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Results for “Complement Pathway, Alternative”

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PubMed1981

The fixation of C3b to pneumococcal cell wall polymers as a result of activation of the alternative complement pathway.

The present study was performed in order to determine the identity of the pneumococcal cell wall polymer(s) to which C3b becomes fixed after activation of the alternative pathway. Purified pneumococcal autolysin was used to solubilize pneumococcal cell walls to which C3b had been fixed via activation of the alternative pathway. The resulting soluble cell wall polymers were then examined for the presence of C3b. Chromatographic separation of cell wall digests containing either radiolabeled teichoic acid or radiolabeled C3b demonstrated that although the elution profiles of the 2 radiolabels were similar, they were not identical. In addition, when teichoic acid-containing polymers were removed from solution by immunoabsorption with TEPC-15 myeloma, only 43 to 65% of the C3b was removed. These results demonstrate that C3b activated via the alternative pathway fixes both to teichoic acid-containing pneumococcal cell wall polymers and to other cell wall constituents and/or serum proteins bound to the cell wall.

Animals↗

PubMed1988

A simple isolation procedure for functionally pure components of the bovine alternative complement pathway (ACP) C3 convertase and bovine conglutinin (K).

A simple multicomponent isolation procedure for bovine C3, factor B, factor D and conglutinin (K) from a single serum sample is described. The components of the alternative pathway C3 convertase were isolated in milligram quantities from 800 ml bovine serum and were found to be functionally pure with respect to each other and to factors H and I.

Animals↗

PubMed1987

Schistosoma mansoni: interactions of adult parasites with the complement system.

The interaction of the mouse complement system with adult male Schistosoma mansoni was studied by immunocytochemical localization procedures and in-vitro assays for complement mediated tegument damage. Mouse C3 was demonstrated to be associated with the parasite's tegument, but was localized only in the infoldings of the tegument and not on its free surface. Freshly harvested parasites manifested no detectable tegumental modification when incubated in normal mouse serum or in immune mouse serum. However, parasites which had been allowed to lose their adsorbed host components by elution (incubation in serum free media for 3 h at 37 degrees C) were severely damaged by incubation in normal mouse serum, but not by incubation in immune mouse serum. This damage was shown to be mediated by the alternative complement pathway and appeared to be initially limited to the tubercles of the adult male parasite. Tegument disruption could be blocked by pre-incubation of the eluted worms in either immune mouse serum or an IgG fraction of immune mouse serum. An IgG fraction of normal mouse serum did not protect the parasite, and infected mouse serum (IMS) which had been depleted of IgG produced tegument damage equivalent to that observed with normal mouse serum (NMS). The addition of I-IgG to NMS abrogated tegument damage. These data suggest that while adult schistosomes possess surface molecules bearing alternative pathway complement activation sites, these sites are masked by adsorbed host components in vivo. These results further indicate that in the absence of these masking host molecules anti-schistosome IgG may play a role in protecting the adult worm from alternative pathway activation, perhaps by binding to and blocking the activation sites on the tegument associated molecules.

Adsorption↗

PubMed1995

Studies on the haemolytic complement of the dromedary camel (Camelus dromedarius). II. Alternate complement pathway haemolytic activity in serum.

Fresh camel serum caused lysis of unsensitised red blood cells (RBC) of chicken, rabbit and guinea pig. Homologous RBC were resistant to lysis. There was only minimal lysis of goat, sheep, rat and cattle RBC. Lysis of heterologous RBC was attributed to the presence of alternate complement activity (ACP) in the serum as adsorption with respective RBC and addition of 10 mM ethylene glycol-bistetraacetate (EGTA) in the SVBS diluent did not abrogate the haemolytic activity. Guinea pig RBC were the most sensitive to lysis, giving a mean ACP activity of 41.5 +/- 1.8 CH50 units ml-1. Clotting, followed by storing of blood between 0 and 37 degrees C for 1 h did not significantly affect ACP activity. However, considerable activity was lost when blood was clotted and stored at 44 degrees C for 1 h, or when serum was kept at 4 degrees C for 24 h. Treatment with zymosan, or incubation at 56 degrees C for 30 min inhibited ACP activity. Maximum ACP activity occurred in the presence of 8 mM Mg2+ in the SVBS-EGTA diluent, at pH 7.3 and incubation time of 2 h at 37 degrees C. Levels of ACP activity were determined in 79 healthy camels of different age groups, ranging from 3 months to 15 years. Calves between 3 months and 1 year of age had higher ACP activity than camels in the age group of 5 years and above. Highest mean ACP activity of 89 +/- 7.9 CH50 units ml-1 were recorded in 1-5 year old camels (P < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1987

Studies on the hemolytic activity of the classical and alternative pathway of complement in various animal species.

