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PubMed2002

Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells.

C4b and C3b deposited on host cells undergo limited proteolytic cleavage by regulatory proteins. Membrane cofactor protein (MCP; CD46), factor H, and C4b binding protein mediate this reaction, known as cofactor activity, that also requires the plasma serine protease factor I. To explore the roles of the fluid phase regulators vs those expressed on host cells, a model system was used examining complement fragments deposited on cells transfected with human MCP as assessed by FACS and Western blotting. Following incubation with Ab and complement on MCP(+) cells, C4b was progressively cleaved over the first hour to C4d and C4c. There was no detectable cleavage of C4b on MCP(-) cells, indicating that MCP (and not C4BP in the serum) primarily mediates this cofactor activity. C3b deposition was not blocked on MCP(+) cells because classical pathway activation occurred before substantial C4b cleavage. Cleavage, though, of deposited C3b was rapid (<5 min) and iC3b was the dominant fragment on MCP(-) and MCP(+) cells. Studies using a function-blocking mAb further established factor H as the responsible cofactor. If the level of Ab sensitization was reduced 8-fold or if Mg(2+)-EGTA was used to block the classical pathway, MCP efficiently inhibited C3b deposition mediated by the alternative pathway. Thus, for the classical pathway, MCP is the cofactor for C4b cleavage and factor H for C3b cleavage. However, if the alternative pathway mediates C3b deposition, then MCP's cofactor activity is sufficient to restrict complement activation.

Animals↗
PubMed1985

In vivo modulation of rat complement activities by infusion of anti-H antibodies.

Regulation of the activity of the alternative pathway of complement occurs by the plasma proteins I and H. H is able not only to prevent formation of the amplification convertase C3bBb but also to cause the decay-dissociation of Bb from C3bBb. The present studies have investigated the role of H in vivo. Affinity-purified goat (Fab')2-anti H was infused intravenously in rats, and its effect on C4, C3 and CH50 activities was assessed. In addition, H, C3, C4 and B were quantitated by immunochemical methods. H depletion was dependent on the dose of anti-H, and maximal consumption in vivo occurred between 5 and 15 min. A maximum of 51% and 77% hemolytic C3-consumption was seen after 15 min with 3.8 and 8.4 mg anti-H, respectively. The injection of 6.3 mg affinity-purified goat IgG anti-rat H caused 96.8 +/- 0.7% and 85.0 +/- 1.4% consumption of CH50 and C3 hemolytic activity, respectively. Using this dose of IgG anti-rat H, it was found that the clearance in rats of rat erythrocytes sensitized with 8000 molecules of guinea pig IgG2 per E was impaired as compared to the clearance of these intermediates in control rats injected with a comparable dose of normal goat IgG. The results indicate that H functions as a potent regulator of C in vivo and that infusion of anti-H can be used as a method to achieve depletion of circulating complement components.

Animals↗
PubMed1989

Effect of decay-accelerating factor on the assembly of the classical and alternative pathway C3 convertases in the presence of C4 or C3 nephritic factor.

Decay-accelerating factor (DAF) is a 70,000 MW membrane protein that regulates the complement system on the cell surface. In the present study, we found that DAF had no effect on the classical pathway C3 and C5 convertases that had been stabilized by C4 nephritic factor (C4NeF). In DAF-incorporated cells, however, the assembly of the classical pathway C3 convertase was markedly inhibited even in the presence of C4NeF. C3 nephritic factor (C3NeF) in the alternative pathway protected the C3 convertase from the action of DAF to some extent, while the generation of C3 convertase was also inhibited by DAF. These results indicate that under physiological conditions, DAF functions to inhibit the assembly of C3 convertases even in the presence of nephritic factors, although it has no or little effect on the stabilized convertases. Thus, it is likely that DAF plays an important role in protection of host cells from damage by autologous complement in patients with nephritic factors.

Autoantibodies↗
PubMed1998

Binding of properdin to solid-phase immune complexes: critical role of the classical activation pathway of complement.

The capacity of serum to support deposition of C3, properdin and factor B was studied by enzyme-linked immunosorbent assay using solid-phase immune complexes (IC) for activation of complement. Deposition of C3 and properdin occurred in fairly dilute normal human serum (NHS), but factor B uptake was hardly detectable. Alternative pathway-mediated deposition of C3 with slow kinetics was demonstrated in C2-deficient serum and in NHS depleted of C1q, factor D and properdin (C1qDP-depleted serum) after reconstitution with factor D and properdin. Efficient uptake of properdin required a functional classical pathway, in the presence of which C3 and properdin were rapidly deposited onto the IC. Judging from findings in C3-deficient serum, factor I-deficient serum, and C1qDPB-depleted serum, the uptake of properdin was strictly C3-dependent, and did not require the presence of factors B and D. Thus, C3b fixed to IC was the principal ligand for properdin in the assay. The findings could have biological implications relating to complement-mediated modification of immune complexes in disease.

