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PubMed1979

Complement abnormalities in diffuse plane xanthomatosis with paraproteinaemia.

Paraproteinaemia may be associated with xanthomatous skin deposits and these can arise in the absence of elevated lipid levels. Two cases of benign monoclonal gammopathy with diffuse plane xanthomatosis are reported. Case 1 exhibited hypolipidaemia and a functional deficiency of C1 esterase inhibitor. Case 2 showed a normal lipoprotein profile, abnormal platelet aggregation, and a cutaneous vasculitis with evidence of complement consumption via the classical pathway. The significance of these abnormalities is discussed.

Aged↗
PubMed1986

Antibody-independent activation of the classical pathway of human serum complement by lipid A is restricted to re-chemotype lipopolysaccharide and purified lipid A.

Incubation of most bacterial lipopolysaccharides (LPS) with normal human sera at 37 degrees C activates the serum complement system, resulting in decreased levels of hemolytic complement. A panel of R-chemotype LPS preparations isolated from Salmonella minnesota rough mutant strains, as well as smooth wild-type LPS from S. minnesota, Escherichia coli O55-B5, Serratia marcescens, and Yersinia enterolitica, were used to examine the effect of LPS polysaccharide chain length on LPS lipid (lipid A)-dependent activation of the classical pathway of complement (CPC). To examine specific lipid A-dependent activation of the CPC, sera deficient in alternative pathway of complement activity were prepared by the removal of factor D. Absorption of normal human sera with formalinized rabbit erythrocytes was found to remove natural antibodies, factors capable of forming LPS complexes which activate the CPC, or both. By using such factor D-depleted formalinized rabbit erythrocyte-absorbed normal human sera, only isolated lipid A and Re-chemotype LPS (R595 LPS) were found to activate the CPC. Thus, the presence of the additional monosaccharide L-glycero-D-mannoheptose in the Rd2 LPS oligosaccharide chain compared with the L-glycero-D-mannoheptose-deficient Re-chemotype LPS structure is sufficient to block lipid A-dependent activation of the CPC by LPS.

Complement Activation↗
PubMed1996

Complement activation by a B cell superantigen.

Staphylococcal protein A (SpA), acting as a B cell superantigen, binds to the Fab region of human VH3+ Igs. Using SpA abrogated of its IgG Fc binding activity (Mod SpA) as a model B cell superantigen, we determined whether such an interaction causes complement activation. Addition of Mod SpA to human serum led to complement consumption and the generation of C3a. To determine whether this complement activation 1) was due to an interaction between VH3+ Igs and the Fab binding site of SpA and 2) proceeded via the classical complement pathway, we tested a panel of monoclonal IgM proteins for the ability to hind C1q following interaction with SpA. C1q binding was restricted to SpA-reactive, VH3+ IgM proteins. To formally determine whether the binding of SpA to the reactive VH3+ IgM proteins led to complement activation, we reconstituted the serum from a hypogammaglobulinemic patient with monoclonal IgM proteins and measured complement consumption and C3a generation following the addition of Mod SpA. We observed complement consumption and C3a production only in Mod SpA-treated serum reconstituted with a VH3+, SpA-binding, IgM protein. Taken together, these results provide compelling evidence that the interaction of the Fab binding site of SpA and VH3+ Igs can lead to complement activation via the classical pathway. This novel interaction may have significant implications for the in vivo properties of a B cell superantigen.

Adult↗
PubMed2001

Opsonization of yeast cells with equine iC3b, C3b, and IgG.

