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PubMed2004

Serum haemolytic complement activities in 11 different MHC (B) typed chicken lines.

To study the relation between serum complement levels and the chicken MHC (B) complex, complement haemolytic activity was measured in sera from hens from seven pure-bred B-typed White and one Brown Leghorn lines, and three ISA-Warren lines that had been divergently selected for antibody responses to sheep red blood cells (SRBC). Significant differences occurred in the serum haemolytic complement activities, both belonging to the classic (CPW) and the alternative (APW) pathways, among the 11 different haplotyped chicken lines. Hens with high CPW and high APW titres predominantly displayed the B2 or B21 haplotypes. Chickens with low CPW and APW were found in B14 and B15 haplotypes. Haplotype B14 appears to be different in complement levels when present into the pure-bred lines or into the ISA-Warren line selected for low antibody responses to SRBC. Otherwise, the presence of B21 in ISA-Warren line selected for high antibody responses to SRBC does not differ with the B21 in the inbred lines (except in the NL-line for CPW values). In general the haplotypes B2 and B21 are found in chicken lines with enhanced disease resistance, and the B15 haplotype has been connected with enhanced disease susceptibility. Our results suggest that levels of haemolytic complement activity, either from the classical or from the alternative pathways, may underlie part of the immunocompetence ascribed to the MHC (B) complex in chickens.

Animals↗

PubMed1985

Inhibition of human and guinea pig complement by heparin fractions differing in affinity for antithrombin III or in average molecular weight.

Heparin comprises a mixture of structurally related molecules. Affinity for antithrombin III (AT III) is a prerequisite for its anticoagulant activity, which also is dependent on its molecular weight. In this study heparin fractions prepared by affinity chromatography on immobilized AT III and by gel filtration chromatography were compared for their ability to inhibit complement mediated haemolysis and both classical and alternative pathway C3 activation as measured by crossed immunoelectrophoresis. In normal human serum, inhibition of haemolysis and of heat-aggregated IgG (HAGG) as well as zymosan induced C3 activation by heparin was found to be independent of its AT III affinity and of its molecular weight (range 4800-17,000), on a weight basis. In guinea pig serum similar results were obtained for inhibition of HAGG induced C3 activation, but inhibition of haemolysis showed a marked molecular weight dependency and was also reduced for the fraction with low affinity for AT III. This may reflect a species difference in the haemolytic action of human and guinea pig complement. It is concluded that inhibition of human complement by heparin is independent of its anticoagulant activity and of its size and it is suggested that a fraction of heparin with reduced risk for bleeding and platelet aggregation is a potential anti-inflammatory agent.

Animals↗

PubMed1990

Reduced activity of DAF on complement enzymes bound to alternative pathway activators. Similarity with Factor H.

Attachment of C3b to activators of the alternative pathway of complement results in a decrease in regulatory activity expressed by Factor H. Decay-accelerating factor (DAF) and Factor H were found to exhibit quantitatively similar decreases in regulatory activity toward the C3 convertase (C3b,Bb) bound to activators, such as zymosan (Zym) and rabbit erythrocytes (ER), compared to non-activators, such as sheep (ES) and bovine (EB) erythrocytes. Purified DAF and Factor H, in 0.1% NP-40, were assayed by measuring the amount required to release 50% of the radiolabelled Bb in 10 min from C3b,Bb on Zym or cross-linked erythrocytes. The relative effectiveness (i.e. the restriction index, RI) of DAF for accelerating the decay of C3b,Bb on the various particles was: ES (1.0), ER (0.04) and Zym (0.03). The RI for Factor H was: ES (1.0), ER (0.04) and Zym (0.07). The rate of decay of C3b,Bb induced by DAF and Factor H showed similar restriction. The results suggest that the regulatory properties of DAF are reduced if the cells on which it resides become activators of the alternative pathway as a result of transformation, virus infection or surface alteration. These findings may explain reports of dysfunctional DAF on alternative pathway-activating cells.

Animals↗

PubMed1979

Quantitation of the membrane attack complex of complement in an air-driven ultracentrifuge.