Antigen-Antibody Complex↗
PubMed1985

The killer molecule of complement.

Cell injury by complement occurs as a consequence of activation of either the classical or the alternative pathway on the surface of a cell. It is accomplished by the membrane attack complex (MAC). Its precursor proteins, C5, C6, C7, C8, and C9, are hydrophilic glycoproteins with Mr ranging from 70,000-180,000. When C5 is cleaved by the serine protease C5 convertase which covalently attaches to target cells, nascent C5b is produced and forms together with C6 a soluble and stable bimolecular complex (C5b,6). Upon binding of C5b,6 to C7 a trimolecular complex (C5b-7) is formed which expresses a metastable membrane-binding site. Membrane-bound C5b-7 constitutes the receptor for C8 and the tetramolecular C5b-8 complex binds and polymerizes C9. During the assembly process the proteins undergo hydrophilic-amphiphilic transition and the end product consists of C5b-8 (Mr approximately 550,000) and of tubular poly C9 (Mr approximately 1,100,000). The functional channel size varies but its maximal diameter is approximately 100 A. C9 polymerization appears to involve initial reversible association of several C9 molecules which is followed by temperature-dependent, constrained unfolding. Unfolded C9 monomers then associate laterally with each other and polymerization terminates with closure of the circular structure which consists of 12-18 C9 monomers. Amino acid composition and sequence indicate that the N-terminal half of the single chain C9 molecule is hydrophilic and the C-terminal half rather hydrophobic. Phospholipid-binding and insertion into membranes are functions of the C-terminal portion of the molecule. Control of the MAC is exerted by the S-protein (Mr 80,000) which binds to the forming complex and prevents its attachment to the cell membrane. Control is also exerted by certain species-specific membrane proteins which interfere with C5 convertase and C9 function.

Binding Sites↗
PubMed1992

Limited tryptic cleavage of complement factor H abrogates recognition of sialic acid-containing surfaces by the alternative pathway of complement.

The potency of complement factor H (H) in accelerating the decay of the alternative pathway C3 convertase, C3b,Bb (decay-accelerating activity), was used as a measure of the affinity of native versus trypsin-treated H for the complement protein C3b bound to surfaces. When about 99% of H was cleaved at the primary tryptic cleavage site 34 kDa from the N-terminus, its decay-accelerating activity on C3b,Bb on sheep erythrocytes fell about 60-fold, whereas the trypsin-treated H was only 3-4 times less potent than native H in dissociating C3b,Bb on Sepharose 4B. The residual decay-accelerating activity, remaining after the primary cleavage, was not affected by secondary cleavage at a site 120 kDa from the N-terminus, as shown with H preparations cleaved to different degrees. Because cell surface sialic acid is known to be responsible for the high affinity of H for C3b bound on sheep erythrocytes, the results strongly suggest that the integrity of the primary tryptic cleavage site of H is essential for the recognition of sialic acid-containing surfaces by the C3b-H complex.

Animals↗
PubMed1980

The effect of cobra venom factor on alternative pathway hemolytic activity in mice.

The in vivo effect of cobra venom factor (CVF) on murine alternative complement pathway hemolytic activity was measured with a recently developed microassay. Four different dosage schedules of CVF were compared. Hemolytic titers were lowered to less than 5% of the baseline value by 6 hours after the first dose of CVF (62.5 - 200 U/kg), and remained low for 3-5 days, depending upon total dose, route and schedule of CVF administration. Titers at days 6-9 after initial CVF injection increased above baseline in animals given two doses of CVF separated by 48 hours.

Animals↗
PubMed2006

Anisakis simplex: the activity of larval products on the complement system.

The effects of the larval products (crude extract and excretory-secretory) of Anisakis simplex on the classical and alternative pathways of human complement system were investigated. This could constitute a mechanism to evade host defences, similarly than in other parasitic diseases. The larval products showed a stronger effect on the classical pathway than on the alternative pathway. The most pronounced modulating effects were found for the excretory-secretory products. Chelation of bivalent cations (Ca(2+) or Mg(2+)) by these larval products may be responsible for their mode of action on the alternative pathway, whereas the chelation is not likely to be particularly involved in the anticomplementary activity found on the classical pathway. Detailed studies revealed that the larval products of A. simplex act at the level of the C3 and other complement components. Heating the crude parasite extract led to a notable loss of haemolysis inhibition activity, and the addition of PMSF (a serine protease inhibitor) also cause variation in the activity of the crude extract.

