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PubMed1989

Phagocytosis of particulate activators of the human alternative complement pathway through monocyte beta-glucan receptors.

Human monocytes phagocytose particulate activators of the alternative complement pathway through beta-glucan receptors in the absence of opsonins. Recognition of soluble beta-glucans by monocytes selectively inhibits ingestion of particulate activators and has no effect on responses mediated by monocyte receptors for Fc-IgG, complement, or fibronectin. The smallest ligand unit recognized by monocyte beta-glucan receptors is an acid-resistant heptaglucoside present in yeast cell walls. Mouse monoclonal anti-beta-glucan antibodies have been prepared, one of which completely neutralizes the inhibitory capacity of the HPLC-purified heptaglucoside. This antibody has been used as immunogen for the preparation of an anti-Id. The pretreatment of monocytes with low concentrations of anti-Id inhibits monocyte ingestion of zymosan particles but not EsIgG, suggesting that this antibody has specificity for monocyte beta-glucan receptors and is a powerful probe for further receptor studies. Other receptors with specificities for carbohydrates are also present on mononuclear phagocytes. Receptors for mannose/fucose and those for galactose have been isolated and cloned. The development of probes, such as structural analogs of the active heptaglucoside and the anti-Id, will bring the beta-glucan receptors to a similar stage of definition. A major factor that adds a considerable degree of difficulty to studies of the beta-glucan receptors and is not shared by the other receptors for carbohydrates is the requirement for structural conformations provided by the alignment of several glucose units rather than the recognition of a hexose residue in, for example, a glycoconjugate. The designation of these receptors as beta-glucan receptors has inadvertently taken us into a new area of nonimmune defense. Animal studies indicate that beta-glucans with 1,3- and/or 1,6-linkages are active pharmacologic agents that rapidly confer protection to a normal host against a variety of biologic insults. The beta-glucan receptors provide a mechanism by which a heightened state of host responsiveness is initiated.

Animals↗
PubMed1988

Activation of the alternative complement pathway and generation of stimulating factors for granulocytes by glass fibers.

Continuous-filament glass fibers coated with organic agents, candidate asbestos substitutes, were assessed for their ability to elicit from normal human serum complement-derived cleavage products which are able to stimulate the chemotaxis and the respiratory burst of polymorphonuclear leukocytes. Glass fibers generated chemoattracting and respiratory stimulating factors for polymorphonuclears from human serum. The effect was dose related for chemotaxis from the serum fiber concentration of 75 micrograms/ml to 1,250 micrograms/ml. The serum chemoattracting activity, as well the respiratory stimulation, were dramatically impaired when serum had been preliminarily absorbed with antiC5 antiserum. Since the impairment of chemotactic activity occurred also in the presence of EDTA, but not in the presence of EGTA, we assumed an activation of the alternative complement pathway. Glass fibers were studied in comparison to a UICC sample of Canadian chrysotile asbestos, which is able to activate in vitro the alternative complement pathway. Glass fibers exhibited less ability than asbestos fibers to generate complement cleavage products with chemotactic activity for polymorphonuclears; however, they produced an activity about equal to 80% of a chemotactic standard stimulus such as zymosan-activated plasma.

Asbestos↗
PubMed1978

Activation of the alternate complement pathway in Staph. aureus infective endocarditis and its relationship to thrombocytopenia, coagulation abnormalities, and acute glomerulonephritis.

Twenty-four patients with infective endocarditis (IE) are described, fourteen with Staph. aureus and ten with other organisms. Despite the acute nature of the infection, ten of the fourteen with Staph. aureus IE were hypocomplementaemic; six of these ten had normal levels of C4 associated with low C3 levels, suggesting activation of the alternate complement pathway. Factor B (C3PA) was also low in three of these six cases. In the ten patients with non-Staph. IE, three had hypocomplementaemia with low levels of C4, C3, and Factor B, probably due to C1 (classical pathway) activation with feedback activation of the alternate pathway. In addition, thrombocytopenia was noted in nine of the twenty-four patients and was associated with hypocomplementaemia; the degree of renal insufficiency noted in these patients also correlated with hypocomplementaemia. In Staph. aureus IE thrombocytopenia and hypocomplementaemia, occurring early in the course of the disease, may be due to a non-immune interaction of Staph. cell wall products (Protein A) with immunoglobulin, complement components, and thrombocytes.