The classical complement pathway (CP) activity (CH50) of sera of 13 animal species was compared by parallel assays using rabbit erythrocytes sensitized with immune antibody (RaE-Ab) and sensitized sheep erythrocytes (ShE-Ab). The alternative complement pathway (AP) activity (ACH50) in various species of animals was also measured using 13 species of erythrocytes and RaE-Ab as target cells. The results have demonstrated that virtually all species of animals studied possess CP and AP activity levels comparable with or higher than those in human sera. Concomitant measurement of the hemagglutinin titer to various species of erythrocytes carried out in the screening ACH50 assays on various species of sera with these erythrocytes disclosed a significant correlation between natural antibody level and AP activity (p less than 0.05).

Animals↗

PubMed1977

Antibody-independent activation of the alternative complement pathway in human serum by parasitic cells.

The lysis of the monocellular parasite Trypanosoma cyclops by normal human serum (NHS) was found to be complement-dependent and to follow activation of the alternative pathway without apparent requirement for conventional antibodies. Lysis of the organisms was inhibited by heat-inactivating NHS at 56 degrees, preincubation of NHS with cobra venom factor or chelation of divalent cations with EDTA. It took place, however, in human C2-deficient serum and was inhibited by prior heating of NHS at 52 degrees to destroy the activity of factor B of the alternative pathway. Moreover, the lytic reaction was magnesium- but not calcium-dependent. Repeated low-temperature (0 degrees) absorption of either human hypogammaglobulinaemic serum or NHS with the parasite failed to remove or significantly decrease their lytic activities.

Complement System Proteins↗

PubMed1983

Preferential activation and depletion of the alternative complement pathway by burn injury.

Complement levels of eight adult burn patients (25% to 90% body surface area) were studied upon admission to a burn unit and sequentially for one week. Mean classical pathway titers (CH50) were 49% below the normal mean, while hemolytic C4 titers were reduced by 53% and C3 by 43%. However, the alternative pathway titer was reduced by more than 90%, suggesting preferential depletion of this pathway. This depletion was associated with sepsis, pneumonia, and "shock lung." Alternative pathway deficiency was still present one week postburn, and may contribute to the susceptibility of burn patients to bacterial sepsis.

Adult↗

PubMed1991

Lysis of Neisseria gonorrhoeae initiated by binding of normal human IgM to a hexosamine-containing lipooligosaccharide epitope(s) is augmented by strain-specific, properdin-binding-dependent alternative complement pathway activation.

We studied the specificity of naturally acquired IgM bactericidal for strains of Neisseria gonorrhoeae that varied in sensitivity to the lytic action of normal human serum (NHS) and the relative ability of these strains to deplete the classical (CP) and alternative (ACP) C pathways. Lysis of both highly sensitive and relatively insensitive strains was inhibited by the same gonococcal lipooligosaccharides (LOS), as well as by Salmonella minnesota Re LOS and three hexosamine-containing glycose polymers. A polymer of N-acetylgalactosamine phosphate was the most inhibitory; a polymer of N-acetylglucosamine phosphate only partially inhibited. Neither 3-deoxy-D-manno-octulosonic acid (dOc1A) nor a polymer that contained dOc1A but not hexosamine inhibited NHS lysis. A co-polymer of N-acetylgalactosamine-dOc1A inhibited both bactericidal activity and the binding of IgM to the LOS of a highly serum-sensitive (sers) gonococcal strain. Carboxyl reduction of the dOc1A in this polymer did not affect its inhibitory capacity for gonococcal antibody, but abolished its binding to homologous antibody induced by vaccination. CP activity was not affected by vaccination. CP activity was not affected by absorption of NHS with gonococcal strains, whereas ablation of CP activity markedly but variously diminished lytic activity for highly sers strains. ACP activity was variously depleted by gonococcal strains, and the proportion of bacteria that could be lysed through the ACP varied among strains and among different populations of a given strain. The titer at which a strain was sensitive to NHS lysis was a function of its ACP consumption (p = 0.006), which accounted for 70% of the differences in titer among strains. Analyses of the absorbed sera revealed that the gonococci had variously depleted properdin from NHS as assessed by using an Ag-capture solid-phase RIA. Addition of purified properdin to absorbed sera restored ACP activity to normal levels. Western immunoblots of gonococcal lysates showed that purified properdin bound directly to a 39-kDa outer membrane protein. We conclude that both CP activation by IgM binding to LOS epitopes, one of which contains hexosamine, and ACP activation, which is a function of strain-specific direct binding of properdin, can initiate lysis of sers strains and that ACP activation, also enhances lysis and accounts for variations in sensitivity of sers strains.

