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At least 883 records · Page 49Linked to original sources
PubMed1982

Action of a new non-steroid anti-inflammatory drug, carprofen (Ro 20-5720) on activation of the complement system: an in vitro research.

Carprofen (Ro 20-5720), DL-6-chloro-alpha-methyl-carbazole-2-acetic acid, is a new non-steroid anti-inflammatory drug. We have studied the possible in vitro interference of the drug with the activation of human complement system. Carprofen exerts a constant inhibitory action of immunohaemolysis at a concentration of 4.5 X 10(-4)M. At the same concentration the drug is able to prevent the activation of the alternate pathway induced by insulin. Its specific site of action is on C1 and C3 components activation, according to the inhibiting activity on both classic and alternate pathway. However at a lower dosage (7.5 X 10(-6)M) carprofen is able to display an inducing action on the alternate pathway, thus confirming the complex in vitro interferences of the drug with the complement system.

Anti-Inflammatory Agents↗
PubMed1989

An affinity for complement C3 as a possible reason for the potency of naturally occurring antibodies in mediating tissue homeostasis.

Certain naturally occurring antibodies stimulate alternative complement pathway C3b deposition. We propose that only those IgG antibodies stimulate alternative complement pathway which have an affinity for C3. Their weak binding to C3 in plasma increases the probability that covalently linked C3b-IgG complexes are formed during C3 activation. Such complexes are known to be much more efficient than C3b in mediating positive feedback of C3 activation, since they are more stable against inactivation by factor I and H. The hypothesis is supported by functional properties of naturally occurring antibodies to erythrocyte band 3 protein. Their ability to stimulate alternative complement pathway C3b deposition increases the potency of these low titer antibodies as opsonins.

Antigen-Antibody Complex↗
PubMed1983

Oxygen and serum complement in phagocytosis and killing of Propionibacterium acnes.

Phagocytosis and killing of Propionibacterium acnes by human peripheral blood leukocytes were promoted by normal human serum and by serum depleted of immunoglobulin G and M. Serum that had been heat-inactivated, depleted of complement component C3, or depleted of C4 and factor B, did not promote phagocytosis or killing. Depletion of complement-component C4 or factor B from normal human serum did not impair its capacity to promote phagocytosis and killing of P. acnes. These results indicate that phagocytosis of P. acnes is mediated by complement component C3, activated either by the classical or by the alternative pathway. P. acnes was phagocytosed as efficiently under anaerobic as under aerobic conditions. The bacteria were, however, killed at a considerably slower rate by anaerobically incubated leukocytes than by leukocytes incubated in air. Thus, oxygen dependent mechanisms were essential for killing of P. acnes.

Adult↗
PubMed1978

Initiation of the alternative pathway of complement: recognition of activators by bound C3b and assembly of the entire pathway from six isolated proteins.

An intact alternative pathway of complement activation was assembled from six isolated proteins present at their respective physiological concentrations (C3, 1200 microgram/ml: factor B, 200 microgram/ml; factor D, 2 microgram/ml; beta1H, 560 microgram/ml; C3b inactivator, 34 microgram/ml; and native properdin, 20 microgram/ml). Initiation of the pathway required the presence of five of these proteins not including properdin. The initial C3 convertase of the system was shown to be a fluid-phase rather than a surface-bound enzyme. The ability of the pathway to discriminate between activator and nonactivator was found to reside in the bound C3b molecule. When bound to the surface of an activator through its labile binding site, C3b interacts with surface structures of the activator through another site on the molecule. This interaction results in diminished beta1H binding to C3b and thereby allows the bound C3b molecule to escape control and participate in C3 convertase formation. Thus, initiation of the alternative pathway is a two-step process, the first being non-specific and the second being discriminatory.

Binding Sites↗
PubMed1980

Opsonization of four Bacteroides species: role of the classical complement pathway and immunoglobulin.

