic skeletal muscle.

After skeletal muscle ischemia, tissue damage is augmented during reperfusion. White blood cells (WBCs) and complement proteins may participate in the reperfusion injury. The purpose of this study was to define the kinetics of classical and alternative pathway complement activation and WBC sequestration by postischemic skeletal muscle during the first 48 h of reperfusion in vivo. The isolated canine gracilis muscle model was used. Systemic levels of the complement proteins factor B (alternative pathway) and C4 (classical pathway) were quantitated by hemolytic assay. WBC sequestration was measured by gracilis arterial-venous WBC differences and tissue myeloperoxidase activity. Reperfusion was associated with an 18% decrease in systemic factor B levels but no consistent change in systemic C4 levels. WBCs were sequestered during the first 4 h of reperfusion, and tissue myeloperoxidase activity was elevated 97-fold after 48 h of reperfusion. These results suggest that skeletal muscle ischemia-reperfusion stimulates 1) activation of the alternative but not the classical complement pathway and 2) an immediate and prolonged sequestration of WBCs.

Animals↗

PubMed1993

Complement activation by Pseudomonas aeruginosa biofilms.

In chronic infections, such as the bronchopulmonary Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients, bacteria persist despite an intact host immune defense and frequent antibiotic treatment. An important reason for the persistence of the bacteria is their capacity for the biofilm mode of growth. In this study we investigated the role of biofilms in activation of complement, a major contributor to the inflammatory process. Complement activation by P. aeruginosa was examined in a complement consumption assay, production of C3 and factor B conversion products assessed by crossed immuno-electrophoresis, C5a generation tested by a PMN chemotactic assay, and terminal complement complex formation measured by ELISA. Two of the four assays showed that P. aeruginosa grown in biofilm activated complement less than planktonic bacteria, and all assays showed that activation by intact biofilms was submaximal. Factor B conversion was of low magnitude indicating the importance of the classical pathway. Complement activation by P. aeruginosa was inhibited by polymyxin B indicating that lipopolysaccharide (LPS) was the main mediator of complement activation. Immune complexes and massive influx of neutrophils are known to cause inflammatory changes in the lungs. P. aeruginosa persisting in biofilms may contribute to the constant inflammation taking place in the lungs of CF patients.

Chemotaxis, Leukocyte↗

PubMed1979

Capsular K1 polysaccharide of Escherichia coli: relationship to virulence in newborn rats and resistance to phagocytosis.

The virulence of Escherichia coli strains for newborn rats was related to opsonic requirements of the strains, sensitivity to the bactericidal activity of serum, and K1 capsular polysaccharide content. K1 E. coli strains were more virulent than non-K1 strains after intraperitoneal injection in newborn rats (P less than 0.05) and were more resistant to phagocytosis than non-K1 strains when the classical complement pathway was blocked with Mg-ethyleneglycoltetraacetic acid (P less than 0.0005). Sensitivity to the bactericidal activity of serum was similar among K1 and non-K1 E. coli strains. Two groups of K1 E. coli strains were defined on the basis of opsonic requirements. Group I strains were efficiently opsonized by the alternative complement pathway, while group II strains required the classical complement pathway for opsonization. Group I strains had less detectable K1 polysaccharide in the washed whole cell fraction than group II strains (10.3 versus 18.9 microgram of K1 polysaccharide per 10(10) colony-forming units) and were less virulent than group II strains (mortality, 44 versus 77%, P less than 0.05). The K1 capsular polysaccharide appears to play an important role in determining virulence in newborn rats and opsonic requirements of these strains, but does not contribute to the sensitivity of strains to the bactericidal activity of serum.

Animals↗

PubMed1981

Deficient activity of the alternative pathway of complement in beta thalassemia major.

Patients with thalassemia major suffer frequent and serious infections, especially after splenectomy. To explore the basis for this susceptibility, we examined activity of the complement system in sera from 24 patients. All sera had normal or increased activity of the classic complement pathway. However, six of the 24 (three with and three without splenectomy) had abnormal alternative pathway function, and mean alternative pathway activity was significantly decreased in both splenectomized and nonsplenectomized patients. Mean concentrations of C3, factor B, properdin, and immunoglobulins were normal. Defective alternative pathway function, especially in conjunction with asplenia, could contribute to the propensity to infection that exists in thalassemia.

