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PubMed1979

Abnormalities of the complement system in Reye syndrome.

Sixteen patients with Reye syndrome had diminished concentration of serum complement proteins and/or hemolytic activity in the earliest blood sample. All 12 studied with hemolytic methods had significantly reduced C1 activity; total hemolytic complement activity was reduced in only three. Low Cl activity was accompanied by equivalent reduction of Cls in 11 of 12 patients; Clq was less than normal in only two of 12. Decreased levels of at least one other classical pathway complement hemolytic activity or protein concentration were found in 13 patients, whereas factor B or the alternate complement pathway was normal or elevated in the ten patients studied. The consistent reduction of Cls protein concentration in Reye syndrome suggests that early metabolic abnormalities regularly affect the production or catabolism of this protein. Although normal serum Clq concentration in the majority of these patients does not support an immune pathogenesis, decreased Clq, C4, and C2 in three patients does suggest that immune mechanisms may be responsible for the serum complement abnormalities in this latter group of patients.

Adolescent↗
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↗
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↗
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↗
PubMed1986

Effect of the nephrotic syndrome on the concentration of serum complement components.

The concentration of 12 component and four control proteins of the complement system was measured in serum from 43 children with a nephrotic syndrome, which subsequently proved to be steroid-responsive, and from 13 children with focal glomerulosclerosis (FGS) and was compared with values from 197 normal subjects. Of classical pathway complement components, 40% of patients had low C1q levels and 20%, low C2 levels. Mean serum levels of C1s, C4, C1INH, and C4bp were elevated. Of alternative pathway components, factors B and I were low in one third, while levels of C3 and H were commonly elevated. Of the terminal components, only C8 and C9 were low. In five patients with FGS with hypoalbuminemia without edema, all component levels were normal. With the exception of C1q, C1s, and C8, high molecular weight (mol wt) components were in high concentration and low mol wt components in low concentration. The three exceptions may be explained by the subunit structure of C1 and C8. From a practical standpoint, the study indicates that edematous patients with a nephrotic syndrome may have low serum levels of C1q and C2, simulating classical pathway complement activation such as commonly occurs in glomerulonephritis. However, low levels of C4, and possibly C1s, can be used as indicators of classical pathway activation since their levels are not reduced by a nephrotic syndrome.

Adolescent↗
PubMed1992

Hereditary dysfunction of the third component of complement associated with a systemic lupus erythematosus-like syndrome and meningococcal meningitis.

OBJECTIVE: We describe a dysfunction of C3 in a patient with a systemic lupus erythematosus (SLE)-like syndrome. Alternative pathway complement function was absent, but classical pathway complement function was partially intact. METHODS: We used functional, preparative, and immunochemical techniques in the study. RESULTS: The patient's C3 proved normally susceptible to trypsin proteolysis and partially resistant to classical pathway, but completely resistant to alternative pathway, convertase-dependent cleavage. CONCLUSION: The dysfunction, thus, was caused by a failure of C3 to interact with the C3 convertases, rather than by a lack of a proteinase-sensitive cleavage site in the deficient protein.

Adult↗
PubMed1987

The classical pathway of complement prevents the formation of insoluble antigen-antibody complexes: biological implications.

There is now clear evidence for a complement dependent physiological system which is capable of processing immune complexes in and outside the vascular compartment so that they remain soluble, and transporting such complexes to the fixed macrophage system where they are safely eliminated. Defects in physiological immune complex disposal can occur at various stages described in this article, and it could well be that several of these stages could present subtle defects which are, however, additive so that under a given set of circumstances immune complexes end up in the wrong places, i.e. outside the fixed macrophage system.

Animals↗
PubMed1985

Suppression of mouse complement activity by contaminants of technical grade pentachlorophenol.

