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PubMed1994

Activation of the classical pathway of complement by non-immune complexes of immunoglobulins with human protein FV (FV fragment-binding protein).

Protein FV, a human sialoprotein recently described in the stools of patients suffering from liver diseases, binds the variable domain of the heavy chains of immunoglobulins. We show here that preincubation of this protein with monoclonal human IgG1 and IgM activates the complement cascade by forming non-immune complexes, as evidenced by haemolysis inhibition of antibody-coated sheep erythrocytes. As negative controls, no inhibition was observed after incubation either with immunoglobulins or with protein FV alone, and with the protein FV-depleted medium. Activation was due to the binding of immunoglobulins with protein FV, as shown by inhibition of protein FV-induced agglutination of the sensitized erythrocytes in the absence of complement. Activation of the classical pathway was demonstrated both by using a human IgG4 or F(ab')2 fragments unable to activate C1q, and by Western blot analysis of the cleavage of C4 in human serum. These results confirm that protein FV-binding mimics antigen-antibody reactions, and suggest its involvement in hepatitis-associated vasculitis and in local lesions of some inflammatory gut diseases.

Carrier Proteins↗
PubMed1982

Activation of the classical pathway of complement by rheumatoid factors. Assessment by radioimmunoassay for C4.

A simple, sensitive solid-phase radioimmunoassay to quantitate the activation of the classical pathway of complement by rheumatoid factor (RF) is described. RF (purified, in serum or synovial fluid) was bound to reduced and alkylated IgG adsorbed to polyvinyl chloride microtiter plates and reacted with diluted normal human serum (complement). The activation and binding of C4 were quantitated with 125I-Fab'2-anti-C4. Purified, polyclonal IgM--RF was 100- to 1,000-fold more effective than purified IgG--RF in activating complement. The amount of complement activation produced by RF in each of the 57 sera and 2 synovial fluid samples correlated directly with the amount of IgM--RF present. The complement activating abilities of polyclonal IgM--RF in the sera of 15 rheumatoid arthritis patients were homogeneous. This novel technique is readily applicable to the investigation of complement activation by RF in disease.

Animals↗
PubMed1982

The interaction of tilorone and RMI 9563DA with the complement system.

RMI 9563DA inhibited the classical complement pathway in rat serum in vitro with an 150 of 51 micrograms/ml in diluted serum and 750 micrograms/ml in undiluted serum. Tilorone was much less active than RMI 9563DA in diluted serum and was inactive in undiluted serum. No complement inhibition could be detected in vivo following a near lethal dose of RMI 9563DA (25 mg/kg i.v.). Thus, complement inhibition is not the mechanism by which these compounds exert their anti-inflammatory activity. Both compounds increase serum hemolytic complement activity 24 h after administration to rats. With RMI 9563DA, this effect is entirely due to the local irritancy produced by s.c. administration of the compound. Tilorone, however, has a specific effect on complement synthesis which may be related to its ability to induce interferon.

Animals↗
PubMed1994

Enhanced cytotoxicity of amyloid beta-peptide by a complement dependent mechanism.

Amyloid beta-peptide (A beta) has been shown to activate the classical complement pathway in vitro. Here, we demonstrate that this interaction is fully capable of killing cells and damaging cellular processes in mixed hippocampal cultures from embryonic day 18 rat fetuses. Lactic acid dehydrogenase (LDH) release and morphologic changes were used to evaluate toxicity.

Amyloid beta-Protein Precursor↗
PubMed1983

Susceptibility of Pasteurella haemolytica to the bactericidal effects of serum, nasal secretions and bronchoalveolar washings from cattle.

Several isolates of logarithmic-phase organisms of Pasteurella haemolytica were shown to be sensitive to an antibody and complement-mediated killing mechanism in adult bovine serum. Data suggested that the classical complement pathway was important in the induction of bactericidal activity of serum. Sera from calves after colostrum feedings (post-colostral sera) killed only 30% of the bacteria in spite of the presence of high levels of antibodies against P. haemolytica. Addition of post-colostral serum to heat-inactivated adult bovine serum decreased the bactericidal capacity of the latter. It was speculated that this inhibition may have been caused by the presence of blocking antibodies (IgA) found in the post-colostral serum. Undiluted nasal secretions collected from adult cattle were not bactericidal to P. haemolytica. The results also suggest that the bronchoalveolar washings (BAW) from vaccinated calves, in spite of having a high antibody titer, were less bactericidal to P. haemolytica than BAW from sham-vaccinated calves (71.12% vs. 83.12%). The bactericidal factor(s) present in BAW from sham-vaccinated calves was heat stable, not complement dependent, and was not related to lysozyme concentration.

