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PubMed2004

C5a anaphylatoxin as a product of complement activation up-regulates the complement inhibitory factor H in rat Kupffer cells.

The 155-kDa complement regulator factor H (FH) is the predominant soluble regulatory protein of the complement system. It acts as a cofactor for the factor I-mediated conversion of the component C3b to iC3b, competes with factor B for a binding site on C3b and C3(H2O) and promotes the dissociation of the C3bBb complex. The primary site of synthesis is the liver, i.e. FH-specific mRNA and protein were identified in both hepatocytes (HC) and Kupffer cells (KC). Previous studies in rat primary HC and KC had shown that the proinflammatory cytokine IFN-gamma influences the balance between activation and inhibition of the complement system through up-regulation of the inhibitory FH. In this study we show that C5a, as a product of complement activation, stimulates the expression of FH-specific mRNA and protein in KC and thus induces a negative feedback. Quantitative-competitive RT-PCR showed an approximate threefold C5a-induced up-regulation of FH. ELISA analyses revealed a corresponding increase in FH protein in the supernatants of KC. The up-regulation of FH was completely inhibited by the C5a-blocking monoclonal antibody 6-9F. Furthermore, an involvement of LPS and IFN-gamma was excluded, which strongly indicates a direct effect of C5a on the expression of FH in KC.

Animals↗
PubMed1996

[Effect of complement modulation with the soluble complement receptor sCR1 on survival and function of kidney xenotransplant. An experimental study with a new guinea pig to rate transplant model].

In this study a modified experimental kidney xenograft model was developed, which reproduced, in a reliable way, the course of hyperacute rejection. In this model guinea-pig kidneys were transplanted to rats using end-to-side anastomoses with recipient aorta and vena cava, respectively, and ureter drainage for diuresis monitoring. The aim of this study was to investigate the protective effects of complement modulation by soluble complement receptor 1 (sCR1) on the xenografts. Twenty-four xenotransplantations were performed and recipients randomized for treatment either by 3 ml saline or 50 mg/kg sCR1 as a 3-ml bolus. It was found that sCR1 was highly efficient in delaying hyperacute rejection from 10.5 +/- 2.1 min in the control group to at least 2 h in the therapy group and in prolongation of graft function. The complement activity was significantly reduced in the sCR1-treated rats, even at the time of rejection, as a result of complement modulation in this group of xenograft recipients. Xenografts from saline-treated animals showed necroses, interstitial haemorrhages and platelet aggregates occluding the vessels as soon as 10 min after the reperfusion started. No such changes could be seen even after 120 min in the xenografted kidneys of sCR1-treated rats. Also C3 deposits in the glomeruli and interstitium were markedly reduced.

Animals↗
PubMed2006

Complement activation in Lyme neuroborreliosis--increased levels of C1q and C3a in cerebrospinal fluid indicate complement activation in the CNS.

A strong initial inflammatory response is important in neuroborreliosis. Since complement is a main player in early inflammation, we monitored the concentration and activation of complement in plasma and cerebrospinal fluid from 298 patients, of whom 23 were diagnosed with neuroborreliosis. Using sandwich ELISAs, we found significantly elevated levels of C1q, C4, C3, and C3a in cerebrospinal fluid, but not in plasma, in patients with neuroborreliosis. This finding indicates that complement plays a role in the human immune response in neuroborreliosis, that the immunologic process is compartmentalized to the CNS, and that complement activation may occur via the classical pathway.

Adolescent↗
PubMed1998

Complement regulation in innate immunity and the acute-phase response: inhibition of mannan-binding lectin-initiated complement cytolysis by C-reactive protein (CRP).