Acute Disease↗
PubMed1987

Activity of the alternative complement pathway during mycobacterial infections in inbred mice.

The relationship between kinetic activity of the alternative pathway (AP) of complement and susceptibility to Mycobacterium bovis (BCG) and M. fortuitum was examined in inbred mice. After subcutaneous injection of BCG, the organisms were mostly contained by the draining lymph nodes, with minimal effects on spleen and no apparent relationship with serum AP. After intravenous injection of BCG or M. fortuitum, male mice, which had a more effective AP than female mice, showed lower spleen bacterial counts. AP kinetics became faster in mice with high spleen bacterial counts and slower in mice with low counts, suggesting that infection or inflammatory processes affected AP. These experiments suggest that if tuberculosis is confined to tissues and draining lymph nodes AP plays no part in pathogenesis or host resistance, but AP might reduce the infectivity of low numbers of organisms spreading by blood or lymph from a primary focus of infection.

Animals↗
PubMed1981

Enzymatic treatment transforms trypomastigotes of Trypanosoma cruzi into activators of alternative complement pathway and potentiates their uptake by macrophages.

In the absence of bound antibody, trypomastigote bloodstream forms of Trypanosoma cruzi fail to activate the alternative complement pathway. We now demonstrate that treatment with trypsin and, to a lesser extent, with sialidase converts these protozoa into activators of the pathway, as judged by their lysis in normal sera or sera genetically deficient in fourth or second component of complement (C4 or C2) and their Mg2+-dependent consumption of C3 as measured by crossed immunoelectrophoresis. In addition, after pretreatment with enzyme and incubation in C5-deficient serum, trypomastigotes were shown to possess both C3 and properdin factor B (B) on their surface as judged by immunofluorescence. Requirement for the late components C5-C9 was suggested by the failure of C5-deficient sera to lyse trypsin-treated parasites. The inability to activate the alternative complement pathway was regained by these organisms after incubation in vitro. This restoration of insusceptibility was inhibited when puromycin was included in the culture medium. Treatment of the trypomastigotes with trypsin also potentiated their uptake by mouse peritoneal macrophages without apparent interference with their capacity to differentiate and multiply inside the cell. These findings suggest that untreated trypomastigotes normally escape recognition by the alternative pathway in vivo because of the presence on their surface of trypsin- and sialidase-sensitive regulatory molecules, the expression of which is dependent on protein synthesis.

Animals↗
PubMed1986

Isolation and characterization of rabbit properdin of the alternative complement pathway.

Rabbit factor P, which is involved in stabilizing the labile C3 convertase of the alternative complement pathway, was isolated from rabbit serum by a simple two-step procedure: polyethylene glycol precipitation and QAE-Sephadex A-50 column chromatography. The chemical properties, and functional activities of the rabbit P were very similar to those of human P, except that there were slight differences in the SDS-PAGE patterns of limited tryptic digests and in the amino terminal sequences. The molecular weights were estimated to be 58 000 for rabbit P and 59 000 for human P on SDS-PAGE under reducing conditions. The amino terminal 36 residues of rabbit P showed 78% homology to the equivalent region of human P.

Amino Acid Sequence↗
PubMed1989

Two forms of guinea pig factor B of the alternative complement pathway with different molecular weights.

