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PubMed1975

Alternate complement pathway induction of aggregation and release of 5-hydroxytryptamine and adenosine diphosphate by rabbit platelets.

The present studies investigated patterns of rabbit platelet aggregation and release of 5-hydroxytryptamine (5HT) utilizing nine variables: three different types of challenge, soluble antigen and antibody (AG-AB), zymosan (Z), an agent known to activate the alternate complement pathway (ACP), and Z preincubated in lightly heparinized plasma so as to become coated with complement (ZC); three different types of platelet-rich plasma (PRP), lightly heparinized PRP in which both complement pathways are active, ethylene glycol tetraacetic acid-PRP (EGTA-PRP) in which only the ACP is active, and ethylene diamine tetraacetic acid PRP (EDTA-PRP), which inhibits both complement pathways; three different types of inhibitors, cobra venom factor (CoF), which causes activation of C3 proactivator (C3PA) to C3 activator (C3A) and fluid phase decomplementation of C3 and C5 through C9, adenosine monophosphate (AMP), a specific antagonist of ADP, and tosyl arginine methyl ester (TAME), an inhibitor thought to act not only on the first component of complement, but also on a platelet membrane site of mediating complement-induced platelet injury as well as on C3PAse. In heparinized PRP, both AG-AB and Z produced biphasic aggregation and prompt and extensive 5HT release. A brief lag period noted with both AG-AB and Z challenge was not observed with ZC challenge, indicating that this lag period represented time required for generation of the necessary complement-dependent membrane-injuring activity. Prior decomplementation by CoF entirely prevented both aggregation and release by either AG-AB or Z but by ZC, indicating first that fluid-phase ACP activation did not produce platelet injury, and second that ZC had on its surface an activity capable of producing immediate biphasic aggregation and prompt 5HT release without the further participation of later acting complement components. Both AMP and TAME eliminated the second phase of aggregation and diminished or eliminated 5HT release with all three challenges, suggesting that both inhibitors might be operative on similar or identical platelet membrane receptors mediating complement-dependent platelet injury. In EGTA-PRP, AG-AB and Z produced delayed monophasic aggregation and delayed and diminished 5HT release, whereas ZC produced immediate although monophasic aggregation but delayed and diminished 5HT release. This suggested that all three challenges were capable of producing ACP-mediated platelet injury.

Adenosine Diphosphate↗
PubMed2000

Production and functional analysis of rat CD59 and chimeric CD59-Crry as active soluble proteins in Pichia pastoris.

Crry (CR1-related gene/protein) is a rodent complement regulator that inhibits C3 convertases. CD59 is a conserved protein inhibitor active towards C8 and C9. We have previously produced rat Crry as a recombinant soluble (rs) protein in Pichia pastoris. In this study we produced functionally active rat rsCD59 and a chimeric rsCD59-Crry protein in P. pastoris. The GPI anchor addition site of rat CD59 (Asn-79) was replaced either by a stop codon to produce rsCD59, or with the sequence of the first five short consensus repeats of Crry to produce rsCD59-Crry. Proteins were generated by fermentation and purified by affinity chromatography on an anti-CD59 column. In a standard classical pathway haemolysis assay, all three rs proteins had inhibitory activity, with 50% inhibition at 0.5 microM (rsCrry and rsCD59-Crry) and 4.4 microM (rsCD59). In an assay examining inhibition of C5b-9, in which C5b-7 was first formed, followed by purified C8 and C9, rsCD59 and rsCD59-Crry were active with 50% inhibition at 0.8 microM (rsCD59-Crry) and 1.3 microM (rsCD59). The degree of inhibition was independent of whether the C8 and C9 were of rat or human origin. Therefore, we have produced rsCD59 and rsCD59-Crry in P. pastoris. The rsCD59 retains its inhibitory activity towards C5b-9, while rsCD59-Crry appears to have the combined activities of Crry and CD59. In a haemolytic assay, the inclusion of CD59 to Crry is of no additional benefit to Crry, which may illustrate the overall importance of the C3 convertase step. Yet, inclusion of Crry to CD59 increases the potency of CD59 towards C5b-9.

Animals↗
PubMed1999

Preconditioning reduces tissue complement gene expression in the rabbit isolated heart.