Animals↗
PubMed1984

Absolute requirement for complement in monoclonal IgM antibody-mediated protection against experimental infection with type III group B streptococci.

The role of complement in the protective and opsonic activity of monoclonal IgM antibody to type III group B streptococci (GBS) was examined in a neonatal rat model of infection and in vitro with human sera as the complement source. C3 levels in uninfected neonatal rats were less than 50% of those in adult rats, similar to the low complement levels observed in human neonates. The monoclonal type III-specific IgM antibody provided protection to neonatal rats (with unaltered complement levels) that were infected intra-peritoneally or intranasally with type III GBS. In contrast, neonatal rats depleted of complement by administration of cobra venom factor were not protected by IgM antibody. In vitro, classical complement pathway activity was adequate in sera from well, term neonates and GBS-infected neonates in the presence of higher concentrations of the monoclonal IgM antibody. At lower IgM levels, however, the alternative complement pathway was less efficient in both neonatal sera and adult sera.

Adult↗
PubMed1987

Inactivation of influenza B virus by normal guinea-pig serum.

Normal guinea-pig serum (GPS) lacking detectable antiviral antibody efficiently neutralized the infectivity of influenza B virus grown in chick embryos or MDCK cells. The inhibitor was heat-labile and sensitive to trypsin digestion. This beta-like inhibitor required Ca2+ and the complement components C1 and C4 for its activity. In contrast, GPS did not inactivate influenza A virus. Influenza B virus from which the neuraminidase activity of the spikes on the viral envelope had been eliminated by trypsin digestion was also inactivated to a level comparable to untreated virus. Complement component C1 alone bound directly to influenza B virus and inhibited its haemagglutinin activity. We suggest that the beta-like inhibitor in GPS is a component of the classical complement pathway which is triggered by the protein moiety of influenza B virus haemagglutinin, leading to virus neutralization.

Animals↗
PubMed1991

The role of lipopolysaccharide in complement-killing of Aeromonas hydrophila strains of serotype O:34.

The role of lipopolysaccharide (LPS) in the susceptibility of Aeromonas hydrophila strains of serotype O:34 to non-immune human serum was investigated using isogenic mutants (serum-sensitive), previously obtained on the basis of phage resistance, and characterized for their surface components. The classical complement pathway was found to be principally involved in the serum-killing of these sensitive strains. LPS preparations from serum-resistant or serum-sensitive strains, or purified core oligosaccharides (low-molecular-mass LPS) inactivated both bactericidal and complement activity of whole serum, while the O-antigen molecules (high-molecular-mass LPS) did not. The results indicate that LPS core oligosaccharide composition contributes to complement resistance of A. hydrophila strains from serotype O:34 with moderate virulence.

Aeromonas hydrophila↗
PubMed1979

Effects of zinc chloride on guinea pig complement component activity in vitro: concentration-dependent inhibition and enhancement.

We have studied the in vitro effects of zinc chloride on the hemolytic activity of each component of the guinea pig classical complement pathway over a wide range (25 to 500 muM) of zinc concentrations. At high concentrations (>200 muM) the activity of all components was strongly inhibited by this metal. Concentrations of 500 muM inhibited C1 and C5 by 80 and 65%, respectively, whereas all other components were inhibited by more than 94%. Zinc chloride at 25 muM produced more varied effects, with C2, C3, and C6 inhibited by 36, 35, and 55%. C7 and C8 were inhibited by approximately 25%, whereas C1, C4, and C9 were not appreciably affected. The activity of the fifth component, on the other hand, was strongly enhanced by the presence of zinc. Concentrations of 25, 50, and 100 muM zinc chloride produced increases of 92, 44, and 18%, respectively, in C5 titers when present during the activation-binding step of this component. Further studies indicated that the activities of cell-bound complement components were unaffected by zinc treatment after activation and/or binding to the sheep erythrocyte surface had occurred. In addition, zinc did not appear to inhibit by causing irreversible denaturation of either total complement proteins or its various components. Rather, it appears that zinc must be present as a reactant during the activation and/or binding step of each component for inhibition or enhancement to occur.

Animals↗
PubMed1985

Immune immobilization of Treponema pallidum: antibody and complement interactions revisited.

