Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Complement Activation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources
PubMed2002

Complement activation in infective endocarditis: correlation with extracardiac manifestations and prognosis.

In an infectious process complement activation is necessary for a proper immune and inflammatory response, but when exacerbated may cause tissue injuries. In infective endocarditis (IE) patients tend to develop high titres of circulating immune complexes (CIC) that activate complement. The aim of this study was to evaluate for the first time complement activation in IE for possible correlation with extracardiac manifestations and clinical prognosis. Twenty patients with IE, 14 healthy controls and 15 patients presenting mitral and aortic valve lesions (with no signs of either infection or other associated diseases), were studied. Plasma levels of C3adesArg, SC5b-9, C1rs-C1Inh and C3b(Bb)P were determined by ELISA and C3d by double decker immunoelectrophoresis. C3 and C4 levels were assayed by turbidimetry and CIC by ELISA. Elevation of plasma levels of all complement activation products, with the exception of C3b(Bb)P, indicated a significant classical pathway activation in IE patients when compared to controls (C3d: P < 0.00004; C3adesArg: P < 0.03, SC5b-9: P < 0.01, C1rs-C1Inh: P < 0.00007). CIC levels were significantly increased (P < 0.005) and C3 reduced in IE patients (P < 0.05). Elevated C3d (P < 0.02) and C3adesArg (P < 0.03) levels were associated with pulmonary manifestations. In addition, C3d was significantly elevated in the patients who died when compared to those who had a good recovery (P < 0.02). Our data demonstrate the activation of the complement classical pathway, most probably mediated by CIC, in IE and suggests C3d and C3adesArg as possible markers for extracardiac lesion and severity of the disease.

Adolescent↗
PubMed1989

Characterization of complement activity in turkeys: evidence for classical and alternative complement pathways.

Complement activity in turkey serum was examined by using inhibitors or activators of mammalian complement. Hemolytic test systems using sheep red blood cells sensitized with specific antibody (SSRBC) and horse red blood cells (HRBC) were developed to measure residual complement activity of turkey sera treated with the various inhibitors or activators. Lysis of SSRBC was blocked by treatment with 6-mM EDTA, 10-mM ethylene glycol-bis-beta aminoethylether N,N,N',N' tetraacetic acid (EGTA), and carrageenan. In contrast, lysis of HRBC was blocked by 6-mM EDTA, but not by 10-mM EGTA or carrageenan. Addition of magnesium to EGTA-chelated serum facilitated the lysis of HRBC but not the lysis of SSRBC. Treatment of serum with zymosan at 1 mg/mL and inulin at 5 mg/mL depleted hemolytic activity against both SSRBC and HRBC, suggesting depletion of components common to both pathways. Differences in the hemolytic activities of sera against SSRBC and HRBC after treatment with the various complement inhibitors and activators demonstrate the presence of two complement pathways in turkeys.

Animals↗
PubMed1984

Initiation of complement activation.

The complement system is an excellent one to look at as an example of a triggered enzyme system. It is found to use almost all the strategies of enzyme cascades and for initiation which were discussed in the introduction. The classical pathway is a fine example of an active zymogen form of activation and the alternative pathway is the canonical example of a tickover. Both may also be activated by exogenous enzymes from other systems. The strategies of enzymes waiting for substrates, of substrates waiting for enzymes, and of both waiting for modifying proteins are all seen in various stages of the reaction. There is an association of a linear cascade with the positive feedback amplification loop. This degree of evolutionary adaptation is not only aesthetically pleasing but must be taken to mean that the system is of considerable biological importance and has been over a long evolutionary time span.

Complement Activation↗
PubMed1999

Resistance to both complement activation and phagocytosis in type 3 pneumococci is mediated by the binding of complement regulatory protein factor H.