Both preconditioning and inhibition of complement activation have been shown to ameliorate myocardial ischemia-reperfusion injury. The recent demonstration that myocardial tissue expresses complement components led us to investigate whether preconditioning affects complement expression in the isolated heart. Hearts from New Zealand White rabbits were exposed to either two rounds of 5 min global ischemia followed by 10 min reperfusion (ischemic preconditioning) or 10 microM of the ATP-dependent K+ (KATP) channel opener pinacidil for 30 min (chemical preconditioning) before induction of 30 min global ischemia followed by 60 min of reperfusion. Both ischemic and chemical preconditioning significantly (P < 0.05) reduced myocardial C1q, C1r, C3, C8, and C9 mRNA levels. Western blot and immunohistochemistry demonstrated a similar reduction in C3 and membrane attack complex protein expression. The K(ATP) channel blocker glyburide (10 microM) reversed the depression of C1q, C1r, C3, C8, and C9 mRNA expression observed in the pinacidil-treated hearts. The results suggest that reduction of local tissue complement production may be one means by which preconditioning protects the ischemic myocardium.

Animals↗
PubMed1991

Localisation of complement components in association with glomerular extracellular particles in various renal diseases.

Intraglomerular extracellular microparticles including so-called virus-like particles and striated membranous structures have been observed in various renal diseases. The presence and localisation of complement components in these extracellular bodies was studied using the protein A-gold electron microscopy method. Ultrastructurally these particles were differentiated into microspherical structures (MSS) and thread-like structures (TS). Both structures showed weak to moderate diffuse labelling with C1s, whilst the intense labelling found with C3d and C9 was confined to individual membrane-like structures of both MSS and TS. Labelling with IgA, IgG, fibrinogen and the complement components C1q, C1r, C3c C4 and C5 showed negative or trace results. There were no differences between the immunolabelling patterns of MSS and TS, nor among different renal diseases in which these structures were found. These findings raise the possibility that formation of so-called virus-like particles such as MSS and TS may be associated with complement activation.

Complement System Proteins↗
PubMed1981

The attack phase of human complement: differentiation between membrane binding and complex formation by the detection of neoantigen expression in situ. A morphometric immunoferritin study.

C5-9 neoantigen was found by morphometric immunoferritin staining on the membrane of guinea pig erythrocytes lyzed by reactive lysis C5b6 or acid-activated C5 + C6 and C7, C8, and C9. Neoantigen first appeared at the C7 step, increasing with C8, and decreasing after the addition of C9. The incubation of E with C5-C8 or C5-C9 at 0 degrees C resulted in EC5-8 without neoantigen. Reincubation of these cells after washing at 37 degrees C for 5 min led to neoantigen expression. An energy-requiring step is postulated after binding of C5-C8 and needed for C9 binding and lysis.

Animals↗
PubMed1984

Changes in the haemolytic activity of bovine serum complement by Hypoderma lineatum (insect oestridae) larval proteinases in naive and immune cattle.

Three serine proteinases (hypodermin A, B and C) of the first instar larvae of Hypoderma lineatum have been assayed for their ability to deplete seric complement of naive or immune cattle. In naive cattle complement consumption is initiated by hypodermin B through the sequence C1-C3 at a concentration of 5 micrograms/ml of serum, and by hypodermin A through the sequence of C3-C9 at a higher concentration of 150 micrograms. The third enzyme presenting a collagenolytic activity has no anti-complementary activity even on C1q. In immune cattle a 70% complement depletion through the classical pathway is observed with 15 micrograms of hypodermin B per ml of serum. The two enzymes A and C appear to play a minor role in the complement depletion via the classical pathway. The biological role of each of these enzymes in the parasite-host interrelationships is discussed. The participation of these enzymes in the immediate hypersensitive reactions following systemic treatment of cattle infested by this endoparasite is considered.

Animals↗
PubMed1990

S protein binds to serum-treated agarose beads independently of complement activation and the formation of the terminal complement complex on the beads.

