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PubMed1979

Complement in tears from normal humans.

Tears from ten normal persons were used in hemolytic assays to test for activity of total hemolytic complement (tested in all ten subjects), activities of each of the nine complement components (tested in two subjects), and activity of the alternate pathway (tested in two subjects). A modified radial-immunodiffusion method was used to confirm the presence of C3 and C4 complement proteins in the tear samples from all ten subjects. Factor B protein was detected in tears from two of four normal subjects tested. In dilutions up to 1:4, hemolytic activity was observed in tears from five of the ten subjects. Samples from the remaining five subjects had CH50 activity at dilutions up to 1:2. In control tests, human serum had CH50 activity at 1:32. No lysis occurred in Veronal-buffered saline or in serum and tears heated to 56 degrees C for 30 minutes. Complement proteins C3 through C9 displayed hemolytic activity in tears from each of two subjects tested for complement components. The classic and alternate complement pathways in tears can be included among the defense mechanisms of the ocular surfaces.

Complement C3↗
PubMed1995

Complement component C7 is a plasminogen-binding protein.

Ab deposition, whether by reaction with the specific Ag or by preformed immune complexes, is followed by activation and deposition of complement components. Tissue destruction is observed in the Ab- and complement-induced lesions. The proteolytic enzyme plasmin is thought to participate in the Ab- and complement-mediated organ pathology. Plasmin is generated from plasma-derived plasminogen by cell-derived plasminogen activators (PAs). Two types of PAs are known, urokinase-type PA (uPA) and tissue-type PA (tPA). We investigated whether the PA system and the complement system can interact to promote local plasmin generation. Among the terminal complement components C5b6, C7, C8, and C9, the nonenzymatic component C7 is a plasminogen-binding protein. Radioligand binding studies revealed that the isolated component, as well as C7 after its incorporation into the terminal complement complex C5b-9, can bind plasminogen. Binding was inhibited by the lysine analogues 6-aminohexanoic acid and tranexamic acid, implicating the lysine binding sites of plasminogen into the binding interaction. tPA-mediated plasminogen activation was enhanced in the presence of C7. Based on these findings, an interaction is proposed between the complement system and the plasminogen activator system; a mechanism that may focus plasmin activity to structures that have been tagged by Ab and complement deposition.

Autoradiography↗
PubMed2000

Free radicals upregulate complement expression in rabbit isolated heart.

Both free radicals and complement activation can injure tissue. Our study determined whether free radicals alter complement production by the myocardium. Isolated hearts from New Zealand White rabbits were perfused on a Langendorff apparatus and exposed to xanthine (X; 100 microM) plus xanthine oxidase (XO; 8 mU/ml) (X/XO). The free radical-generating system significantly (P < 0.05) increased C1q and also increased C1r, C3, C8, and C9 transcription compared with controls. Immunohistological examination revealed augmented membrane attack complex deposition on X/XO-treated tissue. X/XO-treated hearts also exhibited significant (P < 0.05) increases in coronary perfusion pressure and left ventricular end-diastolic pressure and a decrease in left-ventricular developed pressure. N-(2-mercaptopropionyl)-glycine (3 mM), in conjunction with the superoxide dismutase mimetic SC-52608 (100 microM), significantly (P < 0.05) reduced the upregulation of C1q, C1r, C3, C8, and C9 mRNA expression elicited by X/XO. The antioxidants also ameliorated the deterioration in function caused by X/XO. Local complement activation may represent a mechanism by which free radicals mediate tissue injury.

Animals↗
PubMed1972

Mechanism of cytolysis by complement.

The attack of complement is directed against the lipid moiety of the cell membrane; a single lesion at the site of fixation of complement proteins C5-C9 is responsible for lysis of a cell. There are two hypothetical models for the generation of this membrane lesion. The first of these, designated the leaky-patch model, postulates either direct enzymatic attack or enzymatic generation of a lytic substance by C5-C9. As a result, the phospholipid bilayer of the membrane would be disrupted and a leaky patch permitting passage of water and salt would appear. However, this hole would persist only as long as enzymatic action continues. Thus, the leaky-patch model would not produce a stable hole, and for this reason it is considered an unlikely mechanism. The second hypothesis, termed the doughnut model, describes a structural concept for creating a hydrophilic passage through the hydrophobic phospholipid bilayer of the membrane. In essence, this would be a rigid and hollow structure, like a doughnut, with a hydrophobic exterior, which is inserted into the phospholipid bilayer of the cell membrane in such a way that its hollow hydrophilic core becomes a channel through which salt and water can exchange freely between the interior of the cell and the extracellular environment. The late-acting complement proteins C5-C9 are the most probable source of the structural components of the doughnut. A combination of the leaky-patch and doughnut models may represent the most likely mechanism.