Adolescent↗

PubMed1993

Human anti-endotoxin antibody HA-1A mediates complement-dependent binding of Escherichia coli J5 lipopolysaccharide to complement receptor type 1 of human erythrocytes and neutrophils.

HA-1A has been shown clinically to decrease mortality in septic patients with gram-negative bacteremia. In this study, the ability of HA-1A to augment the serum complement-dependent immune adherence of 125I-labeled Escherichia coli J5 lipopolysaccharide (LPS) to human erythrocytes (RBC) and polymorphonuclear leukocytes (PMNL) was evaluated. In vitro studies indicated three things: HA-1A mediates immune adherence of 125I-J5 LPS to human RBC and PMNL in a dose-dependent manner; under these conditions, high concentrations of LPS (400 ng/mL) could be specifically bound. Immune adherence occurs via the classical complement pathway as demonstrated by its calcium dependence; HA-1A-J5 LPS-C' immune complexes bound to CR1 on human RBC and PMNL. PMNL binding and internalization of immune complexes was demonstrated by trypsin stripping of externally bound immune complexes. These studies support the proposal that HA-1A can lower the bioavailability of endotoxin by mediating binding and potential clearance of LPS via human RBC through the reticuloendothelial system or via direct internalization by peripheral blood PMNL.

Antibodies, Monoclonal↗

PubMed2003

Biochemical and functional characterization of the interaction between pentraxin 3 and C1q.

Pentraxin 3 (PTX3) is a recently characterized member of the pentraxin family of acute-phase proteins produced during inflammation. Classical short pentraxins, C-reactive protein, and serum amyloid P component can bind to C1q and thereby activate the classical complement pathway. Since PTX3 can also bind C1q, the present study was designed to define the interaction between PTX3 and C1q and to examine the functional consequences of this interaction. A dose-dependent binding of both C1q and the C1 complex to PTX3 was observed. Experiments with recombinant globular head domains of human C1q A, B, and C chains indicated that C1q interacts with PTX3 via its globular head region. Binding of C1q to immobilized PTX3 induced activation of the classical complement pathway as assessed by C4 deposition. Furthermore, PTX3 enhanced C1q binding and complement activation on apoptotic cells. However, in the fluid-phase, pre-incubation of PTX3 with C1q resulted in inhibition of complement activation by blocking the interaction of C1q with immunoglobulins. These results indicate that PTX3 can both inhibit and activate the classical complement pathway by binding C1q, depending on the way it is presented. PTX3 may therefore be involved in the regulation of the innate immune response.

Apoptosis↗

PubMed1986

A model system for the study of the assembly and regulation of human complement C3 convertase (classical pathway).

The formation of classical C3 convertase of complement and its regulation by C4b-binding protein (C4bp) were studied using two different approaches: (a) the analysis was first carried out in fluid phase; a soluble stabilized C3 proconvertase could be assembled from C4b (or C4b-like C4) and iodine-treated C2 in the presence of Ni2+ ions. Upon activation of this complex by C1s, a C3 convertase C4b(C4b-like C4)-C2a was generated which was able to cleave purified C3. C4bp dissociated both C3 proconvertase and C3 convertase, but its effect was more important on C3 convertase. (b) A model system of phospholipid vesicles has been developed to study the assembly of the C3 convertase on a membrane. Among different phospholipid mixtures tested, P-glycerol/P-choline vesicles were found most effective for C4b binding. Optimal conditions were determined for C4b fixation on these vesicles; bound C4b participated in the formation of a functional membrane-associated C3 convertase. C4bp was found to bind to phospholipid vesicles with a higher affinity than C4b; it was able to dissociate the vesicle-associated C3 convertase.

Buffers↗

PubMed1996

Role of Fc fragments in inhibition of xenogenic hyperacute rejection by intravenous immunoglobulin.