A sensitive assay of complement (C) activation via either the classical or alternative pathway was developed by evaluating assembly of the terminal complexes (C5b-9)2 or SC5b-9. Activation of serum containing [125I]C7 resulted in the formation of a stable, radiolabeled complex which was separable from its precursors by sedimentation in an air-driven ultracentrifuge. The radioactivity in the sediment was directly proportional to the amount of complex formed and assembly of the complex could be detected after C activation by aggregated IgG in concentrations as low as 10 micrograms/ml. Mild detergents such as Triton X-100 could be included in the reaction mixture, because they affected neither the assembly nor the integrity of the complexes. The assay, which detects both assembly of the membrane attack complex (MAC or (C5b-9)2) on target membranes and formation of SC5b-9 in fluid phase, measures the potential of certain substances to trigger the cytolytic phase of C regardless of whether the classical or alternative pathway was activated. However, by using serum depleted of either factor B or C1q, activation of either pathway can be assessed individually.

Cell Membrane↗

PubMed1986

Activation of complement by pathogenic and nonpathogenic Entamoeba histolytica.

Previous studies had demonstrated that strains of Entamoeba histolytica isolated from patients with colitis or amebic liver abscess were resistant to complement-mediated killing, whereas strains from asymptomatic patients were readily lysed by non-immune serum. Both serum-sensitive and serum-resistant strains of E. histolytica depleted complement rapidly as assessed by CH50, C3, and C7, and C5-9 hemolytic activities. Activation of the alternative pathway was important in lysis of nonpathogenic strains, as demonstrated by lysis by NHS (60.9 +/- 15.6%) and NHS + 5 mM EGTA (59.3 +/- 4.5%) as well as by C4-deficient guinea pig serum (72.8 +/- 7.1%) and C2-deficient human serum (64.4 +/- 11.1%), but not by NHS + 5 mM EDTA. Classical pathway activation also occurs as both pathogenic and nonpathogenic strains deplete greater than 98% of C4 activity, although it is not necessary for lysis. Pathogenic strains are not lysed by either the classical or the alternative pathway. These results suggest that pathogenic strains of E. histolytica activate complement but are able to evade an important host defense, complement-mediated lysis.

Animals↗

PubMed1986

Restriction of the alternative pathway of human complement by intact Trypanosoma brucei subsp. gambiense.

We studied the interaction of African trypanosomes with human complement. Bloodstream forms of Trypanosoma brucei subsp. gambiense isolated from mice activated the alternative pathway of complement during a 30-min incubation in vitro. In human serum, all cells remained intact and motile during this period. C3 was detected on the surface by a direct binding assay with a monoclonal antibody which recognizes C3b and iC3b. C3 deposition could also be detected by this radioimmunoassay when parasites were incubated with purified C3. Such C3 binding was enhanced by factor B, factor D, and magnesium. Surface deposition of factor B was demonstrated both by flow immunofluorescence analysis and binding of radiolabeled factor B. C3 binding and factor B binding were inhibitable by EDTA but not by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N' -tetraacetic acid (EGTA). The inhibited binding could be restored by addition of magnesium. No human immunoglobulin G or mouse immunoglobulin was detected on the trypanosome surface. By flow cytometry, neither human C5 nor polymerized C9 was detected on trypanosomes incubated in serum, although this assay was able to detect C5 and C9 on the surface of complement-treated human erythrocytes. Using a radioimmunoassay which measures C5b-9 in serum, we found that there was no generation of SC5b-9 in serum which had been incubated with trypanosomes. We concluded that, although trypanosomes activate the alternative pathway of complement, they are not lysed, because the cascade does not continue beyond the establishment of C3 convertase.

Animals↗

PubMed1989

A knowledge-based system for automatic interpretation of an analytical profile of complement factors.

A comprehensive assay to evaluate the complement system includes functional tests of both classical and alternative pathways and immunochemical measurements of C3, C4, B, C1-INA, and C3d. The purpose of this analytical profile is to screen for rare hereditary deficiencies and acquired abnormalities of complement and to define the activation pathway in cases of complement consumptive processes. Based on several years' experience, a routine was established in our laboratory to report the data to the clinician, together with a computer-generated interpretive statement. This routine was formulated into a knowledge base by specifying a series of decision rules for each of the complement disorders. After the rules were tested and updated against some 400 complement profile analyses, reasonable analytical comments were produced by the system. This knowledge-based system for reporting and interpreting complement results offers several advantages: the interpretative work is facilitated and made more reliable; a consistent interpretative comment is generated that is recognized and therefore more meaningful for the clinician; the communication of analytical procedures and policy is enhanced.