Cell Membrane↗
PubMed1990

Influence of subinhibitory concentrations of cephalosporins on the serum sensitivity of Pseudomonas aeruginosa.

The effect of sublethal concentrations of antibiotics on the serum sensitivity of Pseudomonas aeruginosa was examined. Cefepime, ceftazidime, and imipenem but not amikacin nor ciprofloxacin increased the serum bactericidal activity of pooled normal human serum. Killing was both serum- and antibiotic dose-dependent. Increased sensitivity to the bactericidal action of serum in the presence of cefepime was observed for several different clinical isolates. With the use of C8-deficient sera, the late components of the complement pathway were shown to be essential for bacterial killing. A significant increase in the amount of [125I]C9 based on bacterial mass was observed with bacteria incubated with cefepime compared with non-antibiotic- or amikacin-treated controls. No major change in the amount of type of lipopolysaccharide was observed when cefepime-treated and control bacteria were compared. The data show that cefepime and other cephalosporins at sublethal concentrations increase the complement-mediated bactericidal activity of serum against P. aeruginosa.

Amikacin↗
PubMed1981

The membrane attack mechanism of complement: photolabeling reveals insertion of terminal proteins into target membrane.

We have utilized a membrane-restricted, photoactivable glycolipid probe to investigate the protein-lipid interactions involved in complement (C) mediated lysis of a target membrane. The purified C proteins C5b-6, C7, C8, and C9 were added to artificial membrane vesicles containing the 14C-labeled photoreactive probe anchored in the outer monolayer of the membrane, and 6-carboxyfluorescein trapped in the lumen as an indicator for effective lysis. Irradiation of the membrane samples at different stages of functional complex assembly resulted in labeling of each of the 5 terminal C proteins, indicating that all 5 proteins become inserted into the hydrophobic milieu of the membrane during some stage of complex assembly. However, at the final stage of complex assembly, only C9 appeared to be labeled. Because we can demonstrate that the photoreactive probe has no strong affinity for C9 over the other terminal components (C5b-C8), the extensive change in labeling specificity during assembly is evidence for substantial changes in protein-lipid and possibly protein-protein interactions during formation of the C lesion.

Cell Membrane↗
PubMed1993

Complement component C5 modulates the systemic tumor necrosis factor response in murine endotoxic shock.

Patients with disseminated Neisseria meningitidis infections (meningococcemia) suffer from a fulminant shock syndrome that is accompanied by extraordinarily high concentrations in serum of tumor necrosis factor (TNF). People with homozygous deficiencies of late complement components (C5, C6, C7, and C8) experience a high incidence of disseminated neisserial infections yet suffer from an attenuated form of the disease. The mechanisms that account for this disparity in host response are unclear, but they may in part be related to differences in the systemic TNF response that are modulated by terminal complement components (C5 to C9). The role of C5 in the modulation of the systemic endotoxin-induced TNF response was studied with matched strains of C5-deficient (B10 D2/Osn) and complement-sufficient (B10 D2/Nsn) mice. Following lipopolysaccharide (LPS) administration, complement-sufficient mice exhibited more rapid increases in pulmonary and hepatic vascular permeabilities than did C5-deficient controls. Complement-sufficient mice developed acute passive hepatic congestion, they appeared more ill than C5-deficient mice, and they exhibited a twofold greater rise in serum TNF activity compared with that by C5-deficient mice. C5-deficient mice reconstituted with normal serum before an LPS injection exhibited pulmonary and hepatic vascular permeability increases and serum TNF levels approaching those observed in complement-sufficient mice. Alveolar and peritoneal macrophages isolated from complement-sufficient and C5-deficient mice and incubated in heat-inactivated serum did not exhibit differences in TNF mRNA expression or secreted TNF activity following stimulation with LPS. However, incubation of macrophages in complement-sufficient mouse serum (before LPS stimulation) resulted in increased TNF mRNA expression and TNF activity compared with those in cells incubated in C5-deficient serum. In vitro studies employing human complement components and peripheral blood monocytes revealed that recombinant C5a, in the presence or absence of LPS, can induce increased concentrations of TNF and that C5b to C9 had no additional modulatory effect on the TNF response. These data suggest that C5 modulates the endotoxin-triggered TNF response. The role of complement components distal to C5 (i.e., C5b to C9) in the endotoxin-triggered TNF response remains unclear.