The main opsonins in serum are antibodies and complement factor C3. The opsonization mechanisms including complement activation and deposition are important in studies of phagocytosis and of mechanisms of microbial immune evasion. The objective of the present study was to monitor the deposition of complement C3 and IgG from equine serum on yeast cells (Saccharomyces cerevisiae) using a flow cytometric immunoassay. Correlations were made between the opsonic coating and phagocytic capacity using equine blood neutrophils. In addition, the bound C3 fragments were characterized by SDS-PAGE and Western blot analyses. Opsonic coating of yeast with equine C3 and IgG occurred rapidly with detectable levels with as little as 0.75% serum. C3 deposition was a result of complement activation and no passive adsorption was observed. When complement was inactivated, the fluorescence indicating IgG deposition increased 3-6-fold, indicating spatial competition between C3 and IgG at binding. Opsonization with 1.5% serum led to suboptimal equine neutrophil phagocytosis of yeast cells which was dependent on complement activation by the classical pathway. With > or =6.25% serum, IgG contributed to opsonization and phagocytosis. With 50% serum and more, C3 was deposited also by the alternative pathway. Phagocytosis rates became optimal with 3% serum, and did not increase further with higher serum concentrations. The main form of C3 on the yeast cells was iC3b and the rest was C3b without any detectable breakdown products (C3c or C3dg). The equine complement components are similar in size to the human equivalents. It may be concluded that opsonization of yeast particles leading to phagocytosis, occurs at very low serum concentrations (1.5%) and that it is dependent on activation of the classical complement pathway at this low opsonic level. This is an important finding for efficient host defense, e.g. extravascular phagocytosis at infection sites.

Animals↗
PubMedDate not supplied

[The effect of plasmin on complement in human blood serum].

Plasma exhibited the dose-dependent inactivating effect on human blood serum hemolytic complement both in classic and alternative pathways. Negative correlation (r = -0.8) was found between the rate of complement inactivation and content of C3 component. Plasmin appears to hydrolyze mainly the C3 component of complement as a result of which hemolytic activity of complement is decreased.

Blood↗
PubMed1980

In vitro activation of feline complement by feline leukemia virus.

Incubation of normal feline serum with purified feline leukemia virus (FeLV) at 37 degrees C for 30 min resulted in the activation of the complement system via the classical pathway as demonstrated by consumption of the C1, C4, C2, C3, and, to a lesser extent, the later C components. A similar finding was observed when normal human serum was substituted for normal cat serum. In contrast, complement-dependent lysis of FeLV with normal feline serum as assayed by the release of ribonucleic acid-dependent deoxyribonucleic acid polymerase was one-third that of complement-dependent FeLV lysis with normal human serum. The levels of total hemolytic complement and neutralizing antibody in individual feline sera were also not proportional to the degree of virolytic activity. These observations indicate that the inefficient virolysis of FeLV by normal cat serum may be one of the factors contributing to the high incidence of leukemia observed in cats.

Animals↗
PubMed1979

C142 complement activity and conglutinogen in bovine milk.

Bovine milk, derived from uninflamed glands in mid-lactation, is shown to contain the complement components of the classical pathway up to C3. Using functional tests, C142 activity and conglutinogenic activity can be demonstrated in undiluted whey. Conglutinin is rarely found in normal milk.

Animals↗
PubMed1992

Mechanism of complement activation in the hyperacute rejection of porcine organs transplanted into primate recipients.

The authors investigated the importance of natural antibody and complement in the pathogenesis of hyperacute xenograft rejection using in vivo and in vitro pig to primate models. Studies were carried out in rhesus monkeys transplanted with a pig heart or kidney in which hyperacute rejection was observed within a few hours. The rejected organs showed deposits of IgM, C3, C4, C5, and C9 neoantigen along small blood vessels, but few deposits of factors B and P. Removal of anti-endothelial cell "natural" antibodies by plasmapheresis, immunoabsorption, and immunosuppression techniques resulted in marked prolongation of the survival of a subsequently transplanted heart, even when complement levels were within the normal range. Thus, complement, in the absence of natural antibodies, did not initiate hyperacute rejection in this species combination. The requirements for complement activation in human serum to cause cytotoxicity of porcine endothelial cells were then evaluated. Cytotoxicity was abrogated by depleting human serum of IgM, C2, or C5, but not of factor B. Restoration of the effect of serum on endothelial cells was achieved by reconstitution of the respective depleted sera with purified IgM or with the corresponding complement proteins, indicating that IgM and the classical, but not the alternative, pathway of complement, were involved. Identical conclusions were drawn from experiments to ascertain the requirements for complement activation in human serum to mediate binding of iC3b to porcine endothelial cells. The authors conclude that in a pig to primate xenograft complement does not directly initiate injury to the graft but rather requires activation by bound xenoreactive natural antibodies; IgM antibodies directed against endothelial cells activate the classical complement pathway, which then contributes to endothelial cell activation and subsequent events characteristic of hyperacute rejection.