Pentachlorophenol (PCP) is an antimicrobial agent used chiefly for the preservation of wood. Subchronic oral exposure (14 days) to Technical Grade PCP significantly inhibited the functional activity of female B6C3F1 mouse complement when measured in a microtiter hemolytic assay. When evaluated one day following the final exposure the highest administered dose (100 mg/kg) significantly suppressed the Classical complement pathway, the Spontaneous C1 autoactivation pathway, the Alternate pathway and the level of complement component, C3. Reconstitution studies using C5-deficient serum also demonstrated deleterious effects on this complement component. The Classical pathway was the most sensitive to Technical Grade PCP effects. Animals treated with 100 mg/kg Technical Grade PCP had CH 50 levels 30% of vehicle controls. Animals treated for 14 days and allowed a 15 day recovery period had CH 50 values 36% of control and animals which recovered for 30 days had only 52% of the complement activity of control animals. C3 recovery studies also demonstrated continued suppression on days 15 and 30 post-final exposure. Doses of 10 and 30 mg/kg did not produce the marked effects observed with the highest dose; however, a dose-dependent trend was observed for all responses. Animals treated with 100 mg/kg of EC-7, a PCP preparation with reduced amounts of contaminating dioxins and dibenzofurans, did not demonstrate detrimental effects on the complement system.

Animals↗
PubMed1986

Development of a rapid kinetic assay for the function of the classical pathway of the complement system and for C2 and C4.

A simple functional complement assay (FCA) is described which is based on kinetic turbidimetry. 25 microliter of sample are combined with 250 microliter of a suspension of antibody coated ovine erythrocytes in a microprocessor controlled photometer. After a lag phase the activation of complement leads to a rapid lysis of the cells which is measured photometrically at 578 nm. The time for a decrease of absorbance of 0.1 is defined as the endpoint of the reaction. Normal citrated plasma which is the preferred specimen for the assay shows a reaction time of about 42 sec whereas pathological or diluted samples show a prolongation. With specific antibodies it was demonstrated that the assay was sensitive for a deficiency of factors of the classical pathway. Factors of the alternative pathway do not influence the assay. In combination with deficient sera a modified form of the assay allows also the determination of C2 and C4. Because of its simplicity, speed and accuracy these assays may be well suited to perform functional complement assays in a routine laboratory.

Animals↗
PubMed1986

The activation of C5 in the fluid phase and in the absence of C3 through the classical pathway of the complement system.

Unsensitized guinea-pig erythrocytes (Egp) were lysed by a combination of eight isolated, human-derived complement components, Cls, C4, C2, C5, C6, C7, C8 and C9 (Cls-C9exC3), even in the presence of anti-C3. It was determined that a factor was generated in the reaction mixture of Cls, C4, C2, C5 and C6, which had a lytic activity against Egp when C7, C8 and C9 were added. The lytic factor was similar to C56 in the following properties: the activity of the lytic factor decreased when incubated with C7 prior to its reaction with Egp, the lytic factor did not bind to Egp by itself but it did bind in the presence of C7, EDTA did not have any inhibitory effect on the lytic factor, and the activity of the lytic factor was lost by treatment with anti-C5 or anti-C6 but not by treatment with anti-C4. Furthermore, C5a, a cleavage product of C5, was clearly detected in the reaction mixture of Cls, C4, C2 and C5. These findings indicate that C5 can be activated proteolytically into C5a and C5b in the fluid phase solely by the classical pathway C3 convertase, C42, without any participation of C3.

Animals↗
PubMed1988

Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways.

The serum complement system is a major mediator of inflammation reactions. Two of the complement proteins, the third (C3) and fifth (C5) components, are precursors of potent phlogistic molecules, C3a and C5a. C5a has potent chemotactic activity and plays an active role in pulmonary inflammation. We present evidence suggesting that several complement proteins, including C5, are synthesized locally in the lung in alveolar type II epithelial cells. Lung tissue from normal mice synthesized and secreted C5 protein similar to the C5 protein in mouse serum, whereas lung tissue from C5-deficient mice did not. Lung tissues from both normal and C5-deficient mice synthesized C3. Rat lung tissue synthesized and secreted C5, as well as C2, C4, C3, and factor B. Cultures of type II cells (95% type II cells, 5% macrophages) regularly synthesized all these proteins. In contrast, cultures of macrophages alone synthesized large amounts of C2 and factor B, and in some experiments C3 and C4, but never C5. The C5 synthesized by the rat cells was slightly larger than serum C5 (200 kD compared with 180 kD) and was not processed to the two-chain molecule seen in serum. Rat lung tissue and purified type II cells contained C5 mRNA with the same molecular mass as the C5 mRNA in rat liver and in mouse lung and liver. Human type II cells also synthesized C5, as well as C2, C4, C3, and factor B. Human pulmonary macrophages synthesized only C2, factor B, and, in some experiments, C3. Synthesis of complement proteins in cells that line the alveolar wall may provide a local source of these proteins for inflammatory responses in the lung. Local synthesis of complement proteins could be regulated independently of the synthesis in the liver.