Mannan-binding lectin (MBL) is an acute-phase protein which activates complement at the level of C4 and C2. We recently reported that the alternative pathway also is required for haemolysis via this 'lectin pathway' in human serum. CRP is another acute-phase reactant which activates the classical pathway, but CRP also inhibits the alternative pathway on surfaces to which it binds. Since serum levels of both proteins generally increase with inflammation and tissue necrosis, it was of interest to determine the effect of CRP on cytolysis via the lectin pathway. We report here that although CRP increases binding of C4 to MBL-sensitized erythrocytes, which in turn enhances lectin pathway haemolysis, it inhibits MBL-initiated cytolysis by its ability to inhibit the alternative pathway. This inhibition is characterized by increased binding of complement control protein H and decreased binding of C3 and C5 to the indicator cells, which in turn is attributable to the presence of CRP. Immunodepletion of H leads to greatly enhanced cytolysis via the lectin pathway, and this cytolysis is no longer inhibited by CRP. These results indicate that CRP regulates MBL-initiated cytolysis on surfaces to which both proteins bind by modulating alternative pathway recruitment through H, pointing to CRP as a complement regulatory protein, and suggesting a co-ordinated role for these proteins in complement activation in innate immunity and the acute-phase response.

Acute-Phase Reaction↗
PubMed1996

Complement regulatory molecules on human myelin and glial cells: differential expression affects the deposition of activated complement proteins.

The expression of decay-accelerating factor CD55, membrane cofactor protein CD46, and CD59 was studied on Schwann cells cultured from human sural nerve and myelin membranes prepared from human cauda equina and spinal cord. These proteins are regulatory membrane molecules of the complement system. CD55 and CD46 are inhibitors of C3 and C5 convertases and CD59 inhibits C8 and C9 incorporation into C5b-9 complex and C9-C9 polymerization. The presence of these proteins was assessed by using antibodies to each of the proteins by fluorescent microscopy, fluorescence-activated cell sorter analysis, and also sodium dodecyl sulfate-polyacrylamide gel electrophoresis and western blot analysis. Schwann cells in culture expressed CD55, CD46, and CD59. It is interesting that only CD59 was detected on myelin from both central and peripheral nerve tissue. The ability of these proteins to limit C3 peptide deposition and C9 polymerization in myelin was studied by western blot analysis. C3b deposition was readily detected on antibody-sensitized myelin incubated with normal human serum used as a source of complement but not with EDTA-treated or heat-inactivated serum. C3b deposition was not affected by anti-CD55 antibody. On the other hand, poly-C9 formation in myelin, which was maximum when 50% normal human serum was used, was increased four-to fivefold when myelin was preincubated with anti-CD59. Our data suggest that complement activation on myelin is down-regulated at the step of the assembly of terminal complement complexes, including C5b-9, due to the presence of CD59.

Antigens, CD↗
PubMed1979

C5b-9 dimer: isolation from complement lysed cells and ultrastructural identification with complement-dependent membrane lesions.

The membrane attack complex (MAC) of complement was extracted from the membranes of cells lysed by human complement and its properties were compared with those of the fluid phase complex SC5b-9. Upon sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunochemical analysis, the two isolated complexes had identical subunit compositions, except that the MAC lacked the S-protein. The sedimentation coefficient and molecular weight of the extracted and isolated MAC were, respectively, 33.5 S and 1.7 x 10(6) daltons, compared to 23 S and 1.0 x 10(6) dalton for SC5b-9. Because the molecular weight of the MAC is approximately two times greater than that of C5b-0 (800,000 daltons), the MAC is considered the dimer of C5b-9. Under specified conditions, the 33.5 S dimer could be converted to the 23 S monomer without dissociation of subunits. The MAC had the electron microscopic appearance and dimensions that are characteristic for the complement produced ultrastructural membrane lesions. SC5b-9 had a different ultrastructure that is dissimilar to the morphology of the lesions. The isolated MAC could be reincorporated into phospholipid bilayers and assumed on the surface of the resultant lipid vesicles the orientation and appearance of typical complement lesions.

Animals↗
PubMed1994

Formation of the terminal complement complex on agarose beads: further evidence that vitronectin (complement S-protein) inhibits C9 polymerization.