Antigens, Bacterial↗

PubMed1989

Effect of immune globulin intravenous on opsonization of bacteria by classic and alternative complement pathways in premature serum.

The mechanisms involved in the effect of immune globulin intravenous (IGIV) on bacterial opsonization by both complement pathways in premature serum were elucidated in this study. Of the bacteria used, Staphylococcus aureus and Salmonella enteritidis were nonencapsulated while Streptococcus pyogenes and Escherichia coli 07 K1 were encapsulated. As demonstrated by indirect immunofluorescence, IGIV showed specific antibody titers of 1:32 for S. aureus and S. enteritidis and of 1:8 for S. pyogenes and E. coli 07 K1. IGIV alone had no direct opsonic activity against these organisms. Addition of IGIV did not alter the opsonic activity of normal adult serum against these organisms. In contrast, addition of IGIV promoted the opsonic activity of premature serum against the nonencapsulated bacteria to levels matching that in normal adult serum. The IGIV preparation significantly improved the opsonization of bacteria by the classic (from 39 to 68% of that in adult serum) and alternative (from 22 to 97% of that in adult serum) complement pathways in premature serum. IGIV also markedly augmented C3 deposition on the bacteria by both complement pathways. These studies suggest that IGIV containing high titers of specific antibodies promote opsonization of bacteria by the enhancement of complement pathway activation, especially the alternative pathway, in premature serum.

Complement System Proteins↗

PubMed2004

Functional analysis of the classical, alternative, and MBL pathways of the complement system: standardization and validation of a simple ELISA.

Primary defence against invading microorganisms depends on a functional innate immune system and the complement system plays a major role in such immunity. Deficiencies in one of the components of the complement system can cause severe and recurrent infections, systemic diseases, such as systemic lupus erythematosus (SLE) and renal disease. Screening for complement deficiencies in the classical or alternative complement pathways has mainly been performed by haemolytic assays. Here, we describe a simple ELISA-based format for the evaluation of three pathways of complement activation. The assays are based on specific coatings for each pathway in combination with specific buffer systems. We have standardized these assays and defined cut off values to detect complement deficiencies at the different levels of the complement system. The results demonstrate the value of these ELISA-based procedures for the functional assessment of complement deficiencies in clinical practice. The assay is now available commercially in kit form.

Complement Activation↗

PubMed1976

Activation of the alternative complement pathway by water-insoluble glucans of streptococcus mutans: the relation between their chemical structures and activating potencies.

Water insoluble, sticky glucan was synthesized by reacting glucosyltransferase obtained from the sulture filtrate of cariogenic Streptococcus mutans OMZ 176 on sucrose. This glucan (OMZ 176 glucan), that consisted of the backbone chains of consecutive alpha-1, 3 glucosidic linkages (65%) and the side chain of alpha-1, 6 glucosidic bonds (35%), showed an ability to activate the alternative pathway of the complment system in human serum. Water soluble glucans synthesized from the reaction of glycosyltransferases of S. mutans strain AHT, FA-I, and Ingbritt with sucrose, that have a high content of alpha-1,6 and a low content of alpha-1, 3 glucosidic linkages, were less effective to activate the complement system. Sephadex (G-25) and Dextran (T-2,000 and T-40), that consisted exclusively of alpha-1, 6 glucosidic linkages, did not significantly activate the complement system. Controlled Smith degradation products of OMZ 176 glucan, composed of the alpha-1, 3 linked glucose backbone chain alone, lost its activity. From these results it was concluded that both backbone chain of alpha-1, 3 glucose units and branched alpha-1, 6 glucose units were essential for the OMZ 176 glucan to activate the alternative pathway of the human complement system.