Previous investigators have suggested that opsonization of two Bacteroides species is mediated exclusively by the alternative complement pathway and requires immunoglobulins. In this study, the nature of the opsonic factors in nonimmune human serum for four species of Bacteroides was investigated by measuring uptake of [(3)H]thymidine-labeled bacteria by human polymorphonuclear leukocytes. Normal human serum, C2-deficient serum, immunoglobulin-deficient serum, and serum chelated with ethylene glycol-bis(beta-aminoethyl ether)-N,N-tetraacetic acid (EGTA), MgEGTA, and ethylenediaminetetraacetic acid (EDTA) were used as opsonic sources. Heat inactivation of each of these sera significantly reduced its opsonic activity for all four Bacteroides species, suggesting that serum complement was essential for effective opsonization. All strains were opsonized in the absence of the classical complement pathway; however, kinetics studies revealed that opsonization proceeded at a significantly faster rate when the classical complement pathway was intact. Although two strains were opsonized in immunoglobulin-deficient sera, opsonization was less efficient and appeared to occur via the alternative complement pathway. Unexpectedly, all strains were well opsonized by the classical complement pathway in 10% serum which had been effectively chelated with EGTA or EDTA. The explanation for this finding is unknown; however, it is possible that cell wall cations of Bacteroides species may participate in the activation of complement in chelated serum, resulting in effective opsonization. It was also found that Bacteroides, when incubated with an Escherichia coli strain in normal serum, could compete for opsonins and thereby reduce phagocytosis of E. coli. It is possible that competition for opsonins among bacterial species contributes to the synergistic role these organisms share in mixed floral infections.

Bacteroides↗
PubMedDate not supplied

The role of complement in the host's defense against Streptococcus pneumoniae.

In recent years there has been a growing realization that the complement systems plays an important role in the host's defense against infection and that it plays an especially critical role in both natural and acquired immunity to Streptococcus pneumoniae. The terminal components of the complement system, C3-C9, are responsible for most protective functions of the complement system. However, in order to subserve their protective functions, C3-C9 must first be activated. In vitro studies have shown that pneumococci are able to activate the terminal components of complement, C3-C9, by at least two different mechanisms, the classical and alternative pathways. Regardless of the pathway of their activation, C3-C9 produce anaphylatoxic, chemotactic, and opsonic activities in serum, each of which has the potential to play an important protective role in pneumococcal infections. Studies with experimental animals and the experience gained from study of complement deficiencies in humans have each fulfilled the promise of the in vitro studies by demonstrating that the complement system plays a biologically significant role in vivo in the host's defense against S. pneumoniae.

Animals↗
PubMed1983

Complement levels in normal and inflamed aqueous humor.

C2, C6, and C7 were measured by hemolytic assay and Factor B and IgG were measured by radial immunodiffusion in samples of normal and inflamed aqueous humor. Normal aqueous humor was found to contain functional C2, C6, and C7, but the small ratios of aqueous humor to serum measurements suggested that there was relatively little of these complement components in normal aqueous humor when compared to serum. The mean values of C2, C6, C7, and Factor B in aqueous humor and the median ratios of aqueous humor to serum measurements for each complement component were higher in patients with inflamed aqueous humor than in patients with normal aqueous humor. A comparison of the ratios of IgG to each complement component in normal and inflamed aqueous humor suggested that levels of IgG and complement increased proportionately in inflamed aqueous humor. Factor B, a component of the alternative pathway, was not detected in normal aqueous humor but measured in five of six samples of aqueous humor from eyes with anterior chamber inflammation.

Adult↗
PubMed1992

Avidin-induced lysis of biotinylated erythrocytes by homologous complement via the alternative pathway depends on avidin's ability of multipoint binding with biotinylated membrane.

It was reported that avidin and streptavidin induce lysis of prebiotinylated red blood cells via the alternative pathway of both homologous and heterologous complement. Both of these proteins have four biotin-binding sites, providing a polyvalent interaction with biotinylated components of the erythrocyte membrane. We have compared the effects of mono- and multipoint avidin attachment on the sensitivity of biotinylated erythrocytes to lysis by the complement system. In the presence of anti-avidin antibody, avidin-bearing biotinylated erythrocytes were rapidly lysed by heterologous serum. This lysis was independent from the mode of avidin attachment, implying that complement activation by the classical pathway triggered by interaction between C1 and avidin-bound antibody on the erythrocyte surface is independent from the avidin's ability of polyvalent (multipoint) binding with biotinylated membrane components. In the absence of anti-avidin antibody, biotinylated erythrocytes bearing polyvalently attached avidin were lysed by homologous complement better than cells bearing avidin, which possesses reduced ability for multipoint binding with biotinylated erythrocyte. Two independent approaches to reduce avidin's ability of multipoint binding were used: decrease in surface density of biotin on the erythrocyte membrane and blockage of biotin-binding sites of avidin. Both methods result in reduced lysis of avidin-bearing erythrocytes as compared with erythrocytes bearing an equal amount of polyvalent-bound avidin. Thus the activation of homologous complement via the alternative pathway depends on avidin's ability to 'cross-link' to the biotinylated components of the erythrocyte membrane.