It has been shown that a high dose administration of human intravenous immunoglobulin G (IVIG) prolonged the survival time of xenografted guinea pig heart in the rat. In this study, we compared the effectiveness of intact IVIG (I-IVIG), Fc fragments of IVIG (Fc-IVIG), and F(ab') fragments of IVIG (Fab-IVIG) in preventing xenogenic hyperacute rejection in the guinea pig-to-rat heart transplantation model. Relatively high dose administration of IVIG (0.6 g/kg body weight) induced xenograft survival times of 32.0 +/- 13.0 min and 33.2 +/- 16.8 min with I-IVIG and Fab-IVIG, respectively, which were significantly longer than times for animals treated with Fc-IVIG or for untreated control animals (survival times of 12.6 +/- 7.4 min and 10.4 +/- 7.6 min, respectively). The in vitro inhibitory effect of guinea pig red blood cell hemolysis by fresh rat serum correlated with the results of in vivo study. On the other hand, the in vitro inhibitory effect of IVIG on pig red blood cell hemolysis by fresh human serum showed that Fc-IVIG, which had little effect in the guinea pit-to-rat combination, had a higher inhibitory effect than Fab-IVIG, or I-IVIG. Fc-IVIG and I-IVIG achieved a complete inhibition of in vitro hemolysis in the pig-to-human combination. It is suspected that an interference with the complement classical pathway by the Fc portion of IVIG could be an attractive tool for inhibition of hyperacute rejection in the pig-to-human combination.

Acute Disease↗

PubMed1980

Role of Kupffer cells, complement, and specific antibody in the bactericidal activities of perfused livers.

The relative roles of Kupffer cells, complement, and specific antibody in liver antimicrobial activities were investigated by using a rat liver perfusion model. Normal livers trapped an average of 60% of Salmonella typhimurium in a single pass and in the presence of plasma killed more than 60% of these organisms in 30 min. Livers depleted of Kupffer cell function by silica treatment had significantly less bactericidal ability (ca. 15%) in the presence of plasma, showing that viable Kupffer cells are required for optimal antimicrobial activity. To determine the importance of complement in Salmonella killing, plasma complement activity was inhibited by heating at 57 and 50 degrees C, zymosan absorption, chelation with disodium ethylenediaminetetraacetate (EDTA) and depletion of rat C3 by using specific immunoabsorbent. All treatments significantly reduced bactericidal activity in the perfused liver. Chelation of plasma with EDTA had no effect, suggesting that the alternate and not the classical pathway for complement activation was involved. Immune plasma alone was bactericidal. When immune plasma was heated, zymosan absorbed, or chelated with EDTA, bactericidal activity was inhibited in the perfused liver, but bacterial trapping increased. These results suggest that complement is required for bactericidal activity in perfused livers and that specific antibody only enhances bacterial trapping.

Animals↗

PubMed1994

Complement depletion in rats infected with Fasciola hepatica: in vivo and in vitro studies.

The action of Fasciola hepatica on rat complement was evaluated by measuring the haemolytic activity. Extracts from metacercariae and eggs and the excretory and secretory products of adult flukes reduced the classical pathway of complement-mediated lysis by normal rat sera in a protein dose-dependent manner. Whole metacercariae produced the same effect. In vitro incubation of newly excysted juveniles and intact eggs with normal rat serum had no detectable effect on serum complement activity by either the alternative or classical pathway. During the course of rat fasciolosis a depletion in the classical pathway of complement-mediated lysis was demonstrated particularly 6-9 weeks post-infection; the alternative pathway of complement-mediated lysis was not affected.

Animals↗

PubMed1983

Role of the capsule and the O antigen in resistance of O18:K1 Escherichia coli to complement-mediated killing.

Epidemiological data show that O18:K1 Escherichia coli is a common cause of neonatal bacteremia and meningitis. These bacteria were capable of multiplying in the bloodstream of newborn rats and were resistant to the bactericidal effects of complement in the absence of specific antibodies. The roles played by the O antigen and the K antigen in complement resistance were analyzed by comparing the bactericidal effects of normal sera and of sera deficient in various complement components or in immunoglobulins. These sera were tested on O18:K1 bacteria and on mutants lacking either the lipopolysaccharide O antigen or the K1 capsular polysaccharide. In addition, O1:K1 cells, which can cause pyelonephritis but which are rare in newborn meningitis and which do not multiply in the bloodstream of newborn rats, were also examined. Different mechanisms of protection against the alternative and classical pathways were recognized: K1-positive cells were resistant to the bactericidal activity of sera deficient in classical complement pathway components, whereas K1-negative cells were sensitive to these sera. Based on these results and on those from complement fixation assays, the K1 sialic acid polysaccharide impedes the activation of, and thus protects the bacteria against, the alternative complement pathway. Not only the K1-negative mutant cells but also O1:K1 bacteria and mutants lacking the O18 oligosaccharide repeating units of the lipopolysaccharide were sensitive to the classical complement pathway. These bactericidal effects were observed even in the absence of specific antibodies. It is proposed that both the K1 capsule and the O18 oligosaccharide restrict antibody-independent classical pathway activation by shielding deeper structures on the cell membrane that are capable of activating this pathway.