Two forms of guinea pig factor B (B) of the alternative complement pathway with different mol. wts (Mr) have been isolated from plasma and characterized. The Mr of the two B species, tentatively termed B1 and B2, were estimated to be about 100,000 and 96,000, respectively, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Incubation of B with guinea pig C3 and human factor D (D) in the presence of Mg2+ generated two cleavage fragments of B, namely Ba and Bb. Although the Bb fragments showed the same migration corresponding to an Mr of 62,000, Ba fragments showed different mobilities corresponding to an Mr of 38,000 from B1 and 34,000 from B2. Digestion of B1-Ba, the Ba fragment derived from B1, and B2-Ba, the Ba fragment derived from B2, with endoglycosidase F resulted in a band at Mr 30,000 on an SDS-PAGE in both cases, indicating a difference in structure of the asparagine-linked oligosaccharide moiety in B1-Ba and B2-Ba. No difference in antigenicity was noted between B1 and B2 on immunodiffusion with anti-B sera. Immunoblotting analysis showed that all individual Hartley guinea pigs examined in this study possessed both B1 and B2 at similar levels, as determined by the intensity of staining of their sera. Furthermore, treatment of their serum with zymosan led to the generation of two Ba species corresponding to the Ba fragments from B1 and B2. The capacity to form C3/C5 convertase, as determined by hemolytic assay, was found to be similar between B1 and B2. Furthermore, kinetics of the decay of C3 convertase showed the same half-life of 3.0 min at 30 degrees C. The NH2-terminal amino acid sequences of B1 and B2 and their Bb fragments were determined and found to be identical.

Amino Acid Sequence↗
PubMed1981

Host modification of Sindbis virus sialic acid content influences alternative complement pathway activation and virus clearance.

Previous studies have shown that Sindbis virus, an enveloped alphavirus of the togavirus group, activates the alternative complement pathway in the absence of detectable antiviral immunoglobulin. The present studies examined the role of the host-determined sialic acid content of Sindbis virus on activation of the alternative complement pathway. Purified Sindbis virus grown in baby hamster kidney (BHK-SV) and in mosquito (MOSQ-SV) cells yielded virus with 10.2 and less than 2.0 nmol sialic acid/mg viral protein, respectively. Sindbis virus deficient in sialic acid (2.0 nmol sialic/mg) was also produced by treating the BHK-SV with neuraminidase (NANase-SV). When MOSQ-SV or NANase-SV was incubated in either C4DGPS or C2DHS, each consumed significantly more C3 than did BHK-SV, indicating that the ability of Sindbis virus to activate the alternative pathway is inversely related to its sialic acid content. Studies in vivo showed that virus deficient in sialic acid (MOSQ-SV) was cleared from the blood of mice much more efficiently than was virus rich in sialic acid (BHK-SV), after i.v. inoculation. Furthermore, when animals were depleted of C3 through C9 by cobra venom factor (CoVF) treatment, no differences in the clearance of high and low sialic acid-containing viruses were observed. Thus both the activation in vitro and complement-dependent clearance in vivo are significantly affected by the host-determined sialic acid content of Sindbis virus.

Animals↗
PubMed1984

Control of the immune complex-complement interaction by protein H of the alternative complement pathway and the natural inhibitor heparin.

The potential of the negative regulatory protein H of the alternative complement pathway convertase and of heparin in modulating the complement-dependent capacity of fresh serum to inhibit immune complex precipitation (CIICP) between bovine serum albumin (BSA) and rabbit anti-BSA as well as tetanus toxoid (TT) and human anti-TT was assessed. Additions of purified H to serum to increase the intrinsic concentration of this protein by 80% (BSA-anti-BSA system) and 190% (TT-anti-TT system) resulted in an inhibition of CIICP by 50% and 60%, respectively, whereas further increase of the amount of H lead to a decrease of its inhibitory activity. A similar effect was observed with heparin: at a concentration of 400 U/ml a 90% inhibition of CIICP in the TT-anti-TT system was obtained which diminished at higher heparin concentrations. The effect of H on C3 deposition to immune aggregates was assessed through its influence on C3b-mediated immune adherence hemagglutination; factor H dose-dependently suppressed such hemagglutination induced by aggregated human IgG or preformed TT-anti-TT complexes when added to the immune complex-fresh serum mixture at the outset but not after 45 min of the 37 degrees C incubation period which means that H inhibited more likely decoration of immune complexes with C3b than it did inhibit the interaction of C3b-coated immune complexes with erythrocytes. This suppressive effect of H was reversed by the simultaneous addition of the activating protein B. Complement-mediated binding of tritiated C3 to latex-bound human IgG was assessed and H was found to dose-dependently inhibit such binding with a maximal inhibition of 37% at a H concentration of 7 micrograms/ml.