To study the role of surface-associated proteins in the virulence of Streptococcus pneumoniae, we used two serotype 3 strains, ATCC 6303 and WU2, and two PspA-negative mutants of WU2, an encapsulated one, JY1123 (Caps(+)/PspA(-)), and an unencapsulated one, DW3.8 (Caps(-)/PspA(-)). ATCC 6303 and WU2 were highly virulent in mice, while the virulence of JY1123 was slightly decreased (50% lethal doses [LD(50)s], 24, 6, and 147 CFU/mouse, respectively); DW3.8 was avirulent (LD(50), 2 x 10(8) CFU). In vitro, ATCC 6303, WU2, and JY1123 (Caps(+)/PspA(-)) strongly resisted complement activation and complement-dependent opsonophagocytosis, whereas DW3.8 (Caps(-)/PspA(-)) was easily phagocytized in fresh serum. Trypsin treatment of ATCC 6303, WU2, and JY1123 (Caps(+)/PspA(-)) resulted in enhanced complement activation and complement-dependent opsonophagocytosis. Trypsin had no deleterious effect on the polysaccharide capsule. In addition, trypsin pretreatment of ATCC 6303 strongly reduced virulence upon intraperitoneal challenge in mice. This indicated that surface proteins play a role in the resistance to complement activation and opsonophagocytosis and contribute to the virulence of type 3 pneumococci. In subsequent experiments, we could show that the modulation of complement activation was associated with surface components that bind complement regulator factor H; binding is trypsin sensitive and independent of prior complement activation. Immunoblotting of cell wall proteins of the virulent strain ATCC 6303 with anti-human factor H antibody revealed three factor H-binding proteins of 88, 150, and 196 kDa. Immunogold electron microscopy showed a close association of factor H-binding components with the outer surface of the cell wall. The role of these factor H-binding surface proteins in the virulence of pneumococci is interesting and warrants further investigation.

Animals↗
PubMed1995

HTLV-I activates complement leading to increased binding to complement receptor-positive cells.

This investigation was performed to determine whether HTLV-I can activate complement, since previous studies show that complement activation by some viruses, including HIV-1, can enhance binding to, and infection of complement receptor-positive (CR+) cells. Complement treatment increased binding of HTLV-I to CR+ HPB-ALL cells by approximately 5-fold. In contrast, increased binding was not observed with H9 cells, which lack CR. Heat inactivation or EDTA treatment of complement blocked this increased binding while EGTA treatment only partially blocked binding. Anti-CR2 antibody significantly blocked binding of complement-treated HTLV-I to HPB-ALL cells. Since previous studies showed that HIV-1 could activate complement, activation of complement by this virus was compared with HTLV-I. It was observed that binding of HTLV-I to HPB-ALL cells was enhanced by highly dilute complement (> or = 1:810) while HIV-1 required much higher concentrations of complement (> or = 1:30), indicating that HTLV-I is a much stronger complement activator. Treatment with complement transiently increased the ability of HTLV-I to infect CR+ cell lines as judged by provirus formation (4- to 8-fold increase) and p24 production (5- to 10-fold increase). In contrast, complement treatment did not increase infection of CR- cells. In conclusion this study shows that HTLV-I activates complement leading to increased binding to, and transiently increased infection of, CR+ cells. This complement-mediated increased binding of HTLV-I may dramatically affect viral trafficking and immunological reactivity of virus in vivo.

Antibodies, Blocking↗
PubMed1982

Antibody-independent complement activation by myelin via the classical complement pathway.

Murine or rabbit whole brain homogenates were shown to activate human complement via the classical pathway by an antibody-independent reaction. This activity required Ca++ ions. Anticomplementary activity in fractionated murine brain was found to reside in the myelin fraction and in purified myelin. It was absent, however, both from highly purified myelin basic protein (MBP) and from the MBP-free residue. Because purified MBP is a monomer and this protein exists in brain tissue largely as a dimer, the ability of the cross-linked form of MBP to activate complement was investigated. MBP, dimerized with difluorodinitrobenzene, was highly anticomplementary. The murine brain, inactive when taken from the newborn mouse, was shown to first acquire the capacity to activate complement at 7 d after birth. This finding is consistent with the report that the synthesis of myelin protein has been shown to be initiated in murine brain 8 d after birth. Complement activation by MBP could play an important role in the pathological changes observed in neurological disorders.

Animals↗
PubMed1983

Natural antibodies against a polysaccharide (Bo) from sugar cane mediate its complement-activating effect.

The interaction of a complement activating glucan from sugar cane (Bo) with immunoglobulins was studied. Bo precipitates a small fraction of IgG from human serum. In combination with this fraction, it activates complement by the classical pathway, not in its absence. Bo is adsorbed to and can be eluted from Sepharose containing covalently coupled IgG; it is not bound when the IgG-Sepharose is lacking the Bo-reactive IgG fraction. Bo-IgG complexes activate and fix C1. The binding of C1 to aggregated IgG is not inhibited by Bo. This is in contrast to the strong inhibition of C1 fixation by the Fc-binding protein A. It is concluded that normal human serum contains natural antibodies against Bo which form complement-activating immune complexes with Bo by binding it to their F(ab) region. The antibodies do not cross-react with dextran, a glucan from barley, nor with surface constituents of E. coli.

Antibodies↗
PubMed1988

Granulocyte activation during haemodialysis in the absence of complement activation: inhibition by calcium channel blockers.