Animals↗
PubMed1988

Binding of C3 molecules to membranes via the SH-residue generated by the cleavage of a thioester bond can initiate complement activation.

Dithiopyridine (DTP)-dipalmitoylphosphatidylethanolamine (DTP-DPPE) was incorporated into liposome membranes to prepare DTP-liposomes. The DTP-liposomes could be lysed by reaction with the alternative complement pathway of any kind of serum tested. Activation of the alternative complement pathway has been shown to be mediated by the binding of C3 molecules to DTP on the liposomes via the SH-residue generated by the cleavage of thioester bond in the alpha-chain of the molecules.

Animals↗
PubMed1997

Effect of body weight and caloric restriction on serum complement proteins, including Factor D/adipsin: studies in anorexia nervosa and obesity.

Complement plays important roles in host immune defences, and recent studies suggest that adipose tissue is an important site of production for some complement proteins. Starvation has been associated with low complement levels, but studied populations have usually had concomitant opportunistic infections or other conditions which might affect complement levels. To determine the impact of body weight and changes in body weight on serum complement, we investigated levels of complement proteins in otherwise healthy patients with a wide range of body weights, including patients with anorexia nervosa before and after treatment, obese dieters before and after weight loss, and normal weight controls. We found that complement proteins of the alternative pathway (C3, B, and D), alternative pathway haemolytic activity (AP50) and the inhibitors H and I were low in starving anorectics and normalized with weight gain. C3a levels were comparable in anorectics at low weight and after weight gain, indicating that low serum complement levels were attributable to hypoproduction and not complement cascade activation with consumption. Further, levels of C3, B, AP50, H and I, but not D, were higher than controls in obese patients and decreased toward normal after weight loss. Overall, percentage of ideal body weight, changes in body weight, and serum transferrin were each highly correlated with serum levels of complement proteins. We conclude that levels of alternative pathway complement components are determined in part by factors that influence body weight and by weight changes, possibly due to changes in production in adipose tissue or at other sites.

Adult↗
PubMed1985

Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3.

The human end-stage kidney and its experimental analogue, the remnant kidney in the rat, exhibit widespread tubulo-interstitial disease. We investigated whether the pathogenesis of such tubulo-interstitial injury is dependent upon adaptive changes in tubular function and, in particular, in ammonia production when renal mass is reduced. Dietary acid load was reduced in 1 3/4-nephrectomized rats by dietary supplementation with sodium bicarbonate (NaHCO3), while control rats, paired for serum creatinine after 1 3/4 nephrectomy, were supplemented with equimolar sodium chloride. After 4-6 wk, NaHCO3-supplemented rats demonstrated less impairment of tubular function as measured by urinary excretory rates for total protein and low molecular weight protein and higher transport maximum for para-aminohippurate per unit glomerular filtration rate, less histologic evidence of tubulo-interstitial damage, less deposition of complement components C3 and C5b-9, and a lower renal vein total ammonia concentration. Such differences in tubular function could not be accounted for simply on the basis of systemic alkalinization, and differences in tubular injury could not be ascribed to differences in glomerular function. Because nitrogen nucleophiles such as ammonia react with C3 to form a convertase for the alternative complement pathway, and because increased tissue levels of ammonia are associated with increased tubulo-interstitial injury, we propose that augmented intrarenal levels of ammonia are injurious because of activation of the alternative complement pathway. Chemotactic and cytolytic complement components are thereby generated, leading to tubulo-interstitial inflammation. Thus, alkali supplementation reduces chronic tubulo-interstitial disease in the remnant kidney of the rat, and we propose that this results, at least in part, from reduction in cortical ammonia and its interaction with the alternative complement pathway.

Acid-Base Equilibrium↗
PubMed1982

Serum-induced lysis of Pseudomonas aeruginosa.

The sensitivity of 12 Pseudomonas aeruginosa strains (5 mucoid and 7 non-mucoid strains) to serum and the interaction of these strains with the complement system was studied. Five strains (4 mucoid and 1 non-mucoid strains) were lysed in 20% normal serum as measured by the release of radiolabelled material from 3H-adenine labelled bacteria. Three of these strains were also lysed in MgEGTA chelated serum. All strains activated complement via the classical pathway, and six strains were able to activate the alternative complement pathway as well. Slime production did not interfere with bacteriolysis and complement consumption.