Animals↗
PubMed1990

C4b-binding protein, a regulatory component of the classical pathway of complement, is an acute-phase protein and is elevated in systemic lupus erythematosus.

A radioimmunoassay using monoclonal and polyclonal antihuman C4b-binding protein (C4BP) antibody was developed to quantitate C4BP in serum. Using the assay, the levels of C4BP in healthy individuals, in patients with systemic lupus erythematosus (SLE), and in acute-phase individuals were determined. The levels of C4BP are significantly elevated in individuals with SLE (186%; p = 0.0001) and are even higher in individuals during the acute phase (286%; p = 0.0001). To confirm whether or not individuals were in the acute-phase response, serum C-reactive protein (CRP) levels were assessed. In the acute-phase response, CRP levels were 100-fold elevated over normals, but did not correlate with increases in C4BP (r = -0.031; p = 0.899). In SLE patients, the CRP levels were significantly, but moderately, elevated (5-fold; p = 0.028). The data indicate that C4BP is an acute-phase reactant and is differentially regulated from CRP during the acute-phase response.

Acute-Phase Proteins↗
PubMed1990

Rapid in vitro immobilisation of purified Treponema pallidum (Nichols strain), and protection by extraction fluids from rabbit testes.

The use of Percoll-purified treponemes in an assay similar to the Treponema pallidum Immobilisation test demonstrated that immobilisation of purified treponemes by seronegative normal human serum proceeded at a much higher rate than that of unpurified treponemes. This suggests that the removal of the testicular extract makes the treponemes more vulnerable to this action. A preincubation of the purified treponemes with the testicular extract from infected or uninfected testes delayed their rate of immobilisation to that demonstrated by the unpurified treponemes. This showed that substances produced during the infection are probably not responsible for the delay in immobilisation. Discrimination between the classical and the alternative pathway of complement activation, studied by the ethylene glycol-bis (beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) method, showed that the classical pathway was responsible for the rapid immobilisation of the purified treponemes. However, the slow immobilisation in the EGTA-serum samples suggested a minor role of the alternative pathway in the immobilisation of the purified treponemes. Since the testicular extracts exerted an anti-complement activity, it needs to be investigated whether the protection offered to the purified treponemes by the testicular extracts is based on their deteriorating effect on the classical complement pathway or is due to a re-establishment of the protective cover around the treponemes.

Animals↗
PubMed1991

Human serum induced opsonization of immunoglobulin G-coated polystyrene microspheres with complement components C3 and C4 as measured by flow cytometry.

Human IgG-coated polystyrene microspheres (IgG-ms) were incubated with human serum followed by biotinylated monoclonal anti-C3d or anti-C4d antibody, and phycoerythrin-streptavidin. The intensity of fluorescence was measured by flow cytometry and corresponds to the amount of deposited C3 and C4. Binding of C3 and C4 was dependent on the activation of the classical pathway of complement and on the amount of IgG adsorbed to the particles. No deposition was observed on control particles coated with bovine serum albumin or ovalbumin. Incubation of constant amounts of IgG-ms with increasing amounts of normal human serum (NHS) resulted in a dose-dependent increase in C3 deposition. The same result was found for C4 deposition at moderate NHS dilutions, but less C4 was detectable using a higher input of NHS. Half-maximum C3 and C4 deposition was observed at a mean serum dilution of 1/114 and 1/520, respectively (n = 26). No correlation was found between C4 or C3 deposition and either total C4 and C3 serum concentrations as measured by nephelometry or complement-mediated lysis of antibody-coated sheep red blood cells. Reduced or absent C4 or C3 deposition was found in the sera of patients with low amounts or deficiencies of components involved early in classical complement pathway activation whereas essentially normal C4 or C3 deposition was obtained with the sera of patients with deficiencies in components of the membrane attack complex. With this simple and specific functional assay using stable reagents an altered function of early components of the classical pathway of complement may be quickly and reliably detected in routine diagnostic laboratories. Moreover, such opsonized and well characterized particles may be useful in assays of phagocytic cell function.

Complement C3↗