Aspergillus niger↗

PubMed1985

Species specificity of recognition by the alternative pathway of complement.

The recognition function of the alternative complement pathway was studied with isolated human and rabbit components. Zymosan and homologous and heterologous erythrocytes were used as representative activators or nonactivators. The binding affinity of Factor B and Factor H for particle-bound C3b was measured. In both species, the average affinity of Factor H for bound C3b on homologous cells (nonactivators) was eight to 10 times higher than on zymosan particles (activators). The interaction between Factor H and C3b on rabbit erythrocytes was species-specific: rabbit Factor H bound strongly to rabbit C3b on rabbit erythrocytes and also on human erythrocytes, which are nonactivators for the rabbit alternative pathway. Human Factor H bound strongly to human C3b on human erythrocytes but seven times weaker on rabbit erythrocytes, which are activators of the human alternative pathway. No substantial differences were found in the binding of Factor B to bound C3b regardless of the nature of the particle to which C3b was bound. The results indicate that in the two species studied, the molecular mechanism of recognition is analogous and that recognition is species-specific.

Animals↗

PubMedDate not supplied

Role of complement in host resistance against members of the Bacteroidaceae.

Considerable evidence has been reported in recent years suggesting that complement plays an important role in host resistance against members of the Bacteroidaceae. Most of the investigations in this area have focused on the genus Bacteroides because of its clinical importance. Various species of Bacteroides have been shown to activate the complement system in vitro via the classical and alternative pathways. Complement activation results in the generation of chemotactic factors that mobilize polymorphonuclear leukocytes to sites of infection. Activated complement also facilitates bacteriolysis and opsonophagocytic killing by polymorphonuclear leukocytes and macrophages. Strains possessing dense fibrillar polysaccharide capsules are resistant to both of these defense mechanisms. The putative importance of complement-dependent bacteriolysis and opsonophagocytic killing in resistance against Bacteroides infections in vivo requires confirmation. In addition, the role of complement in synergistic interactions between Bacteroides and facultative bacteria remains to be elucidated.

Antibodies, Bacterial↗

PubMed1995

Cardioprotective effects of selective inhibition of the two complement activation pathways in myocardial ischemia and reperfusion injury.

The complement (C) system-mediated neutrophil activation, adhesion to the coronary endothelium and accumulation into cardiac tissue are key steps in the pathogenesis of myocardial ischemia-reperfusion (MI/R) injury. We examined the differential role of the classical and the alternative complement pathway in MI/R injury in vivo. Rats were subjected to 20 min of myocardial ischemia followed by 24 h of reperfusion. Either a classical pathway inhibitor [C1 esterase inhibitor (C1-INH) (15 mg/kg)] or an alternative pathway inhibitor soluble complement receptor 1 (sCR1)[des-LHR-A](15 mg/kg) or their vehicle were administered intravenously 1 min prior to reperfusion, and myocardial necrosis (creatine kinase loss) and neutrophil accumulation, cardiac myeloperoxidase activity, were examined. C1-INH significantly attenuated cardiac creatine kinase loss compared to MI/R rats given only vehicle (p < 0.05) 24 h after reperfusion. An alternative pathway inhibitor, sCR1 [des-LHR-A] attenuated myocardial injury to a lesser extent, although it was not significantly different from the value for C1-INH or vehicle. Besides cardiac myeloperoxidase activity, the ischemic cardiac tissue was significantly attenuated by both C1-INH and sCR1[desLHR-A] (p < 0.05 vs. vehicle). Both the classical and alternative pathways may contribute to MI/R injury via a neutrophil-dependent mechanism in vivo. Selective inhibition of the classical pathway of complement activation seems to be slightly more effective in limiting necrotic MI/R injury than the selective alternative pathway inhibition in this 24 h model of reperfusion injury, but equal doses of each inhibitor attenuated neutrophil accumulation.