Comparison of initial (early-phase) and terminal (late-phase) sequence activation of complement by agarose beads and endotoxin was evaluated in an enzyme immunoassay (EIA) of serum levels of C3c and C9 neoepitopes, respectively. EIA and Western blotting with anti-S protein monoclonal antibody revealed lower S protein values and weaker S protein bands in serum activated by agarose beads than by endotoxin, implying that S protein was removed from serum by binding to agarose. The binding of S protein to the beads was confirmed by radioimmunoassay and was found to be equal in normal and heat-inactivated serum. In contrast, the terminal complement complex was formed only on agarose beads incubated with normal serum and not with inactivated serum.

Blood Proteins↗
PubMed1982

Decreased chemotactic activity in activated newborn plasma.

The roles of complement levels and CFI activity in the regulation of chemotactic factor generation were evaluated in newborn and adult plasmas. Plasma samples were obtained from 19 healthy adults, 19 neonates, and 12 3-day-old infants. CFI levels were determined in all samples, chemotactic activity in 15 of the 19 adult and newborn samples, and complement levels in 10 of these 15. Compared to adult plasmas, CFI activity was higher in newborn and infant plasmas and chemotactic activity was lower. A close reciprocal relationship was shown between these two activities (r=-0.958). When corrected for the effects of CFI, the difference in chemotactic activity between newborns and adults disappeared. Mean levels of C1, C3, C4, C5, C3 to C9, CH50, factor B, and properdin were lower in newborn plasmas; however, C2 levels were higher. Partial correlations between these complement components and the chemotactic activity were of small magnitude and statistically not significant. These data suggest that higher CFI activity, rather than lower complement levels, accounts for most of the differences in chemotactic activity between newborn and adult plasma. (J Lab Clin Med 99:331, 1982.)

Adult↗
PubMed1981

Fluid-phase SC5b-8 complex of human complement: generation and isolation from serum.

A rapid, simple method for isolating SC5b-9 generated in human serum, and SC5b-8 generated in C9-depleted serum is described. The procedure leads to approximately 30% recovery of either complex and consists of polyethyleneglycol precipitation followed by 1 DEAE ion exchange chromatography and a sucrose density gradient ultracentrifugation. The SC5b-8 complex is a water-soluble macromolecular of alpha-electrophoretic mobility. Apart from the absence of C9, it exhibits an identical SDS-gel electrophoresis polypeptide pattern as SC5b-9. A sedimentation coefficient of 19 to 20S and an effective molecular radius of approximately 10 nm were determined by sucrose density gradient centrifugation and gel filtration, respectively. From these values, a m.w. of 800 to 850,000 is tentatively assigned to the SC5b-8 complex. The S-protein was not dissociable from either SC5b-8 or SC5b-9 through treatment with desoxycholate and no alterations in the hydrodynamic properties of either complex were discernible after action of this detergent.

Alpha-Globulins↗
PubMedDate not supplied

Evidence suggesting the occurrence of C3-independent intravascular immune hemolysis. Reactive hemolysis in vivo.

The authors present circumstantial evidence for the involvement of reactive hemolysis, i.e., C3-independent binding of the cytolytic C5b-9 complement complex to bystander red cells (RBC), in a case of intravascular immune hemolysis. Fresh serum obtained from a 6-year-old patient during the hemolytic episode, but not obtained thereafter, induced C5b-9-dependent hemolysis of human RBCs but the indirect C3 antiglobulin test remained negative. Particles (presumably RBC ghosts) isolated from the patient's plasma anticoagulated with EDTA at the peak of hemolysis were coated with C5b-9 complexes, whereas the direct antiglobulin test was strongly positive for IgA, only weakly positive for IgG, and negative for C3. Moreover, neither the autoantibodies isolated by elution (IgG plus IgA), nor free serum autoantibodies (IgA alone) activated complement in vitro. Additionally, serum samples collected later during the 12-month period of observation contained normal levels of C3, C4, C8, and C9, but markedly reduced levels of C7. These serums all produced strong reactive lysis in agarose plates, but not in test tubes. These results appear compatible with the working hypothesis that the intravascular hemolytic episode in this patient might have arisen through a local initiation of complement activation with subsequent C3-independent binding of C5b-9 to and hemolysis of bystander RBCs.