Animals↗
PubMed1984

Amino acid sequence of human D of the alternative complement pathway.

The primary structure of human D, the serine protease activating the C3 convertase of the alternative complement pathway, has been deduced by sequencing peptides derived from various chemical (CNBr and o-iodosobenzoic acid) and enzymatic (trypsin, lysine protease, Staphylococcus aureus V8 protease, and chymotrypsin) cleavages. Carboxypeptidase A was also used to confirm the COOH-terminal sequence. The peptides were purified by high-pressure liquid chromatography. The proposed sequence of human D contains 222 amino acids and has a calculated molecular weight of 23 748. It exhibits a high degree of homology with other serine proteases, especially around the NH2-terminus as well as the three residues corresponding to the active-site His-57, Asp-102, and Ser-195 (chymotrypsinogen numbering). This sequence homology is highest (40%) with plasmin, intermediate (35%) with pancreatic serine proteases, such as elastase, trypsin, chymotrypsin, and kallikrein, and least (30%) with the serum enzymes thrombin and factor X. D, however, exhibits only minimal amino acid homology with the other sequenced complement serine proteases, Clr (25%) and Bb (20%). The substitution of a basic lysine for a neutral amino acid three residues NH2-terminal to the active-site serine as well as a small serine residue for a bulky aromatic amino acid at position 215 (chymotrypsinogen numbering) in the binding pocket may be important in determining the exquisite substrate specificity of D. The presence of His-40 which interacts with Asp-194 (chymotrypsinogen numbering) to stabilize other serine protease zymogens [Freer, S. T., Kraut, J., Robertus, J. D., Wright, H. T., & Xuong, N. H. (1970) Biochemistry 9, 1997] argues in favor of such a D precursor molecule.

Amino Acid Sequence↗
PubMed1985

Increased activation of the alternative complement pathway in sickle cell disease.

Complement proteins play an important role in host defenses against Streptococcus pneumoniae, a major cause of serious infections in sickle cell (SS) disease. Previous studies have suggested abnormalities of the alternative complement pathway in SS disease. We measured activation of the alternative pathway in sera from patients with SS disease utilizing an enzyme immunoassay which detects C3b,P complexes, derivative of the C3b,Bb,P alternative pathway convertase. In all, 89% of SS sera had elevated concentrations of C3b,P complexes, indicative of increased alternative pathway activation. Chronic activation of the alternative pathway may contribute to impaired host defense in SS patients.

Anemia, Sickle Cell↗
PubMed1990

Curdlan, a (1----3)-beta-D-glucan from Alcaligenes faecalis var. myxogenes IFO13140, activates the alternative complement pathway by heat treatment.

From the results of consumption experiments of guinea pig complement, Curdlan, a (1----3)-beta-D-glucan obtained from Alcaligenes faecalis var. myxogenes IFO13140, has been found to lack the ability to activate complement when unheated or preheated at either 40 degrees C or 50 degrees C. However, Curdlan heated at or above 60 degrees C increased complement consumption. This activation, dependent on the temperature of the Curdlan, was via the alternative complement pathway as assessed by cleavage of factor B into Ba and Bb fragments. These results suggest a substantial change must occur in Curdlan with heat treatment for alternative pathway activation.

Alcaligenes↗
PubMed1991

Reconstitution of C5 convertase of the alternative complement pathway with isolated C3b dimer and factors B and D.