Animals↗
PubMed1997

Acquired C3 deficiency in patients with alcoholic cirrhosis predisposes to infection and increased mortality.

BACKGROUND: Acquired deficiencies of certain complement proteins and impaired opsonisation activity have been implicated in the pathogenesis of the increased susceptibility to infections of patients with alcoholic cirrhosis. METHODS: Serum concentrations of C3 and C4, plasma concentrations of C3bc, C9, and the terminal C5b-9 complement complex (TCC), and haemolytic complement activity (classic and alternative pathway) of serum, and serum opsonic activity were determined in 46 patients with compensated alcoholic cirrhosis, 31 who were decompensated, and in 15 healthy subjects. After 19 months (median) the investigated variables were analysed for their use in prognosis of recurrent infections and survival. RESULTS: C3 and C4 concentrations and the haemolytic complement activity of the alternative pathway were decreased in decompensated cirrhotic patients compared with controls (p < 0.01). Univariate analysis (log rank test) showed that low concentrations (< or = lower quartile) of C3 (p < 0.001) and C3bc (p < 0.05), haemolytic complement activity of the alternative pathway (p < 0.01) and classic pathway (p < 0.05), and decompensated cirrhosis (p < 0.001) were associated with an increased risk of infection and increased mortality. Multivariate (Cox) analysis showed that low C3 concentrations and decompensation of cirrhosis were significant predictors of infections and mortality (p < 0.02). CONCLUSIONS: Low serum C3 concentrations and decreased haemolytic complement function predisposes to infection and increased mortality in patients with alcoholic cirrhosis.

Adult↗
PubMed1988

Synthesis of soluble C3 and C9 neoepitopes by human alveolar macrophages in vitro.

The aim of this study was to examine whether soluble neoepitopes of activated C3 (C3b, iC3b, C3c) and C9 are produced by human alveolar macrophages cultured in serum-free medium. There was a significant and inhibitable production of C3 and C9 neoepitopes and C9 by the macrophages from all donors, as detected by enzyme-linked immunosorbent assays based on monoclonal (bH6, aE11) and polyclonal (anti-C9) antibodies. A strong donor-dependent variation in the levels of the C3 neoepitope and C9 (five- to sevenfold) and the C9 neoepitope (twofold) was found. After 1 day (24 h) of incubation, the complement levels were largely unaltered. The presence of an exogenous alternative pathway activator (agarose beads) reduced the amount of soluble complement because of binding to the agarose. However, the relative fraction of C9 neoepitope versus C9 increased (two- to threefold), due to agarose-mediated activation of C9. The results demonstrate activation of the complement system in serum-free alveolar macrophage cultures, irrespective of the presence of a known complement activator.

Antibodies, Monoclonal↗
PubMedDate not supplied

Macrophage toxicity and complement sensitivity of virulent and avirulent strains of Legionella pneumophila.

Virulent strains of Legionella pneumophila that are preincubated with specific antiserum are cytotoxic for alveolar macrophages when added at a multiplicity of infection of 100 L. pneumophila per macrophage. Under the same conditions, avirulent strains exhibit little cytotoxic activity. Virulent strains are also resistant to the bactericidal activity of normal human serum and fail to bind complement components on the cell surface. In contrast, avirulent strains are serum-sensitive and both C3 and C9 are deposited on the surface. Results of experiments suggest that the shift from virulence to avirulence of L. pneumophila may be the result of the selection of a small number of avirulent cells present in the population of a virulent culture.

Animals↗
PubMed1979

Evidence for a two-domain structure of the terminal membrane C5b-9 complex of human complement.

Lipid vesicles carrying the purified membrane C5b-9 complex [C5b-9(m)] of complement were analyzed immunochemically and in the electron microscope after treatment with a combination of trypsin and alpha-chymotrypsin. Under reducing conditions, the externally oriented annulus was removed. The remaining part of the C5b-9(m), representing approximately half of the total mass of the macromolecular complex, was visualized in the electron microscope as a hollow cylindrical structure with walls of 1-nm thickness. This structure remained tenaciously attached to the lipid bilayer, projecting 8-9 nm from the external membrane surface into the aqueous environment. Cleavage of C5b-9(m) by proteolysis and reduction resulted in a sharp reduction of tis antigenic determinants. One hydrophilic protease-resistant C5 derivative was released from the membrane and recovered in the fluid phase. The membrane-bound residue almost totally lacked antigens precipitable with antisera to C5, C6, C9, and C5b-9(m).