Artificial Intelligence↗

PubMed1989

Complement-mediated enhancement of IgA-induced H2O2 release by human polymorphonuclear leucocytes.

In a previous study we have demonstrated that heat-killed Staphylococcus aureus opsonized with either purified human serum IgA or secretory IgA (sIgA) can induce a respiratory burst (measured as H2O2 release) in human polymorphonuclear leucocytes (PMN; Gorter et al., 1987). In the present study we have investigated whether opsonization of IgA-coated staphylococci with complement has an additional effect on the H2O2 release of PMN. It was demonstrated that staphylococci coated with IgA (or sIgA) and subsequently opsonized with complement induced at least a two-fold increase in the specific H2O2 release compared with bacteria coated with IgA (or sIgA) alone (P less than 0.05 and P less than 0.02, respectively). The co-operative effect of IgA and complement was also observed in the presence of 10 mM ethyleneglycoltetraacetic acid containing 5 mM MgCl2 (MgEGTA), suggesting that activation of the alternative pathway of complement is sufficient to exert this effect. Using D-deficient serum as a source of complement we could demonstrate that activation of the alternative pathway is essential for the co-operative effect of complement and IgA. The increase in specific H2O2 release caused by complement was found to be dependent on the amount of IgA initially used to opsonize the bacteria. Finally the co-operative effect of IgA and complement was not restricted to one IgA subclass, because an additional opsonization of S. aureus coated with sIgA1 or sIgA2 with complement resulted in both cases in a statistically significant enhanced specific H2O2 release by PMN (P less than 0.05).

Complement C3↗

PubMed1997

Transgenic expression of a CD46 (membrane cofactor protein) minigene: studies of xenotransplantation and measles virus infection.

CD46 (membrane cofactor protein) is a human cell-surface regulator of activated complement and a receptor for the measles virus. A CD46 transgenic mouse line with an expression pattern similar to that of human tissues has been produced, to develop an animal model of (i) the control of complement activation by complement regulators in hyperacute rejection of xenografts, and (ii) measles virus infection. The mouse line was made using a CD46 minigene that includes promoter sequence and the first two introns of genomic CD46, which was coinjected into mouse ova with chicken lysozyme matrix attachment region DNA. A high level of CD46 expression in homozygotic transgenic mice was obtained with spleen cells having approximately 75% of the level found on human peripheral blood mononuclear cells. CD46 was detected in all tissues examined by immunohistochemistry, radioimmunoassay and Western blotting, showing that these mice were suitable for transplantation and measles virus infection studies. It also indicated that the transgene included the important regulatory elements of the CD46 promoter. Transgenic spleen cells were significantly protected in vitro from human complement activated by either the classical or alternative pathways and from alternative pathway rat complement. Furthermore, transgenic mouse hearts transplanted to rats regulated complement deposition in an in vivo model of antibody-dependent hyperacute xenograft rejection. Similar to human lymphocytes, transgenic lymphoblasts could be infected in vitro with measles virus; infected cells expressed viral proteins and produced infectious viral particles. The data demonstrate the suitability of this minigene for obtaining high-level CD46 expression sufficient for enhanced resistance of transgenic cells to complement attack and for obtaining wide tissue distribution of CD46, analogous to human tissues and, therefore, useful for comparative studies.

Acute Disease↗

PubMed1981

'Nephritic factor' may be an autoantibody to C3b or C4b.

We attempted to clarify the character of 'Nephritic Factor' in the alternative (NeFA) and classical pathways (NeFC) of the complement, using an agglutinating and a hemolytic activity assay. The results suggested a possibility that NeFA and NeFC were different in their ability but might appear at the same time in some cases, and that NeFA was anti-C3b autoantibody and NeFC anti-C4b autoantibody.