The effect of the calcium channel blockers nifedipine (9 and 18 micrograms kg-1 h-1), diltiazem (100 and 200 micrograms kg-1 h-1) and verapamil (19 micrograms kg-1 h-1) continuously infused during haemodialysis on granulocyte and complement activation was investigated. Plasma levels of lactoferrin, elastase in complex with alpha 1-proteinase inhibitor (E-alpha 1PI) and C3a were measured in patients dialysed with dialysers made of cuprophane, polymethylmethacrylate (PMMA) and polyacrylonitrile (PAN). Calcium channel blockers caused no change of blood pressure during haemodialysis in all patients. There was no effect of nifedipine, diltiazem or verapamil on plasma lactoferrin, E-alpha 1PI or C3a levels in patients dialysed with cuprophane. However, plasma lactoferrin and E-alpha 1PI values were significantly reduced by all calcium channel blockers in patients dialysed with PMMA, and also by nifedipine and verapamil in patients dialysed with PAN. Our data indicate that calcium channel blockers inhibit granulocyte activation occurring in dialysers with very little anaphylatoxin formation. These drugs, however, are ineffective in patients dialysed with cuprophane where complement activation takes place. Therefore, granulocyte activation during haemodialysis in the absence of complement activation seems to be mediated by calcium ions.

Aged↗
PubMed1978

Possible mechanisms of the first step of the classical complement activation pathway: binding and activation of C1.

Different immunoglobulin preparations of human monoclonal IgM, normal human and rat IgG, as well as purified rabbit antibodies were treated by various methods, fragmentation, aggregation and complexing with antigen. The ability of the treated and untreated preparations to fix isolated human C1, to activate the classical complement pathway (to consume C4 in normal human serum) were compared. It was found that the different methods affected the conformation of the immunoglobulin molecules in different ways and induced changes to a greater or lesser extent in the two capacities of the preparations tested. In the case of the monoclonal IgM preparation a strong C1-fixation was observed without measurable complement activation. Other preparations, interfacially aggregated human IgG, BSA-anti-BSA and OA-anti-OA immune complexes had a very weak C1-fixing but a marked complement activating capacity. Some preparations, e.g. heat-aggregated IgG, both fixed and activated C1 effectively, aggregates with a complement-activating capacity without C1-fixing effect were separated by gel-filtration. It was demonstrated further, that at a given time only a part of the activated C1 molecules could be found fixed to the immunoglobulins, the other part was released into the fluid phase after activation. On the basis of the results of this and previous studies a hypothesis is proposed suggesting three possible results of the interaction between C1 and the different preparations: (1) firm fixation and activation; (2) binding not followed by activation and (3) a transient binding leading to activation. The possible application of this hypothesis for the interpretation of the results of the different methods for detecting immune complexes is discussed.

Angioedema↗
PubMed1988

Attachment of human polymorphonuclear leukocytes to herpes simplex virus-infected fibroblasts mediated by antibody-independent complement activation.

Herpes simplex virus (HSV)-infected cells can activate the human complement system without interference of specific anti-HSV antibodies. Analysis by flow cytometry showed that C3-like molecules were deposited on the membrane of the infected cell when incubated with human serum without specific antibodies. Depletion of calcium to block the classical pathway of the complement system had no effect on fluorescence intensity. The complement activation could be blocked by chelating both calcium and magnesium or by heating the serum. Furthermore, in the fluid phase C3 was converted to C3b by infected cells and not by uninfected cells. The antibody-independent activation did not lead to lysis of the virus-infected fibroblasts, indicating that the complement cascade is abrogated before formation of the membrane attack complex. This was also confirmed by measurement of the 50% hemolytic complement activities for total and alternative pathways. Polymorphonuclear leukocytes attached to infected fibroblasts after incubation of these fibroblasts with intact complement. This is most probably mediated by complement receptor binding of C3b and C3bi which is deposited on the membrane of the HSV-infected cell. Both type 1 and type 2 HSVs showed the same characteristics in complement activation and thereby mediated polymorphonuclear leukocyte adherence.

Calcium↗
PubMed2002

A soluble chimeric inhibitor of C3 and C5 convertases, complement activation blocker-2, prolongs graft survival in pig-to-rhesus monkey heart transplantation.