Complement C5↗
PubMed1978

Electron spin resonance studies on interaction of complement proteins with erythrocyte membranes.

Sheep erythrocytes have been spin labeled with 5-, 12-, and 16-nitroxystearic acid in order to investigate complement-induced changes in the physical state of the lipid bilayer. Formation of osmotic lesions in the membrane causes an increase in the fluidity of the membrane which overcomes the decrease in membrane fluidity caused by the interaction of the complement proteins. A decrease in membrane fluidity is observed only when complement-lysed membranes are resealed or when complement proteins react with isosmolar ghosts that do not undergo osmotic lysis. The decrease in bulk fluidity of the membrane is first observed when C8 binds to the membranes bearing C5b67 and is enhanced upon the subsequent binding of C9. The decrease in membrane fluidity shown by the electron spin resonance spectra of spin-labeled fatty acids suggests that certain of the complement proteins penetrate the membrane and interact with hydrophobic regions of the lipid bilayer.

Animals↗
PubMed1979

Studies on the terminal stages of immune hemolysis. V. Evidence that not all complement-produced transmembrane channels are equal.

The inhibitory effects of 0.1 M EDTA on the lysis of E prepared by incubating EA with whole GPC was studied. At high end point lysis (greater than 70%) 0.1 M EDTA failed to prevent hemoglobin release whereas at lower end point (less than 60%) 0.1 M EDTA was effective. In all cases hemoglobin release was inhibited by 25% BSA. When E were prepared by incubating EAC1-8 with C9, similar results were obtained. In this system the difference in the ability of 0.1 M EDTA to inhibit hemoglobin release at high or low end point lysis could not be correlated with the low end point lysis could not be correlated with the number of lesions/cell but appeared to be related to the C9 to SAC1-8 ratio. With limiting SAC1-8 and excess C9, E were produced from which hemoglobin release could not be prevented by 0.1 M EDTA whereas at lower C9 to SAC1-8 ratios hemoglobin release was prevented by 0.1 M EDTA. These differences most probably reflect functionally different sized transmembrane channels that were produced at different C9 to SAC1-8 ratios.

Albumins↗
PubMed1986

Complement activation in vitro by antiplatelet antibodies in chronic immune thrombocytopenic purpura.

Many chronic ITP patients have increased amounts of platelet-associated IgG, C3, C4 and C9, suggesting in vivo complement activation. In this study, we assessed the ability of various antiplatelet antibodies (APA) to activate and deposit complement proteins and to cause platelet lysis in vitro. Platelet sensitization with rabbit APA, anti-P1A1 antibody (one patient), anti-HLA antibody (two patients) and ITP autoantibodies (four patients) resulted in the deposition of C4 and C3 onto platelets in an amount proportional to the quantity of antibody-containing sera used to sensitize the platelets. Although C9 deposition onto platelets could not be quantitatively demonstrated on platelets sensitized with ITP serum, platelet lysis (51Cr release) was noted after incubation with each of three ITP sera and complement. When compared, ITP autoantibodies, anti-HLA and anti-P1A1 antibodies activated complement to a similar degree. We conclude that some autoantibodies in chronic ITP activate the classical complement pathway. The demonstration of in vitro platelet lysis by autoantibodies and complement suggests that in vivo platelet lysis may occur in some chronic ITP patients.

Autoantibodies↗
PubMed1995

Determination of the active site of CD59 with synthetic peptides.