Animals↗
PubMed1980

Effect of intravenously injected killed pneumococci on leukocytes, complement, and phagocytosis in rabbits.

A pneumococcal infection may be lethal in the absence of overwhelming pulmonary involvement, and death may occur even after the organisms have been killed with antibiotics. The mechanism of death is not understood but may be related to circulating pneumococcal products. For investigating the effects of nonviable pneumococci on several host defense mechanisms, rabbits were injected intravenously with 4 X 10(8) colony-forming units of killed sonified type 13 or type 29 pneumococci. Blood was sampled periodically for the next 24 h, and the following were measured: (i) circulating levels of leukocytes; (ii) activity of the classical and alternate complement pathways; and (iii) ability of the serum to opsonize pneumococci for ingestion and killing by polymorphonuclear leukocytes. Saline-injected control rabbits showed no change in any of the functions. Nonimmune rabbits injected with either pneumococcal serotype showed progressive and profound leukopenia, no change or an increase in classical and alternate complement pathway activity, and a profound reduction in the serum-opsonizing capcity for pneumococci of the same serotype as that used in the injection. The opsonizing capacity remained normal for the other serotype. When a previously immunized animal was injected, the opsonizing capacity for the homologous organism remained intact, but leukopenia nervertheless occurred.

Animals↗
PubMed2001

Mechanism of complement resistance of pathogenic Borrelia burgdorferi isolates.

Borrelia burgdorferi, the causative agent of Lyme disease, differ in their susceptibility to normal human serum and are consequently classified as complement-resistant, complement-sensitive and intermediate complement-sensitive. Most isolates belonging to the genospecies B. afzelii are complement-resistant, while particularly B. garinii isolates were rapidly killed by complement. In general, isolates of the genospecies B. burgdorferi sensu stricto (s.s.) are intermediate complement-sensitive. Independent of the genospecies, all Borreliae were capable to activate the classical and/or the alternative pathway. Deposition of the activation products C3, C6, and TCC is much stronger by B. burgdorferi s.s. and B. garinii isolates than by B. afzelii isolates. The mechanism(s) on how Borreliae evade complement-mediated bacteriolysis has recently been described by showing that complement-resistant B. afzelii isolates but not the complement-sensitive B. garinii isolates absorb human complement regulators FHL-1/reconectin and factor H. Surface-attached FHL-1/reconectin maintains its complement regulatory activity and supports factor I-mediated C3b cleavage to iC3b. In complement-resistant Borreliae, two outer surface proteins, the 27.5 kDa (CRASP-1, complement regulator-acquiring surface protein 1) and the 20/21 kDa (CRASP-2), are responsible for the surface attachment of the two complement regulators. CRASP-1, which is present in complement-resistant Borreliae, binds preferentially FHL-1/reconectin while CRASP-2, which is restrictively expressed, binds preferentially factor H. Thus, complement-resistant Borreliae bind human complement regulators and control complement activation on their surface and prevent the formation of toxic activation products.

Bacterial Outer Membrane Proteins↗
PubMed1992

Detection of complement in relation to disease.

If a single component is lowered, it is reasonable to question whether the patient has a genetically-controlled defect. Studies of family members may be required. If split products, complexes, or neoantigens are present, it is likely that there is ongoing complement activation. If most of the components of a pathway are lowered, a reasonable supposition is that complement is being activated. We then turn to a consideration of the factors that may activate complement. When hypocomplementemia is associated with a decrease in titer of several components, it is often possible to determine whether the classic or alternative pathway is the major pathway being activated; this, in turn, may suggest certain diagnoses and rule out other diagnoses. The nature of the circulating complexes or split products may provide the same information. Thus, a consideration of the pathophysiology of the complement system and of the factors that activate complement provides an approach to an understanding of the function of complement and the role of complement causing a damage in a clinical setting.