Animals↗
PubMed1994

Collectins: collagenous C-type lectins of the innate immune defense system.

Collectins are humoral lectins found in mammals and birds. They are oligomers whose subunits comprise three polypeptide chains each containing a collagenous section and a C-terminal lectin domain. They are related structurally and functionally to the first component of the classical complement pathway, C1q, and seem to serve important roles in innate immunity through opsonization and complement activation. The lectin domains bind carbohydrates on microorganisms, while the collagenous regions are ligands for the collectin receptor on phagocytes and also mediate C1q-independent activation of the classical complement pathway.

Animals↗
PubMed1995

Circulating levels of mannose binding protein in human immunodeficiency virus infection.

Mannose binding protein (MBP) is a serum lectin which, upon binding to a carbohydrate extremity, acquires the ability to activate the classical complement pathway. MBP binds human immunodeficiency virus (HIV) in vitro via glycans on gp120 and thus, it may play a defensive role in HIV infection and contribute to virus clearance through the activation of complement associated with this condition. We measured serum MBP and activation indices of the classical complement pathway (plasma C4d and C3d) in HIV-seropositive patients at different stages of disease severity, and in normal subjects. MBP was higher in HIV patients as a whole and in each Centers for Disease Control (CDC) group than controls (P<0.01). MBP was not significantly different between CDC groups and and did not significantly correlate either with CD4-positive lymphocytes, neopterin or beta2-microglobulin or with C4d and C3d. The possibility that MBP plays a defensive role in HIV infection cannot be excluded, but, it it is, it does not appear to act by recruiting complement for vital elimination.

Adult↗
PubMed1995

Diversity of sites for measles virus binding and for inactivation of complement C3b and C4b on membrane cofactor protein CD46.

The complement system membrane cofactor protein (MCP) CD46 serves as a C3b/C4b inactivating factor for the protection of host cells from autologous complement attack and as a receptor for measles virus (MV). MCP consists of four short consensus repeats (SCR) which are the predominant extracellular structural motif. In the present study, we determined which of the four SCR of MCP contribute to its function using Chinese hamster ovary cell clones expressing each SCR deletion mutants. The results were as follows: 1) SCR1 and SCR2 are mainly involved in MV binding and infection; 2) SCR2, SCR3, and SCR4 contribute to protect Chinese hamster ovary cells from human alternative complement pathway-mediated cytolysis; and 3) SCR2 and SCR3 are essential for protection of host cells from the classical complement pathway. These results on cell protective activity of the mutants against the human classical and the alternative complement pathways were compatible with factor I-mediated inactivation profiles of C4b and C3b, respectively, in the fluid-phase assay using solubilized mutants and factor I; the results were mostly consistent with those reported by Adams et al. (Adams, E. M., Brown, M. C., Nunge, M., Krych, M., and Atkinson, J. P. (1991) J. Immunol. 147, 3005-3011). SCR2 and SCR3 were required for C3b and C4b inactivation, and SCR4-deleted MCP showed weak cofactor activity for C4b cleavage but virtually no cofactor activity for C3b cleavage. The functional domains of MCP for the three natural ligands C3b, C4b, and MV, therefore, map to different, although partly overlapping, SCR domains.

Animals↗
PubMed1982

Biological effects of the interaction of staphylococcal alpha-toxin with human serum.