Animals↗

PubMed1984

Inhibition of immune precipitation by complement.

Normal human complement serum (NHS) inhibited precipitin reactions between tetanus toxoid and human or rabbit anti-tetanus toxoid IgG antibody, between bovine serum albumin (BSA) and rabbit anti-BSA IgG antibody, and between hen egg albumin and rabbit anti-egg albumin IgG antibody. Ethylene-diaminetetraacetic acid (EDTA) prevented this inhibition. Mg-ethyleneglycol-bis(aminoethyl)-tetra-acetic acid-(EGTA) also prevented the inhibition except with lower concentrations of antibody and antigen. Therefore, the inhibition of immune precipitation seemed to occur mainly through the classical pathway of complement activation. The alternative pathway was usually dispensable, but it augmented the inhibition. Guinea pig complement serum (NGS) was less effective than NHS in inhibiting immune precipitation. Guinea pig serum deficient in C4 (C4DGS) did not inhibit the immune precipitation. Mouse complement serum was effective for inhibiting precipitation, and C5-deficient serum was as effective as normal serum. Therefore, the inhibition of immune precipitation is considered to occur by activation of complement up to the step of C3. The size of the soluble immune complexes formed in the presence of NHS varied depending on the concentrations of antibody and antigen, even when the ratio of antigen to antibody was constant. On incubation at 37 degrees C immune precipitation was inhibited by 1/2 dilution of NHS for 2 to 3 hr and then gradually increased to the level in the absence of complement. When the immune complexes were formed in the presence of serum containing complement, fragments of C4 and C3 were incorporated into the soluble immune complexes. The C3 fragments incorporated into the soluble complexes were C3b, iC3b, C3c, and C3d, some of which were bound covalently with heavy chains of IgG antibody molecules. Some of the covalent linkages between C3 fragments and IgG seemed to be destroyed by alkali treatment, but not by hydroxylamine treatment. The formation of covalent bonds between IgG and C3 and probably C4 was essential for inhibition of immune precipitation, because inhibitors of their formation, such as putrescine, cadaverine, and salicylhydroxamic acid, effectively prevented the inhibition of precipitation. When antigen and antibody reacted in the presence of mixtures of various combinations of isolated complement components, C1, C4, C2, and C3 showed maximal inhibition of immune precipitation, whereas factors I and H had little effect.

Animals↗

PubMed2006

The double-edged flower: roles of complement protein C1q in neurodegenerative diseases.

A role for the complement cascade in AD neuropathology was hypothesized over a decade ago, and the results of a significant number of in vitro studies are consistent with the involvement of this pathway in AD pathogenesis (reviewed in). Since C1q is colocalized with thioflavine-positive plaques and the C5b-9 complement membrane attack complex is detected in AD brain at autopsy, it is reasonable to hypothesize that complement activation has a role in the manifestation of AD either by its lytic capacity or as a trigger of glial infiltration and initiation of potentially damaging inflammation. The observed diminished glial activation and reduced loss of neuronal integrity in a murine model overexpressing mutant human APP but lacking the ability to activate the classical complement cascade provide the first direct evidence for a detrimental role of C1q, and presumably activation of the classical complement pathway in an animal model of AD. Research is now focused on generating mouse models that more closely mimic the human disease, so that the role of complement activation and inflammation on the behavioral/learning and memory dysfunction that occurs in this disease can be assessed. In addition, candidate therapies such as targeted inhibition of complement activation will need to be tested in these animal models as a step toward treatment of humans with the disease. However, it is important that the potential for a protective effect of C1q early on in disease progression should not be overlooked. Rather, strategies that enhance or mimic the protective effects of C1q as well as strategies that inhibit the detrimental processes should be fully investigated.