The Treponema pallidum immobilization test was designed for serodiagnosis of syphilis and is dependent upon specific antibody and a heat labile component of normal serum. Investigators have shown the component to be dependent upon divalent cations and it is presumed to be complement. Experiments were performed to reevaluate the interactions of antibody and complement and the mechanism of immobilization. The loss of treponemal motility was correlated to the loss of complement activity in the reaction mixture. When motility of treponemes incubated with immune serum IgG and complement had dropped to 50% (3.4 h), 72% of the available complement had been consumed. At the same time, treponemes incubated with normal serum IgG and complement were 82% motile and only 51% of the complement had been consumed. C6 deficient rabbit serum and C4 deficient guinea pig serum were used in conjunction with immune serum IgG to determine which components of the complement cascade were necessary for immobilization. Treponemes were not immobilized by either sera. Results suggest that the heat labile factor in normal sera is complement, that both early and late components of the complement cascade are necessary, and that the reaction proceeds via the classical complement pathway. Although T. pallidum is susceptible to the actions of antibody and complement, the organisms must interact with these components for at least 2 h before immobilization will result.

Animals↗
PubMed1984

Membrane-bound hemagglutinin mediates antibody and complement-dependent lysis of influenza virus-treated human platelets in autologous serum.

Influenza A virus-treated human platelets were lyzed in autologous serum. Lysis required the presence of antibody and occurred predominantly through activation of the classical complement pathway. Binding of the virus followed by its elution at 37 degrees C resulted in a dose-dependent desialation of the cells with a maximal release of 45% of total platelet sialic acid. In contrast, platelets that had been treated with Vibrio cholerae neuraminidase and from which 55% of total sialic acid had been removed were not lyzed in autologous serum and did not bind C3 as shown in binding assays using radiolabeled monoclonal anti-C3 antibody. Thus, the immune-mediated lysis of virus-treated platelets in autologous serum did not involve neoantigens expressed by desialated cells. To assess the effect of viruses on the platelet surface, treated platelets were incubated with galactose oxidase and sodium [3H]borohydride prior to separation and analysis of the labeled glycoproteins by SDS-PAGE. Viral treatment resulted in a desialation of each of the surface glycoproteins. At the same time, a labeled component of Mr 72,000 (nonreduced) and Mr 55,000 (reduced) was observed that was not present when V. cholerae-desialated platelets were examined in the same way. Immunoblotting experiments performed using antiwhole virus and anti-hemagglutinin antibodies demonstrated this component to be viral hemagglutinin. Involvement of membrane-bound hemagglutinin in antibody and in complement-mediated lysis of virus-treated platelets in autologous serum was supported by the increased lytic activity of a postvaccinal serum containing an elevated titer of complement fixing anti-hemagglutinin antibodies. Binding of a viral protein to the platelet surface provides a model for immune thrombocytopenias occurring during acute viral infections at the time of the specific immune response.

Adult↗
PubMed1983

The role of complement in the opsonization of mucoid and non-mucoid strains of Pseudomonas aeruginosa.

Requirements for complement and/or antibody for opsonization were assessed for 34 strains of Pseudomonas aeruginosa. Included were mucoid strains from patients with cystic fibrosis (CF), non-mucoid derivatives of these strains, and non-CF strains with classical morphology. Non-CF strains are known to vary as to opsonic requirements, but this study shows that mucoid strains are also diverse. Among the 14 mucoid strains, five could not be opsonized and completely resisted phagocytosis. All non-mucoid strains can be opsonized. When the bacteria were incubated in fresh human serum and stained with fluorescein, conjugated anti-C3 non-opsonizable strains did not bind C3 on the surface whereas five of six mucoid strains, which could be opsonized by complement alone, stained with anti-C3. In mucoid strains, surface characteristics correlate with differences in functional requirements for opsonization. In non-CF strains this specificity was not seen. Most mucoid strains required an intact classical complement pathway for opsonization. A number of mucoid strains could not be opsonized in the absence of a functional alternative complement pathway whereas in contrast, non-CF strains were not greatly affected by inactivation of the alternative pathway.

Antibodies, Bacterial↗
PubMed1981

Shunt nephritis. Role of the complement system in its pathogenesis and management.

Three cases of shunt nephritis in which serial complement levels were obtained during the course of treatment are presented to illustrate the value of monitoring complement levels in the management of this condition. In shunt nephritis, circulating immune complexes are formed which contain antigen from bacteria of low virulence. These complexes, which activate the classical complement pathway, are reflected in most cases by lowering of the serum levels of C1, C2, C4, and C3. These levels promptly return to normal after the initiation of effective therapy. Serial determinations of serum levels of complement protein provide a sensitive and reliable method for early determination of efficacy of therapy in shunt nephritis.