Complement Pathway, Alternative↗
PubMed1980

Activation of human complement by Yersinia enterocolitica: ultrastructural alterations and C3b-deposition.

Rapid killing of Yersinia enterocolitica strain 75 in smooth form (Ye 75 S) was observed in the presence of serum or of lysozyme-free serum whereas the killing activity of EGTA-serum was slow, and absent in heated (30 min 56 degree C) serum. Similarly, complement (C) activation by Ye 75 S was rapid in serum and lysozyme-free serum but slow via the alternative pathway (EGTA-serum). These data suggest that C is sufficient for killing of the cells and most active via an intact classical pathway. Electronmicroscopic studies were performed on bacterial killed by serum (C + lysozyme) or by lysozyme-free serum (C). In these experiments cell fragmentation and spheroplast formation were seen after exposure of Ye 75 S to serum; in bacteria incubated with lysozyme-free serum "blebs" formation was observed as the most prominent alteration. These blebs most likely originate from the outer membrane as a result of C activation on the cell surface. The deposition of activated C (C3b) on Ye 75 S was analyzed kinetically in the presence of serum or EGTA-serum. With serum (30 vol%) massive C3b deposition was observed within 20--30 min whereas with EGTA-serum (30 vol%) the deposition of C3b was slower and less complete. Experiments with EGTA-serum also revealed that the deposition of C3b started at single sites mainly located in the region of the cell poles; from these sites spreading of C3b occurred until large areas of the cell surface were covered. These data suggest that C activation via the alternative pathway is restricted to certain regions of the bacterial surface.

Blood Bactericidal Activity↗
PubMed2000

Interaction between human complement and a pectin type polysaccharide fraction, PMII, from the leaves of Plantago major L.

The interaction between a pectin type polysaccharide fraction, PMII, isolated from the leaves of Plantago major, and human complement was tested in two different hemolytic complement-fixation tests and in addition by two ELISA methods detecting complement-activation products. Sera were used as a complement source of 10 arbitrary human volunteers, individually and as a pool. The complement-fixation tests were designed to measure the concentration of the pectin necessary to inhibit 50% of the hemolysis (ICH(50)). The ELISA tests for complement-activation products were measured in AU/mg using a fully activated serum as a standard. We observed a more than 200-fold difference in ICH(50) activity of the PMII pectin in one of the hemolytic tests by varying the individual sera used as complement-source. On the other hand, the ELISA complement-activation tests showed no significant variation in activity of the PMII depending on the complement-serum used. The level of antibodies against PMII detected in the complement-sera did not correlate with the ICH(50) activity of PMII. The results show that PMII is a potent complement activator with an activity of the same order of magnitude on a weight basis as that of aggregated human immunoglobulin (Ig)G. This activation leads to a complement consumption probably explaining the PMII's effect in the complement-fixation tests. PMII seems to be an activator both on the classical and the alternative pathway of activation. The results might be related to the reported wound-healing effect of the leaves of Plantago major.

Adult↗
PubMed2004

Antibodies directed against O-acetylated sialoglycoconjugates accelerate complement activation in Leishmania donovani promastigotes.

BACKGROUND: An enhanced presence of 9-O-acetylated sialoglycoconjugates (9-O-AcSGs) triggers the alternate pathway (AP) in Indian visceral leishmaniasis (VL). Antibodies directed against these epitopes are present in high titers. The biological relevance of these antibodies, with regard to activation of the classical pathway (CP), was investigated. METHODS: Complement activators were affinity purified, complement activation via the CP, AP, and lectin-mediated complement pathway was measured by use of an anti-C3 radio-binding assay, and the number of C3 molecules was quantitated by Scatchard analysis. Cell death induced via the complement pathways was measured by use of MTT (tetrazolium salt 3- [4, 5-dimethylthiazol-2-yl] -2, 5-diphenyltetrazolium bromide) assay, and uptake of propidium iodide (PI) was measured by flow cytometry. RESULTS: Anti-O-AcSGs from both healthy donors and patients with VL elicited C3 deposition as early as 3 min, which triggered parasite lysis, as demonstrated by use of MTT assay and corroborated by the high rate of uptake of PI. Analysis of complement activation by mannan-binding lectin and C-reactive protein demonstrated their negligible contribution during the 3-min time frame. CONCLUSIONS: Anti-O-AcSGs were identified as an important source of CP activation under normal physiological conditions, suggesting that they play a role in conferring host protection against parasite infection.