Anemia, Hemolytic, Autoimmune↗
PubMed1974

Formation and biologic role of polyoma virus-antibody complexes. A critical role for complement.

Interaction of polyoma virus, specific antibody, and complement has been studied. Firm evidence has been gathered that C1 through C3 and not C5 through C9 enhance neutralization of virus-antiviral antibody (V-Ab) complexes. C enhancement of neutralization occurs primarily by agglutination of V-Ab complexes and not by virion lysis or attachment of large protein molecules to the V-Ab complex. In this model, binding of C1, 4, 2, 3 to the V-Ab complex may explain why some viruses concentrate in or infect certain cells bearing C3 receptors such as B lymphocytes, macrophages, and monocytes.

Animals↗
PubMed1985

High-density lipoprotein and its apolipoproteins inhibit cytolytic activity of complement. Studies on the nature of inhibitory moiety.

Human high-density lipoprotein (HDL) and its apolipoproteins A-I and A-II inhibit complement-mediated lysis of human and sheep erythrocytes. This inhibitory activity under study is exerted after C9 is bound to membrane-associated C5b-8 complexes but prior to completed assembly and insertion of the C5b-9 complex. In this paper, we define some structure-activity relationships of the inhibitory moiety. With the exception of weak lytic inhibitory activity found in LDL/VLDL pools and in some unconcentrated minor fractions of plasma obtained by hydrophobic chromatography, all inhibitor activity was found in fractions which contained either apolipoprotein A-I, apolipoprotein A-II, or both. Intact HDL has a high level of inhibitor activity but delipidation by chloroform-methanol extraction was associated with an increase in activity on a protein-weight basis. Purified apolipoprotein A-I and apolipoprotein A-II exhibited equal inhibitory activity, greater than that exhibited by intact HDL. Nevertheless, ultracentrifugal fractions in which no free apolipoproteins could be demonstrated still possessed inhibitory activity. These experiments suggest that delipidation of HDL is not necessary for expression of inhibitor activity, although we could not rule out the possibility that apolipoproteins in dynamic equilibrium with HDL are responsible for the inhibitor activity observed in whole serum and plasma and in HDL preparations. Limited proteinase digestion completely abolished the inhibitory activity of partially delipidated HDL. Phospholipase C had little or no effect on the inhibitory activity of delipidated HDL, apolipoprotein A-I or apolipoprotein A-II, but reduced the inhibitory activity of intact HDL. These data suggest that the phospholipid polar headgroups are not necessary for inhibitory activity. However, the loss of these headgroups is associated with decreased activity, possibly due to increased hydrophobicity of HDL, or increased association among HDL micelles, and subsequent decrease in effective molar concentration of the inhibitory moiety.

Apolipoprotein A-I↗
PubMed1985

The cobra complement system: II. The membrane attack complex.

Rabbit erythrocytes are lysed by cobra plasma. The membranes of the lysed rabbit erythrocytes exhibited typical ultrastructural complement lesions with an inner diameter of 72 A. Structures similar to human C5b-8 complexes were also visualized. The proteins found in membranes lysed by cobra plasma resembled closely the proteins of the human membrane attack complex in number and molecular weight. Cobra poly C9 that is resistant to reduction and boiling in SDS could also be demonstrated. These results indicate that the membrane attack complex of cobra complement is very similar to its mammalian counterpart.

Animals↗
PubMed1982

Behaviour of immune complexes and the complement system in normal pregnancy and pre-eclampsia.

A quantitative study of the circulating immune complexes (IC) was carried out on women during normal pregnancy (286) and the post-partum period (20) and women with pre-eclampsia (30). Furthermore, the behaviour of the complement (C) system was followed. Results showed that IC were low in the first trimester of normal pregnancy (25.3%) and decreased in the following trimesters, whereas they were always present in pre-eclampsia. A very significant difference (p less than 0.0001) was seen when we compared the incidence of IC in normal pregnancy at the third trimester and the pre-eclamptic patients. The follow-up study of the IC, carried out on 4 pre-eclamptic women, showed an increase in the IC levels associated with the exacerbation of the pre-eclamptic picture and a decrease after delivery. The study of complement in normal pregnancy showed a decrease in C1-INH, C1s and C1q, whereas C3, C5, C9 and the properdin factor B increased during the following weeks of gestation; CH50 did not vary excepting during the 1st trimester. In the puerperium all values increased. There was no significant difference between the serum levels of the C components in the 3rd trimester of normal pregnancy and pre-eclampsia. High levels of C3d were observed in normal pregnancy at the 3rd trimester and in pre-eclampsia. The study of this split product of C3 showed that there is activation of the C system, but, since the synthesis of the C components is increased, activation could be masked. Alloantibodies and circulating IC could be the factors responsible for this activation in normal pregnancy and in pre-eclampsia, respectively.