CD59 inhibits the formation of membrane attack complex (MAC) of human complement by binding to C8 and C9 in the nascent membrane attack complex and inhibiting C9 binding to C8 in C5b-8 and C9 polymerization. Considering five disulfide bridges of CD59, we divided the molecule into two portions and synthesized the two peptides. One represented an amino-terminal half, P1-41, consisting of residues 1-41, while another represented a carboxyl-terminal half, P42-77, consisting of residues 42-77. P1-41 inhibited the MAC formation much more strongly than P42-77, indicating that the amino-terminal half contained the active site. We further synthesized P4-18 that consisted of residues 4-18 and P19-41 that consisted of residues 19-41. The activity of P4-18 was less than that of P19-41. Surprisingly, P19-41 showed higher activity than P1-41 and was comparable to urine CD59. Residues 19-41 were further divided into two portions: P20-25 which consisted of residues 20-25 and P27-38 which consisted of residues 27-38. Although their activities were significantly less than the activity of P19-41, P27-38 showed higher activity than P20-25. Residues 27-38 were further divided into three portions: P27-32 which consisted of residues 27-32, P30-34 which consisted of residues 30-34 and P33-38 which consisted of residues 33-38. When these peptides were assayed for the activities, all of them showed significant activities, even though they needed 10-fold more concentrations than P19-41. These data suggest that the portion made up of residues 27-38 is the active site constituting the binding site to C8 and C9.

Amino Acid Sequence↗
PubMed1996

Purification and characterization of the eighth and ninth components of carp complement.

Complement components corresponding to mammalian C8 and C9 were isolated from carp (Cyprinus carpio) serum. Carp C8 (M(r) 146,000) proved to be a gamma-globulin composed of three polypeptide chains (alpha-chain, M(r) 62,000; beta-chain, M(r) 62,000; gamma-chain, M(r) 22,000). The alpha-chain was disulfide-linked to the gamma-chain and the beta-chain was non-covalently associated with the alpha-gamma chain, in fair agreement with mammalian C8. However, the N-terminal amino acid sequences of the three subunits showed no homology with those of human C8. Carp C9 was an alpha-globulin composed of a single polypeptide (M(r) 91,000) and the N-terminus was blocked. Carp serum depleted of C8 did not hemolyse either carp antibody-sensitized sheep erythrocytes or non-sensitized rabbit erythrocytes, while C9-depleted carp serum did not hemolyse the former, but did hemolyse the latter target cells, as in the case of C9-depleted human serum.

Animals↗
PubMed1984

Schistosoma mansoni: escape from complement-mediated parasiticidal mechanisms following percutaneous primary infection.

Schistosomula were recovered from the skin of mice following primary infections. On the surface of such "infecting schistosomula", mouse C3 could not be detected by immunofluorescence. Subsequent incubation in vitro with fresh mouse serum led to the effective deposition of mouse C3 on schistosomula only when they were recovered within a few hours but not after one or two days following infection. In vitro deposited murine C3c was lost from i.v. injected schistosomula in the mouse circulation within one day as was human C3c. Infecting schistosomula exhibited a close to complete resistance to the lytic in vitro activity of human complement. This resistance was complete in older parasites. It existed in spite of the presence of parasite-bound human C9, which was detectable on all developmental stages of schistosomes following incubation in fresh, but not inactivated human serum. Lung schistosomula, 3-week and 6-week-old schistosomes were resistant to cellular cytotoxicity upon incubation with fresh human serum and rat peritoneal exudate cells although cell adherence mediated by human C3b was demonstrated with lung worms. The data suggest that schistosomula may evade in vivo the lytic activity of complement and also complement-mediated cellular cytotoxicity. Depending on the species of serum, this can be demonstrated in vitro by lack of opsonization or by resistance to lytic and cellular attack mechanisms.

Animals↗
PubMed1992

Differences of two Borrelia burgdorferi strains in complement activation and serum resistance.

Complement activation and serum resistance of the Borrelia burgdorferi strains B31 (American strain) and PKo (European strain) were compared. In 25% (v/v) normal human serum (NHS) free of B. burgdorferi-specific antibodies the cells of the PKo strain were high activators of complement as indicated by rapid and strong C9 consumption, by deposition of up to 336763 C9 molecules per cell and by the formation of the terminal complement complex on the cell surface. By comparison, complement activation by the B31 strain was low with 5.4-fold less C9 deposited per cell. The addition of B. burgdorferi-specific antibodies to NHS either as purified IgG or heat-inactivated patient sera, had no influence on the results with both strains. After an incubation period of 2h at 37 degrees C in 25% (v/v) NHS most cells of the PKo strain had lost their viability as indicated by cell immobilization and failure to multiply in subcultures. In addition, extensive cell fragmentation and bleb formation were observed in the electron microscope. In contrast, the B31 strain remained alive and morphologically intact after the same incubation with NHS. We conclude from our results that complement activation and serum resistance are properties which differ considerably between isolated strains of B. burgdorferi.

Antibodies, Bacterial↗