The alpha-toxin (hemolysin) of Staphylococcus aureus is known to be an important determinant of pathogenicity although its precise role in the process of infection is not understood. In this study, the interaction of alpha-toxin with the human complement system was evaluated in terms of its effect on the opsonic activity of serum for S. aureus. Phagocytosis by human polymorphonuclear leukocytes was studied by measuring the uptake of preopsonized radiolabeled bacteria. It was found that alpha-toxin-treated serum had reduced opsonic activity and that this change was associated with complement consumption via the classical pathway. Levels of C3 to C9 were reduced in proportion to the amount of toxin added to the reaction mixture; levels of C2 were markedly reduced but those of factors B and D of the alternative pathway were unaltered in the presence of alpha-toxin. Heat-inactivated toxin, which had no hemolytic activity, also interacted with the complement system but with a significantly reduced effect. In addition, alpha-toxin behaved as a chemotaxinogen for polymorphonuclear leukocytes: human serum was activated by the toxin. These studies demonstrate that the interaction of staphylococcus alpha-toxin with human serum affects two important aspects of the host response to the staphylococcus.

Bacterial Toxins↗
PubMed1982

Antibody-independent classical pathway-mediated opsonophagocytosis of type Ia, group B streptococcus.

The opsonophagocytic requirements of human sera containing endogenous complement for a variety of type Ia, and group B streptococcal strains were defined. Significant reduction (>==90%) in colony-forming units was noted after a 40-min incubation for the highly encapsulated, mouse-passed prototype strain 090 by sera containing moderate to high concentrations of antibody to type Ia polysaccharide (mean, 16.5 mug/ml), whereas bacterial growth occurred in 25 sera with low levels of specific antibody (mean, 2.1 mug/ml). This absolute requirement for a critical amount of specific antibody in promoting opsonophagocytic killing of strain 090 was not found when 18 fresh clinical type Ia isolates were tested. In antibody-deficient and agammaglobulinemic sera, respectively, mean reductions in colony-forming units of 94 and 95% were seen for fresh clinical isolates, whereas strain 090 was not killed by polymorphonuclear leukocytes in the presence of these sera. All strains required a considerable amount of specific antibody for alternative pathway-mediated opsonophagocytosis. That opsonophagocytic killing of clinical type Ia isolates was mediated by the classical pathway in a nonantibody-dependent fashion was shown when MgEGTA chelation of agammaglobulinemic serum or use of serum deficient in C2 resulted in bacterial growth. The addition of C2 to C2-deficient serum restored bactericidal activity of this serum. These experiments indicate that substances other than the exposed surface of the type Ia capsular polysaccharide initiate classical pathway-mediated opsonophagocytosis of clinical isolates of type Ia, group B streptococci by human sera in the absence of immunoglobulin. Perhaps, a deficiency in classical complement pathway function is critical to the susceptibility of neonates to type Ia, group B streptococcal disease.

Animals↗
PubMed1998

Human heart generates complement proteins that are upregulated and activated after myocardial infarction.

In human heart, we detected mRNAs and proteins for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 with the use of reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical techniques. We found an upregulation of both mRNAs and proteins in areas of recent and old myocardial infarctions. In both situations, the classical complement pathway was activated, with C4d, C3d, and the membrane attack complex (C5b-9) being deposited on damaged cardiac myocytes. These activated complement components were also identified on Western blots of infarcted tissue. Complement mRNAs in infarcted heart tissue were higher than those in liver, and liver complement mRNAs were not upregulated in cases with infarcted hearts. Our results establish that (1) complement proteins are endogenously produced by human heart; (2) the classical complement pathway is fully activated after myocardial infarction; (3) complement activation is directly involved in myocardial damage after ischemic insults; and (4) damage from complement activation may be chronically sustained. These data suggest that inhibition of the complement system should be effective in treating myocardial infarction.

Adult↗
PubMed1990

The complement system. Activation, modulation, and clinical relevance.

Activation of the classic or the alternative pathway of the complement system results in the generation of biologically active products and the assembly of MAC. Homeostasis is achieved by the presence of control proteins that modulate the activation at various levels. Complement proteins play an important role in the pathogenesis of several dermatologic disorders. Their deficiency is associated with impairment of host-defense; uncontrolled activation of the system results in the development of angioedema or chronic hemolysis.