Autoantibodies↗

PubMed1981

Involvement of membrane-associated sialic acid in the resistance of sheep erythrocytes to lysis by mouse complement.

The sensitivity of the murine complement system to regulation by membrane-associated sialic acid was investigated. Therefore the C-mediated lysis of sialic acid-rich sheep erythrocytes, sialic acid-poor rabbit erythrocytes and enzymatically desialylated sheep erythrocytes was studied. Mouse complement differed from human and guinea pig complement in that besides the alternative, also the classical pathway appeared sensitive to regulation by surface sialic acid. The possible reaction mechanisms behind the selective sensitivity of the murine classical pathway to membrane-linked sialic acid are discussed and will be subject of further study.

Animals↗

PubMed1999

The role of complement activation in tumour necrosis factor-induced lethal hepatitis.

Injection of tumour necrosis factor (TNF) in animals causes severe liver cell toxicity, especially when D-(+)-galactosamine (GalN) is co-administered. After challenge with TNF/GalN, serum complement activity (CH50 and APCH50) decreased dramatically, suggesting strong activation of both the classical and the alternative pathways. TNF or GalN alone had no such effect. A cleavage product of complement protein C3 [C3(b)] was deposited on the surface of hepatocytes of TNF/GalN-treated mice. Intravenous administration of cobra venom factor (CVF), which depletes complement, inhibited the development of hepatitis. However, CVF pretreatment also protected C3-deficient mice. Pretreatment of mice with a C1q-depleting antibody did not prevent TNF/GalN lethality, although the anti-C1q antibody had depleted plasma C1q. Factor B-deficient and C3-deficient mice, generated by gene targeting, proved to be as sensitive to TNF/GalN as control mice. Furthermore, induction of lethal shock by platelet-activating factor, an important mediator in TNF-induced hepatic failure, was not reduced in C3-deficient mice. These data indicate that complement, although activated, plays no major role in the generation of acute lethal hepatic failure in this model and that CVF-induced protection is independent of complement depletion.

Animals↗

PubMed1995

Murine complement reduces infectivity of Plasmodium yoelii to mosquitoes.

The alternative pathway of complement in the mouse serum significantly reduced, but did not eliminate, the infectivity of Plasmodium yoelii to Anopheles stephensi. The reduction of the infectivity is mainly due to the inability of the zygote to transform into the ookinete in the mosquito midgut.

Animals↗

PubMed1986

The interaction of complement components with Aeromonas species.

The interaction of seven serum-sensitive Aeromonas strains with the complement system was investigated using a 2-h quantitative assay. Of the strains tested, four isolates activated both the alternative and classical pathways, two activated only the alternative pathway, and one strain was sensitive to the bactericidal action of complement through the classical pathway only. Two of the four Aeromonas caviae strains were such efficient activators of the complement system that when challenged with human sera deficient in normal concentrations of C3 and C4, they were still subject to complement-mediated bacterial lysis. This phenomenon, in conjunction with previous studies on complement activation by Aeromonas spp., may help account for the decreased incidence observed of systemic disease caused by Aeromonas caviae.

Aeromonas↗

PubMed1986

Inhibition of complement by a series of substituted 2-aryl-1,3-indandiones: interaction with the fifth component of complement.

A series of substituted 2-aryl-1,3-indandiones were investigated for their ability to inhibit the complement system. Some of them were found to be considerably strong inhibitors. The inhibitory activity was mainly dependent on substitutions at positions 3 and 5 of the phenyl ring. 3,5-dichloro-(8), 3,5-bis(trifluoromethyl)- (7), 3,5-diisopropyl- (3) and 3,5-di-t-butyl- (5) phenylindandiones were the strongest inhibitors of the series. The generation of EAC1-5 cells from EAC1-3 cells and C5 was most strongly inhibited by these compounds although some inhibition of the interaction of EAC1-5 with C6-C9 and EAC1-6 with C7-C9 was also observed. Slight inhibition at other steps of complement activation was also seen but this was not considered to be appreciable. Dialysis of normal serum or purified C5 pre-incubated with compounds 3, 5, 7 and 8 did not cause recovery of the hemolytic activity of normal serum or purified C5. Thus, the main site of inhibition in the complement cascade appeared to be at C5. The total alternative pathway was also inhibited to some extent by these compounds, probably due to their interaction with C5.