Adult↗
PubMed1984

Mechanism of complement cytolysis and the concept of channel-forming proteins.

Complement damages membranes via the terminal reaction sequence that leads to the formation of membrane-bound, macromolecular C5b-9(m) protein complexes. These complexes represent C5b-8 monomers to which varying numbers of C9 molecules can be bound. Complexes carrying high numbers of C9 (ca. 6/8-12/16?) exhibit the morphology of hollow protein channels. Because they are embedded within the lipid bilayer, aqueous transmembrane pores are generated that represent the primary lesions caused by complement in the target cell membrane. Many other proteins damage membranes by forming channels in a manner analogous to the C5b-9(m) complex. Two prototypes of bacterial exotoxins, Staphylococcus aureus alpha-toxin and streptolysin-O, are discussed in this context, and attention is drawn to the numerous analogies existing among these protein systems. Common to all is the process of self-association of the native proteins to form supramolecular complexes. This event is in turn accompanied by a unique transition of the molecules from a hydrophilic to an amphiphilic state.

Animals↗
PubMed1999

Up-regulated production and activation of the complement system in Alzheimer's disease brain.

We used reverse transcriptase-polymerase chain reaction and Western blotting techniques to measure the levels of complement mRNAs and their protein products in Alzheimer's disease (AD) brain compared with non-AD brain. mRNAs for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 were detected in the 11 regions of brain that were investigated. The mRNA levels were markedly up-regulated in affected areas of AD brain. In the entorhinal cortex, hippocampus, and midtemporal gyrus, which had dense accumulations of plaques and tangles, C1q mRNA was increased 11- to 80-fold over control levels, and C9 mRNA 10- to 27-fold. These levels were substantially higher than in the livers of the same cases. Western blot analysis of AD hippocampus established the presence of all of the native complement proteins as well as their activation products C4d, C3d, and the membrane attack complex. These data indicate that high levels of complement are being produced in affected areas of AD brain, that full activation of the classical complement pathway is continuously taking place, and that this activation may be contributing significantly to AD pathology.

Adult↗
PubMed1989

A third mechanism of serum resistance in Escherichia coli.

15 serum-resistant strains of E. coli group III characterized by binding of both C3 and factor H in the immunofluorescence test were studied in respect of the mechanism on which serum resistance is based in these strains. Serum resistance in 7 strains were found to be established by one of the mechanisms first described by Joiner et al. or by Kubens et al. The classification of these strains should therefore be altered. The binding and consumption of C5 as well as the binding of C9 was investigated for the remaining 8 strains. All strains were found to bind the two complement components which are part of the membrane attack complex (MAC) without causing cell death. These results suggest that resistance in strains of group III is based on a third mechanism which shows similarities to data obtained for other species but has not yet been described for E. coli.

Blood Bactericidal Activity↗
PubMed1994

[Mechanisms of the intractability of bacterial infections in immunodeficiency status in childhood].

Most of the primary immunodeficiency diseases develop in childhood. The patients with antibody deficiency are susceptible to pyogenic bacteria since antibody is essential to opsonize bacteria. T cell deficiency causes defect of cytokine production needed to activate macrophages to kill intracellular bacteria such as mycobacteria and leeds to intractable infection of such bacteria. Complement mediated bacteriolysis is important to protect neisseria such as meningococcus and deficiency of C5-C9 provides susceptibility to the bacteria. Defect of superoxide synthesis or adhesion of neutrophils is related to severe infection of pyogenic bacteria. On the way of development of immune system, children especially in early infancy display susceptibility to bacterial infections.

Age Factors↗