Complement Activation↗
PubMed1994

Interaction between serum amyloid P component and C4b-binding protein associated with inhibition of factor I-mediated C4b degradation.

Serum amyloid P component (SAP) is a member of the pentraxin protein family. Although present in all types of amyloid deposits, it is also a normal constituent of blood and extravascular tissues. In blood, SAP forms a calcium-dependent, noncovalent complex with C4b-binding protein (C4BP). C4BP regulates the classical complement pathway as it binds C4b and functions as cofactor in its degradation by factor I. Although SAP and C4b bind to distinct sites on C4BP, it is not known whether the SAP-C4BP interaction affects the function of C4BP. We report that in a fluid phase system, SAP inhibited degradation of C4(H2O) (which is C4b-like) in a dose-dependent manner. Phosphorylethanolamine was found to alleviate the inhibitory effect of SAP on C4(H2O) degradation. Because this compound is known to inhibit the SAP-C4BP interaction, this indicated direct binding of SAP to C4BP to be required for inhibition of C4(H2O) degradation. Even though C4BP, C4(H2O), and SAP form a multimolecular complex in fluid phase, SAP was found to inhibit binding of C4BP to immobilized C4(H2O). The inhibitory effect was calcium dependent and alleviated by phosphorylethanolamine. Heparin, which is known to inhibit the interaction between SAP and C4BP, was also found to counteract the inhibitory effect of SAP on C4BP binding to C4(H2O). However, the effect of heparin was biphasic because high concentrations of heparin directly inhibited binding of C4(H2O) to C4BP. The inhibition of C4BP function by SAP suggests that SAP may be involved in regulation of the classical complement pathway C3 convertase.

Calcium↗
PubMed1991

Influence of C4 null alleles on C4 activation in systemic lupus erythematosus.

Deficiencies of early components of the classical complement pathway are known to be associated with systemic lupus erythematosus (SLE). C4 null alleles, C4A Q0 and C4B Q0, are prime candidates for the major histocompatibility complex associated factor which determines susceptibility to SLE. There is poor correlation, however, between the presence of low concentrations of C4 and possession of C4 null alleles, and thus the basis of the association between C4A Q0, C4B Q0 and SLE remains obscure. The possibility that activation of C4 may be related to the possession of C4 null alleles was examined. C4 phenotypes were investigated, and C4 concentration and activation were estimated in patients with SLE. C4 activation was determined by measuring the concentration of C4d--a split product of C4. Twenty five of 35 patients had C4 phenotypes which include null alleles. No association between low C4 concentrations and C4 null alleles was found, but a significant association between low C4d concentrations and C4 phenotypes including null alleles, particularly those with C4A Q0, was noted. No correlation between concentrations of C4 and C4d was found. These results show an influence of C4 null alleles on the activation of the C4 molecule, which is independent of the concentration of C4. The possession of silent genes coding for C4 null alleles might predispose to SLE by conditioning poor C4 activation, a critical event for the clearance of immune complexes mediated by the classical complement pathway.

Alleles↗
PubMed1986

Emergence of bactericidal and opsonizing antibody to Vibrio vulnificus following bacterial infection.

Virulent isolates of Vibrio vulnificus resist the bactericidal and opsonizing effects of normal human serum, in contrast to environmental isolates, which are highly serum susceptible. Immune responses to bacteremic V. vulnificus infections in human subjects have not been characterized. Serum from a patient who survived sepsis caused by V. vulnificus had substantial bactericidal and opsonizing immunoglobulin G (IgG) for his own bloodstream isolate. Killing was mediated by the classical complement pathway, whereas opsonization was effected by either the classical or the alternative pathway. IgG that reacted strongly with 55-, 58-, and 68-kilodalton outer membrane proteins was present in the patient's convalescent-phase serum but was absent from normal human serum. These findings suggest that humoral immunity to V. vulnificus, mediated by bactericidal and opsonizing antibody, emerges during infection and may be due, in part, to IgG directed against identifiable outer membrane proteins.

Antibodies, Bacterial↗