Animals↗

PubMed1998

High dose intravenous immunoglobulin does not affect complement-bacteria interactions.

Pooled IgG preparations for i.v. use (IVIg) have been shown to possess anticomplementary activity in autoimmune and systemic inflammatory diseases. Both in vitro and in vivo, IVIg is a preferential acceptor of activated C4 and C3, thus diverting complement activation from the target surface. We explored the effect of IVIg on complement-bacteria interactions in an attempt both to determine the safety of IVIg preparations in relation to natural immunity to bacteria and to extend our knowledge of the physiologic mechanism of action of IVIg. Using both complement-sensitive and complement-resistant bacterial strains, we investigated the effect of IVIg on C3 binding to bacterial surfaces. In all cases, whether complement could be directly activated by bacteria through the classical or the alternative pathway, IVIg had no effect on the amount of C3 bound to bacteria. In addition, IVIg did not inhibit complement-dependent bacterial lysis. Interestingly, increasing concentrations of IVIg induced an increase in C1q binding, suggesting the presence of low affinity complement-fixing antibacterial Abs in certain preparations. Using serum samples from patients treated with IVIg, complement binding to and lysis of complement-sensitive bacterial strains were not modified as compared with normal controls and pretreatment samples, although a decrease in C3 binding to sensitized human erythrocytes was observed. Our data suggest that IVIg does not affect direct complement-bacteria interactions, although it is a potent agent to use for diversion of complement activation on sensitized target surfaces.

Animals↗

PubMed1981

Isolation and properties of a complement inhibitor from Naja haje venom, distinct from known anticomplementary factors in cobra venom.

A complement inhibitor (CI) has been isolated from cobra (Naja haje) venom which is distinct from the two known anticomplementary factors in cobra venom [1], in functional properties as well as structure. CI is a small (mol. wt 26,000, determined by sodium dodecyl sulphate gel electrophoresis), heat-labile glycoprotein; the amino acid composition is that of a globular protein. CI interferes at various steps of the complement sequence, including reactions of the classical and alternative pathway. No effect was observed on C4 fixation and on the assembly of the membrane attack complex from C6-9 (minor inhibiting effects, if present, have not been excluded). Initiation of the alternative pathway is inhibited by CI already at the stage of cleavage of factor B. CI binds to C4, C4b, C3 and C3b; since the major inhibitory action of CI is lost after washing of cell intermediates, complex formation and, as a consequence, steric hindrance may be responsible for the inhibiting effects of CI. CI also interferes with binding of C3b to C3b receptors on human erythrocytes. CI is non-toxic in mice when given intraperitoneally in doses of 5 microgram/g.

Amino Acids↗

PubMed1975

Stimulation of neutrophil oxidative metabolism by the alternate pathway of complement activation: a mechanism for the spontaneous NBT test.

The reduction of nitroblue tetrazolium dye by human neutrophils was measured in the presence of serum in which the complement system had been activated through the alternate pathway by interaction with inulin. Neutrophils incubated with serum inulin supernatants reduced the dye and showed a general increase in oxidative metabolism. The oxidation of glucose-1-14-C by supernatant prepared from selectively depleted sera indicated that the neutrophil-stimulating factor(s) was generated through the alternate pathway of complement activation. The possibility that inulun had been ingested as a particle was ruled out by light microscopy and radiolabeling studies. The failure of neutrophils stimulated by the serum-inulun supernatants to migrate after exposure to a chemotactic agent suggested that the site of neutrophil-complement interaction was on the cell membrane. It is concluded from these results that biologically active fragments generated through the alternative pathway of complement activation can stimulate neutrophil metabolism in the absence of phagocytosis. Interaction of such fragments with circulating neutrophils in vivo and the subsequent metabolic activation of these cells is one explanation for the spontaneous reduction of nitroblue tetrazolium dye in vitro by neutrophils from patients with certain infections and inflammatory disorders.

Absorption↗