Amyloid beta-Peptides↗

PubMedDate not supplied

[Role of the classical and alternative complement pathways in chemotaxis of human C2 deficiency (author's transl)].

The roles of the classical and alternative complement pathways in the formation of chemotactic factors were comparatively evaluated in a normal serum and a serum from a child with congenital C2 deficiency. Neutrophil chemotactic index was determined by a direct microscopic observation using serum activated by an immune complex for the classical pathway, and by zymosan A or liposaccharide of Salmonella enteritidis for the alternative pathway. Chemotactic activity was observed only when the C2-deficient serum was activited by the alternative pathway in the presence of zymosan A. But, in comparison to normal serum, the chemotactic activity of C2-deficient serum was impaired by dilution or short incubation time. Addition of purified C2 resulted in the normalisation of chemotactic activity induced by activation of classical and alternative pathways. These results suggest that integrity of the classical pathway of the complement is necessary for the optimal formation of the chemotactic mediators induced by the alternative complement pathway. The implications of the alternative complement pathway alteration with regard to susceptibility to bacterial infections, are discussed.

Antigen-Antibody Complex↗

PubMed1987

Effect of differences in antibody and complement requirements on phagocytic uptake and intracellular killing of "c" protein-positive and -negative strains of type II group B streptococci.

The influence of antibody and complement on the polymorphonuclear leukocytic uptake and killing of type II group B streptococci (GBS) was examined with 11 adult sera and three type II strains possessing the trypsin-resistant and trypsin-sensitive components (II/TR+TS) of the "c" (formerly Ibc) protein or two type II strains lacking both components (II/no c) of the c protein. All tested sera mediated a greater than 1 log10 reduction in colony-forming units (CFUR) of a type II/no c strain, even in the absence of measurable type-specific antibody (less than 1.08 micrograms/ml), but only 5 of 11 mediated a greater than 1 log10 CFUR of any type II/TR/TS strain, even in the presence of moderate levels of type-specific antibody. The classical pathway of complement activation appeared to be more important than the alternative pathway, and even absorbed or immunoglobulin G (IgG)-depleted serum (IgG, 10 mg/dl) mediated a greater than 1 log10 CFUR without magnesium ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (magnesium EGTA) chelation. Chelation with magnesium EGTA reduced the CFUR in 4 of 11 test sera and greatly reduced the CFUR in absorbed or IgG-depleted sera for type II/no c strains. Despite variation in the phagocytic killing of two representative strains of type II GBS, both strains were well phagocytized, as measured by radiolabeled bacterial uptake or electron microscopy. This study suggested that poorly killed type II/TR+TS GBS were easily phagocytized but apparently resisted intracellular killing.

Antibodies, Bacterial↗

PubMed2004

The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation.

Complement activation with formation of biologically potent mediators like C5a and the terminal C5b-9 complex (TCC) contributes essentially to development of inflammation and tissue damage in a number of autoimmune and inflammatory conditions. A particular role for complement in the ischaemia/reperfusion injury of the heart, skeletal muscle, central nervous system, intestine and kidney has been suggested from animal studies. Previous experiments in C3 and C4 knockout mice suggested an important role of the classical or lectin pathway in initiation of complement activation during intestinal ischaemia/reperfusion injury while later use of factor D knockout mice showed the alternative pathway to be critically involved. We hypothesized that alternative pathway amplification might play a more critical role in classical pathway-induced C5 activation than previously recognized and used pathway-selective inhibitory mAbs to further elucidate the role of the alternative pathway. Here we demonstrate that selective blockade of the alternative pathway by neutralizing factor D in human serum diluted 1 : 2 with mAb 166-32 inhibited more than 80% of C5a and TCC formation induced by solid phase IgM and solid- and fluid-phase human aggregated IgG via the classical pathway. The findings emphasize the influence of alternative pathway amplification on the effect of initial classical pathway activation and the therapeutic potential of inhibiting the alternative pathway in clinical conditions with excessive and uncontrolled complement activation.

Antibodies, Monoclonal↗