Complement plays a critical role in many pathologic processes and in xenograft rejection. Therefore, effective complement inhibitors are of great interest. In pig-to-primate organ transplantation, hyperacute rejection results from antibody deposition and complement activation. Complement activation blocker-2 (CAB-2), a recombinant soluble chimeric protein derived from human decay accelerating factor (DAF) and membrane cofactor protein, inhibits C3 and C5 convertases of both classical and alternative pathways. CAB-2 reduces complement-mediated tissue injury of a pig heart perfused ex vivo with human blood. Therefore, we studied the efficacy of CAB-2 when a pig heart is transplanted heterotopically into rhesus monkeys receiving no immunosuppression. Graft survival in three control monkeys was 1.26 +/- 0.2 h; it was markedly prolonged in eight monkeys that received CAB-2. Of the six monkeys that received a single dose of CAB-2 (15 mg/kg i.v.), four had graft survivals of 21, 95, 96, and 108 h, and two died at 7 to 11 h post-transplant with a beating graft, as a result of technical complications. The two monkeys given multiple doses of CAB-2 had graft survivals of 95 and 96 h. CAB-2 markedly inhibited complement activation, as shown by a strong reduction in generation of C3a and SC5b-9. At graft rejection, tissue deposition of iC3b, C4 and C9 was similar or slightly reduced from controls, and deposition of IgG, IgM, C1q and fibrin did not change. Thus, complement inhibition with CAB-2 abrogates hyperacute rejection of pig hearts transplanted into rhesus monkeys, but does not prevent delayed/acute vascular rejection. These studies demonstrate that the beneficial effects of complement inhibition on survival of a pig heart xenograft in rhesus monkeys are similar to those in other primate species and that CAB-2 may be useful in xenotransplantation and other complement-mediated conditions.

Animals↗
PubMedDate not supplied

Thrombolytic treatment and complement activation.

Details of possible complement activation in acute myocardial infarction (AMI) and the in vivo effects of fibrinolytic agents on this activation are not yet known. We measured complement activation in 40 patients with AMI: 20 were treated with streptokinase, and 20 did not receive any fibrinolytic agent. Anaphylatoxin C4a, C3a and membrane attack complexes SC5b-9 increased about 10-fold (p < 0.0001) during streptokinase infusion. There were no increases in complement catabolic products in AMI patients not treated with streptokinase. Significant transient leukopenia (-29.5%, 7.0 SEM, p = 0.001) and a drop in systolic pressure (-29%, 3.4 SEM, p < 0.0001) occurred after 15 min of streptokinase infusion simultaneously with the peak of anaphylatoxins in plasma.

Anaphylatoxins↗
PubMed1982

Complement: activation, consequences, and control.

The activation of complement provides the humoral (fluid-phase) effector mechanism most responsible for immune-mediated injury. The classical pathway is activated by an antigen-antibody reaction. The binding of C1q initiates the sequential activation of the eleven proteins. The classical pathway has a calcium-dependent step (C1q, C1r, C1s) and a magnesium-dependent reaction (the enzymatic action of C1s on C4 and C2). The alternative pathway appears to be spontaneously activated, but the perpetuation of that activation is dependent upon the availability of an activating (or protective) surface which interferes with the inactivation of C3b by control proteins. The alternative pathway has a magnesium-dependent step, the binding of B to C3b to form the C3 convertase. Once initiated, the alternative pathway activation results in the sequential activation of nine proteins, six of which are common to both pathways. The activation of complement results in a variety of biologic consequences which can result in injury to the host. The potential destructiveness of the effects of complement activation is modulated by a series of control proteins.

Carrier Proteins↗
PubMed2000

Complement activation in acquired and hereditary amyloid neuropathy.

The pathogenesis of the axonal degeneration in acquired or hereditary amyloidosis is unknown. In this immunohistochemistry study, we examined 20 sural nerve biopsies from individuals with amyloid neuropathy (14 acquired and 6 hereditary) for evidence of complement activation. Complement activation products were detected on and around amyloid deposits within peripheral nerves. We found no difference in the extent, location or pattern of complement activation products between the 2 forms of amyloidosis. The presence of early classical pathway activation markers in the absence of antibody in hereditary cases suggests an antibody-independent activation of the classical pathway through binding of C1q. The lack of Factor Bb-suggested alternative pathway activation was not significant in these cases. The detection of C5b-9 neoantigen on amyloid deposits demonstrated that the full complement cascade was activated. Complement activation on amyloid deposits and the generation of C5b-9 in vivo may contribute to bystander injury of axons in the vicinity of amyloid deposits.

Aged↗
PubMed1987

Complement activation in experimental IgA nephropathy: an antigen-mediated process.