C5 convertase of the alternative complement pathway is a trimolecular complex consisting of two molecules of C3b and one molecule of Bb. We previously proposed a model of the alternative pathway C5 convertase in which the second C3b molecule binds covalently to the first C3b molecule bearing Bb, and the C5 molecule binds to each C3b molecule of the covalently linked C3b dimer, resulting in its appropriate presentation to the catalytic site on Bb. In the present study, we purified the covalently linked C3b dimer and reconstituted the C5 convertase with the C3b dimer and factors B and D to obtain evidence in support of this model. An insoluble glucan, OMZ-176, was incubated with human serum to activate the alternative pathway and to allow formation of the alternative C5 convertase on the surface of the glucan, and the glucan bearing the C5 convertase was then solubilized by incubation with glucosidases. In this way, the covalently linked C3b dimer was obtained in solution without using a detergent. The C3b dimer was then separated from enzymes, C3b monomer, C3b oligomer, and other materials by chromatographies. SDS-PAGE analysis demonstrated that the purified C3b dimer had intact alpha'-chains. Alternative pathway C5 convertase was reconstituted when the isolated C3b dimer was incubated with factors B and D. The presence of P enhanced C5 convertase formation threefold. These results support the notions that the formation of the covalently linked C3b dimer is a general phenomenon associated with activation of the alternative pathway and that the C3b dimer acts as a part of the C5 convertase.

Complement C3-C5 Convertases↗
PubMed1990

Membrane damage to Escherichia coli and bactericidal kinetics by the alternative complement pathway of channel catfish.

1. Increased permeability of cytoplasmic membranes in Escherichia coli was a consequence of alternative complement pathway (ACP) activity of serum of channel catfish, Ictalurus punctatus. Evidence was provided by beta-galactosidase activity extracellularly when E. coli was incubated with catfish serum. 2. Lesions were detected on outer membranes of E. coli following exposure to catfish serum. 3. Catfish ACP induced a temporal sequence of pre-killing and killing phases. 4. Loss of cell viability, killing rate and cytoplasmic enzyme release increased with increasing serum concentrations. 5. By incubating E. coli with sera treated to remove complement, both release of cytoplasmic enzyme and bactericidal activity were eliminated. 6. Lethal activity associated with channel catfish ACP against Gram-negative bacteria was functionally comparable to that seen in mammalian and reptilian systems.

Animals↗
PubMed1983

Opsonization of various capsular (K) E. coli by the alternative complement pathway.

A virulence factor of E. coli K-1 is its capacity to avoid opsonization via the alternative complement pathway (ACP). Since it is not known if E. coli with other capsular (K) antigens have similar properties we examined various capsular E. coli for opsonization by the ACP. To assess opsonization we used whole blood luminol-dependent chemiluminescence (CL) and the magnesium salt of ethyleneglycol tetraacetic acid to block the classical pathway. E. coli K-types 6, 7, 27, 30, 42, 53, 57 and 75 were effectively opsonized via the ACP (greater than 65% of CL obtained with unchelated normal serum). K types 2 and 13 were opsonized by the ACP in both the high range greater than 65% and intermediate range 36-65%. Only K-types 1, 3, 5, 12 and 92 were poorly opsonized (less than 35%) by the ACP. The data demonstrate that most E. coli K-types were opsonized via the ACP. The poor opsonization of E. coli K3, 5, 12 and 92 by the ACP may be virulence factor for these bacteria.

Antigens, Bacterial↗
PubMedDate not supplied

Participation of immunoglobulin and the alternative complement pathway in opsonization of Bacteroides fragilis and Bacteroides thetaiotaomicron.

Studies were conducted to determine the requirements for immunoglobulin and complement in opsonization of Bacteroides fragilis and Bacteroides thetaiotaomicron. The ability of human sera depleted of immunoglobulin or of components of complement to promote the phagocytosis and intracellular killing of the two strains of Bacteroides by human leukocytes was measured in vitro under anaerobic conditions. Neither hypogammaglobulinemic sera nor pooled normal human serum that was heated at 56 C for 30 min supported phagocytosis and killing of the two strains of Bacteroides. Neither sera depleted of terminal complement components by treatment with inulin or cobra venom factor nor human serum deficient in C8 supported phagocytosis of the tested strains. In addition, pooled normal human serum depleted of C3, factor B, or factor D did not support phagocytosis of either strain. Dose-dependent restoration of the opsonic activity of factor B-depleted serum was accomplished by purified human factor B but not by human C2. The results indicate that immunoglobulin and components of the alternative comed in this study.

Animals↗