Anti-Bacterial Agents↗
PubMed1982

Complement-mediated lysis of African swine fever virus-infected cells.

Using an homologous pig system, th lysis of African swine fever virus-infected cells by antibody and complement was investigated. The optimal conditions necessary for lysis are described, and it was found that the system was unique amongst reported virus infections in that infected cells were lysed by the classical complement pathway and not the alternative pathway. Development of antibody capable of initiating complement-mediated lysis was relatively late in the infected pig, although functional in vitro assays suggested that it might act as a significant effector mechanism. Investigations of sera taken from pigs infected with varying African swine fever isolates indicate that the assay may provide a means of discriminating between strains.

African Swine Fever↗
PubMed1990

Evidence of IgG-mediated enhancement of the antibody response in vivo without complement activation via the classical pathway.

The complement (C) dependency of IgG-mediated enhancement of the antibody response was investigated by immunizing mice with trinitrophenyl-coupled keyhole limpet hemocyanin (TNP-KLH) and either a C-activating TNP-specific monoclonal IgG2a antibody (Hy-1.2) or a mutant, non-C-activating variant of Hy-1.2 (M12). Hy-1.2 as well as M12 efficiently enhanced the anti-KLH response, although Hy-1.2 was more active. In addition, also a naturally non-C-activating TNP-specific IgG1 antibody enhanced the response to TNP-coupled bovine serum albumin. Moreover, C-activating IgG could enhance the antibody response in mice depleted of C3 by treatment with cobra venom factor. These findings suggest that the classical pathway of C activation is not required for IgG-mediated enhancement.

Animals↗
PubMed1994

In vitro activation of the classical pathway of complement by a streptococcal lipoteichoic acid.

The purpose of this study was to find whether a glycerolphosphate-containing lipoteichoic acid prepared from Streptococcus sobrinus OMZ 176 cells would activate the classical pathway of complement while in solution. Reference activators were lipopolysaccharide from Escherichia coli 0111:B4 and heat-aggregated immunoglobulin G. Serum samples were taken from healthy students. Analysis through crossed immunoelectrophoresis showed that lipoteichoic acid caused an almost complete dissociation of the C1qrs macromolecule. All activators decreased the area of and slowed the electrophoretic mobility of the C4 protein peaks, with lipoteichoic acid causing the most pronounced alterations. Electroimmunoassays showed that lipoteichoic acid separately, yielded detectable amounts of free C1r2s2 subunits; it also generated significantly more trimer complexes between C1r, C1s and C1 inhibitor (C1INH) than did the other two activators. Lipoteichoic acid was, however, a comparatively weak inducer of tetramer C1INH-C1r-C1s-C1INH complexes. Analysis through Western blotting showed that all activators accelerated consumption of C1r, induced complex formations between C1INH and C1s and produced cleavage products of C2. Altogether, the immunochemical analysis gave clear evidence of classical pathway activation by lipoteichoic acid, but its activation profile differed from those seen with lipopolysaccharide and aggregated immunoglobulin G.

Analysis of Variance↗
PubMed1990

A mechanism of activation of the alternative complement pathway by the classical pathway: protection of C3b from inactivation by covalent attachment to C4b.

In this work we studied the role of the classical pathway complement component C4b in the activation of the alternative pathway. It was found that nascent C3b attaches with high efficiency to C4b and that C3b in C4bC3b complexes is protected from inactivation by factors H and I. Activation of C3 by factors B and D in the presence of Mg2+ ions and excess C4b led to 35% incorporation of nascent C3b into C4bC3b complexes in the fluid phase. In comparison, when human IgG was tested as an acceptor under similar conditions, only 12% of generated C3b was incorporated into IgGC3b complexes. The half-life time of dissociation of C3b from purified C4bC3b complexes was approximately 2.3 h at 37 degrees C. C4b in these complexes protected C3b from inactivation as effectively as any known alternative pathway activator. Thus, C3b bound to C4b was tenfold more stable than free C3b or C3b bound to a nonactivating surface. In comparison, the protection provided by attachment to human IgG was only 67% of that of C4b. The results provide an explanation for observations of alternative pathway recruitment following classical pathway activation and for the stability of the classical pathway C5 convertase on surfaces which do not provide protection for C3b from factors H and I.

Complement C3-C5 Convertases↗