Animals↗

PubMed1976

Factor B of the alternative complement pathway on human lymphocytes.

A factor on human lymphocytes has been identified as factor B of the alternative pathway. Lymphocytes can replace factor B in the fluid phase formation of C3 convertase with cobra venom factor (CVF). This lymphocyte activity is inhibited by specific anti-human factor B, and it is shown by Burkitt lymphoma cell lines cultured in the absence of any factor B source. After the reaction with CVF all the C3-converting activity is found in the cell supernatant, and the same cells can undergo several successive cycles of 'activation' by CVF. Factor B is distinct from the C3b receptor, and its presence could not be detected antigenically on the lymphocyte membrane. It may be secreted by the cells, but the reaction was not affected by sodium azide or cytochalasin B. No detectable factor B activity was found in the culture medium of cells grown in the absence of CVF.

Animals↗

PubMed2001

In situ complement activation by polyethylene wear debris.

A frequent long-term complication of total joint arthroplasty is aseptic loosening, the end result of wear debris accumulation, synovitis, and osteolysis about the implant-bone or cement-bone interface. Complement, an effector system in plasma, synovial fluid, and tissue, has powerful chemotactic, inflammatory, and osteoclast-activating potentials. This study explored the complement-activating ability of polyethylene, a material used in joint implants. In vitro hemolytic assays using sheep red blood cells (E(sh)), human serum, and particulate polyethylene suggested alternative pathway complement activation, as well as polyethylene adsorption of activated complement components. These results were confirmed by enzyme-linked immunosorbent assay (ELISA) quantification of activated complement factors Bb and C3b. In situ double antibody immunoperoxidase staining for factors Bb, C3a, iC3b, and SC5-9 in synovial tissue from revision hip specimens showed localized alternative pathway activation and component adsorption. These results introduce a likely role for complement activation in particle-mediated recruitment, proliferation, and activation of macrophages during early events in osteolysis and implant loosening.

Biocompatible Materials↗

PubMed2006

Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2.

Lectin pathway activation of C3 is known to involve target recognition by mannan-binding lectin (MBL) or ficolins and generation of classical pathway C3 convertase via cleavage of C4 and C2 by MBL-associated serine protease 2 (MASP-2). We investigated C3 activation in C2-deficient human sera and in sera with other defined defects of complement to assess other mechanisms through which MBL might recruit complement. The capacity of serum to support C3 deposition was examined by ELISA using microtiter plates coated with O antigen-specific oligosaccharides derived from Salmonella typhimurium, S. thompson, and S. enteritidis corresponding to serogroups B, C, and D (BO, CO, and DO). MBL bound to CO, but not to BO and DO, and efficiently supported C3 deposition in the absence of C2, C4, or MASP-2. The existence of an MBL-dependent C2 bypass mechanism for alternative pathway-mediated C3 activation was clearly demonstrated using CO, solid-phase mannan, and E. coli LPS. MASP-1 might contribute, but was not required for C3 deposition in the model used. Independent of MBL, specific antibodies to CO supported C3 deposition through classical and alternative pathways. MBL-dependent C2 bypass activation could be particularly important in various inherited and acquired complement deficiency states.

Complement Activation↗

PubMed1976

Evidence that C1s participates in the alternative complement pathway.

Purified C1s, subcomponent of C1, induced electrophoretic conversion of factor B and consumption of hemolytic C3 and C5 in sera genetically deficient in C2 or C4. Blocking of the hemolytic activity of C1s in C2-deficient serum by F(ab')2 anti-C1s resulted in inhibition of the alternative pathway, as indicated by the failure of zymosan or cobra venom factor to induce comsumption of C3 and C6. Zymosan also failed to activate the alternative pathway when C1s was absorbed from C1r-deficient serum using a solid immunoabsorbent. These data, showing that C1s participates in the alternative pathway under certain experimental conditions, suggest the interesing possibility that C1s is important in the activation sequence of both the classical and the alternative pathway more generally.

Animals↗