Bacteriolysis↗
PubMed1982

Chemotactic efficiency of various chemoattractants for polymorphonuclear leukocytes in inflammatory acne vulgaris.

The chemoattractant efficiencies of a Propionibacterium acnes (P. acnes) cell wall preparation, a P. acnes culture supernatant, and a soluble comedonal extract in the presence and absence of autologous serum for polymorphonuclear leukocytes (PMNs) have been compared in the present study. It has been found that all three preparations have no or very little chemotactic activity for PMNs in the absence of serum. In the presence of autologous serum chemotactic factors is generated by all preparations via the alternative complement pathway. The relative efficiencies of the various preparations to induce chemotactic factor by the alternate complement pathway has been evaluated. Based on the bacterial numbers of the original preparations from which the test preparations had been derived the comedonal extract appears to be more efficient in generating chemotactic factor than the other preparations. It is concluded that in vivo generation of chemotactic factors occurs mainly via the alternate complement pathway activated by soluble comedonal factors diffusing through the follicular wall.

Acne Vulgaris↗
PubMed1987

Inhibitory effects of FUT-175, a new synthetic protease inhibitor, on intravascular hemolysis by human serum in mice.

Effects of FUT-175, a new protease inhibitor, on intravascular hemolysis of mouse erythrocytes caused by intravenous injection of human serum was studied in mice. In in vitro experiments, unsensitized erythrocytes obtained from various species of animals were lysed with sera in EGTA-GVB-Mg++. After heat inactivation of sera at 50 degrees C for 30 min, hemolysis in EGTA-GVB-Mg++ was abolished, indicating loss of activity of the alternative complement pathway. FUT-175 inhibited the alternative complement pathway-mediated hemolysis with IC50 values of 1.3 X 10(-7) to 4.0 X 10(-7) M. Intravenous injection of human serum caused intravascular hemolysis of mouse erythrocytes in mice. No remarkable change was observed in the mice that were injected with heat-inactivated (56 degrees C, 30 min) human serum. Intravenous administration of FUT-175 at a dose of 3 or 10 mg/kg inhibited intravascular hemolysis of mouse erythrocytes regardless of whether it was administered before or after injection of human serum. These results indicated that FUT-175 prevents intravascular hemolysis of mouse erythrocytes through the inhibitory effect of both alternative and classical complement pathway.

Animals↗
PubMed1982

Effects of decomplementation on mercuric chloride-induced glomerulonephritis in Brown-Norway rats.

The course of mercuric chloride-induced immune glomerulonephritis is characterized by complement activation, intensive proteinuria, linear and then granular IgG and C3 deposits in the glomeruli. To assess the role of complement activation in the occurrence of the disease, decomplementation was achieved by intravenous injections of cobra venom factor in rats injected with mercuric chloride. In these animals, proteinuria still appeared while rats were decomplemented by cobra venom factor through the alternative pathway. These rats exhibited linear IgG deposits without detectable C3 deposits. In the rats injected with cobra venom factor alone, no proteinuria, no classical pathway complement activation and no renal IgG or C3 deposits were observed. Therefore, in Brown-Norway rats intoxicated with mercuric chloride, proteinuria appears to be at least in part complement independent.

Animals↗
PubMed1975

Interaction of complex polysaccharides with the complement system: effect of calcium depletion on terminal component consumption.

Complex polysaccharides and lipopolysaccharides can activate the terminal components of complement by either the classical (antibody, C1, C4, and C2) or alternative complement pathways, but the relative importance of either pathway for terminal component consumption in normal serum is poorly understood. Since classical complement pathway function requires both calcium and magnesium ions, whereas the alternative pathway requires only magnesium ions, selective chelation of calcium ions in serum can be used to block the classical complement pathway while leaving the alternative pathway intact. In these studies, ethyleneglycol-bis-(beta-aminoethyl ether)N, N-tetraacetic acid, a potent chelator or calcium, was used to block the classical complement pathway in normal guinea pig serum. Consumption of the terminal complement components by endotoxin, inulin, and zymosan in such serum was strikingly depressed when compared to serum containing an intact classical complement pathway. These studies demonstrate that in normal serum, both the classical and alternative complement pathways participate in the consumption of the terminal complement components by complex polysaccharides and lipopolysaccharides.

Animals↗
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↗