Animals↗
PubMed1980

Extracts of airborne grain dusts activate alternative and classical complement pathways.

This study investigated the action of aqueous extracts of airborne grain dusts on the human alternative and classical complement pathways. Extracts were shown to consume hemolytic complement in vitro in a dose-dependent manner. No relationship was determined between complement activity ranking and either protein or endotoxin levels. Differential serum chelation with EDTA or EGTA showed that the alternative pathways were activated, while hemolytic titers of the early complement components (C1, C4, C2 and C3) showed that the classical pathway was also involved. Extract-treated sera were chemotactic for human polymorphonuclear leukocytes and complement was required. The in vitro data suggest the potential for the in vivo contribution of the activation of the complement cascade (by either pathway) in eliciting pulmonary pathophysiology after the inhalation of airborne grain dusts.

Chelating Agents↗
PubMed2002

Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells.

C4b and C3b deposited on host cells undergo limited proteolytic cleavage by regulatory proteins. Membrane cofactor protein (MCP; CD46), factor H, and C4b binding protein mediate this reaction, known as cofactor activity, that also requires the plasma serine protease factor I. To explore the roles of the fluid phase regulators vs those expressed on host cells, a model system was used examining complement fragments deposited on cells transfected with human MCP as assessed by FACS and Western blotting. Following incubation with Ab and complement on MCP(+) cells, C4b was progressively cleaved over the first hour to C4d and C4c. There was no detectable cleavage of C4b on MCP(-) cells, indicating that MCP (and not C4BP in the serum) primarily mediates this cofactor activity. C3b deposition was not blocked on MCP(+) cells because classical pathway activation occurred before substantial C4b cleavage. Cleavage, though, of deposited C3b was rapid (<5 min) and iC3b was the dominant fragment on MCP(-) and MCP(+) cells. Studies using a function-blocking mAb further established factor H as the responsible cofactor. If the level of Ab sensitization was reduced 8-fold or if Mg(2+)-EGTA was used to block the classical pathway, MCP efficiently inhibited C3b deposition mediated by the alternative pathway. Thus, for the classical pathway, MCP is the cofactor for C4b cleavage and factor H for C3b cleavage. However, if the alternative pathway mediates C3b deposition, then MCP's cofactor activity is sufficient to restrict complement activation.

Animals↗
PubMed1985

In vivo modulation of rat complement activities by infusion of anti-H antibodies.

Regulation of the activity of the alternative pathway of complement occurs by the plasma proteins I and H. H is able not only to prevent formation of the amplification convertase C3bBb but also to cause the decay-dissociation of Bb from C3bBb. The present studies have investigated the role of H in vivo. Affinity-purified goat (Fab')2-anti H was infused intravenously in rats, and its effect on C4, C3 and CH50 activities was assessed. In addition, H, C3, C4 and B were quantitated by immunochemical methods. H depletion was dependent on the dose of anti-H, and maximal consumption in vivo occurred between 5 and 15 min. A maximum of 51% and 77% hemolytic C3-consumption was seen after 15 min with 3.8 and 8.4 mg anti-H, respectively. The injection of 6.3 mg affinity-purified goat IgG anti-rat H caused 96.8 +/- 0.7% and 85.0 +/- 1.4% consumption of CH50 and C3 hemolytic activity, respectively. Using this dose of IgG anti-rat H, it was found that the clearance in rats of rat erythrocytes sensitized with 8000 molecules of guinea pig IgG2 per E was impaired as compared to the clearance of these intermediates in control rats injected with a comparable dose of normal goat IgG. The results indicate that H functions as a potent regulator of C in vivo and that infusion of anti-H can be used as a method to achieve depletion of circulating complement components.

Animals↗