Complement activation associated with immune complex glomerular deposition plays an important role in renal injury. In the present studies we performed three series of experiments to identify how IgA immune complexes activate complement. The first series of experiments was designed to determine whether the presence of an antigen within a glomerular IgA immune deposit is required for complement activation. In these experiments, large-sized covalently cross-linked IgA oligomers (X-IgA) were prepared with purified IgA anti-dinitrophenyl (DNP) and a bivalent affinity-labeling antigen, bis-2,4-DNP-pimelic acid ester. These X-IgA oligomers have free antigen-binding sites that will bind DNP-conjugated antigens. Two groups of mice were treated with either X-IgA or X-IgA followed, after two hours, by an antigen DNP-Ficoll. Immunofluorescent examination of renal tissues, obtained six hours after the initial injection, revealed an equal intensity of IgA glomerular deposits in both groups of mice. Glomerular C3 deposits were only detectable in the renal tissues of mice that had DNP-Ficoll bound to X-IgA. In the second series of experiments, a pair of preformed IgA immune complexes, differing only in one antigenic structural feature (DNP), were used to examine the role of the antigen in inducing glomerular C3 deposits in two groups of mice. These pre-formed immune complexes were prepared with IgA anti-phosphorylcholine (PC) and either PC-conjugated to bovine serum albumin (PC-BSA) or PC-BSA which was further modified with DNP (PC/DNP-BSA). Although the IgA immunofluorescent intensity and pattern in the glomerular deposits were equivalent for both groups, intense C3 deposits were exclusively associated with the PC/DNP-BSA-containing immune complexes. Analysis of the relative conversion of normal human serum C3 to inactive C3b (iC3b) by X-IgA, various antigens and their respective IgA immune complexes was highly dependent on the nature of the antigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Antibodies to the HIV-1 V3 loop in serum from infected persons contribute a major proportion of immune effector functions including complement activation, antibody binding, and neutralization.

Previous studies have shown that the V3 region of the HIV envelope is both critical to viral functions and immunogenic. However, the relative contribution of anti-V3 antibodies in the sera of infected individuals in mediating immune effector functions directed at whole intact virus and infected cells has not been determined. This study used peptides corresponding to several regions of the HIV envelope as inhibitors of antibody binding and antibody effector functions directed at virions and virus-infected cells in order to assess the relative importance of V3-specific antibodies in sera from infected persons. Approximately 40% of the antibody in serum which could bind to native viral proteins on HIVMN-infected cells was blocked by a peptide corresponding to the central 15 amino acids of the V3 loop. In contrast, little if any blocking of serum antibody binding was observed with peptides corresponding to flanking regions of HIVMN V3 or three regions of gp41. Since antiviral antibody can also activate immune effector functions, we determined whether peptides could block antibody-dependent activation of the complement system by HIV-infected cells or free virus. Surprisingly, the V3 loop peptide blocked 75-95% of complement activation on HIV-infected cells. While the V3 loop peptide also blocked a substantial portion of the neutralizing activity in serum from infected persons for free virus it was again more effective in inhibiting complement-mediated effects on free virus. Accordingly, antibody-dependent, complement-mediated virolysis was inhibited by 61-79%. The results of these experiments indicate that (1) a substantial portion (30-40%) of the antibody in sera from infected persons that is capable of binding to HIV-infected cells and HIV virions is V3-specific, and (2) these V3-specific antibodies are particularly important for complement activation on infected cells and virions. This indicates that the central portion of the V3 loop, while constituting less than 3% of the amino acid sequence of the HIV envelope, apparently provides a major gp160 site for immune effector functions, especially complement activation.

Acquired Immunodeficiency Syndrome↗
PubMed1985

The development of complement activating ability as an age related factor in murine brains.

We recently reported on the ability of the myelin fraction of the murine brain to activate the complement system through the classical pathway, which might be important in the induction of secondary inflammation in various pathological conditions where brain tissue has been exposed to the complement. The present study was undertaken to investigate the relationship between the appearance of complement activity in the mouse brain and the synthesis of myelin in ICR mice up to ninety days of age. Here, we show that anti-complementary activity in the murine brain is closely related to murine brain weight and that its activity seems to be dependent on the amount of myelin in the murine brain. Myelin was isolated from brains of equal weight taken from both two-day old and ninety-day-old mice, and we found that ninety-day-old myelin consumed a much greater amount of complement (C) than two-day-old myelin. However, for equal concentrations of myelin, almost an equal amount of C was consumed by the myelin of the two-day-old mice and by that of the ninety-day-old mice. It was suggested that the difference of anti-complementary activity was caused by the myelin contents of the murine brains, but the possibility of maturation of myelin was not excluded. The mechanism involved in the anticomplementary activity of the myelin was found to be related to the consumption of complement, mainly via the classical pathway but also less activity via the alternative pathway.

Aging↗