Vitronectin occupies the metastable binding site of C5b-7, which is unable to insert membranes as part of the complement lytic attack. Some evidence has been presented that vitronectin inhibits also membrane-associated pore formation by inhibiting C9 polymerization in the terminal complement complex (TCC). The authors wished to add to this background by studying the effect of vitronectin on formation of TCC on a carbohydrate surface like agarose beads, an alternative complement pathway activator. Bound TCC was detected by monoclonal and polyclonal antibodies to C9-neoepitopes. Soluble SC5b-7 and TCC (SC5b-9) did not bind to the agarose beads. Using serum or isolated complement factors for the alternative and terminal pathways, the authors found that vitronectin reduced the density of C9-neoepitopes on the beads. As there was no convincing evidence for association of vitronectin with the factors C5b-8 of the agarose-bound TCC, it was concluded that vitronectin bound directly to C9 in TCC and inhibited C9 polymerization within the complex. The authors have shown that TCC can bind to a carbohydrate surface like agarose (an alternating polymer of galactose moieties) in the absence of lipid. These results suggest that vitronectin can limit the lytic effect of membrane-bound TCC by inhibiting C9 polymerization.

Animals↗
PubMed1977

Metabolism of the fifth component of complement, and its relation to metabolism of the third component, in patients with complement activation.

The metabolism of the fifth component of complement (C5), and its relatonship to metabolism of the third component of complement (C3), has been studied in normal subjects and patients by simultaneous administration of radioiodine labeled C5 and C3. In seven normal subjects the fractional catabolic rate of C5 ranged from 1.5 to 2.1% of the plasma pool/h and extravascular/intravascular distribution ratio from 0.22 to 0.78, these values being similar to those obtained for C3, and synthesis rate from 71 to 134 mug/kg per h, In patients with complement activation the increase in fractional catabolic rate of C5 was nearly always less than that of C3. The data also showed that there was increased extravascular distribution of C3 and C5 in most patients and considerable extravascular catabolism of both proteins in some. However, there were differences in metabolic parameters between patients with different types of complement activation. In patients with systemic lupus erythematosus, fractional catabolism and extravascular distribution of C3 and C5 were both increased, and there was marked extravascular catabolism of both proteins. There was increased fractional catabolism and extravascular distribution of C3 in patients with mesangiocapillary nephritis and (or) partial lipodystrophy, and fractional catabolism of C5 was also increased in three of six studies although distribution of C5 was always within the normal range; however, in two patients with nephritic factor in their serum fractional catabolism of C5 was normal despite markedly increased C3 turnover, suggesting that in patients with alternative pathway activation by nephritic factor little or no C5 convertase is generated.

Adolescent↗
PubMed1990

Comparative study of assays detecting complement activation. Complement-split product C3d (rocket immuno-electrophoresis) and C3d neodeterminants (ELISA).

The aim of the study was to investigate the correlation between two types of assay measuring specific products of complement C3 activation and their clinical application. Complement C3d split product was estimated using double-decker rocket immunoelectrophoresis (DD-RIE) and measurements of C3d neodeterminants exposed after C3 activation was carried out with an enzyme-linked immunosorbent assay (ELISA). A total of 595 blood samples were measured in parallel in the DD-RIE and the ELISA test systems. The samples originated from blood donors (44), uraemic patients undergoing dialysis (135), serial samples from rheumatoid arthritis (RA) patients during steroid treatment (88) and 328 randomly collected patient samples. The mean values for DD-RIE and ELISA (+/- 1 SD) for the 595 samples were 48 (+/- 20) mU/l and 48 (+/- 28) mU/l respectively. The interassay coefficient of variation (CV) in the ELISA was 18%. The Spearman rho-correlation coefficient between the two assays was 0.63 for all 595 samples. The mean values using ELISA and DD-RIE were practically identical for the 328 successively incoming samples, the samples from the 135 dialysis patients and the 44 donors. In RA patients a higher mean value was found for the 88 samples using DD-RIE than ELISA. In the majority of patient samples there was a good correlation between the two assays. However, the ELISA appears to be more sensitive in detecting acute complement activation and to give lower levels in RA patients with chronic complement activation.

Anaphylaxis↗
PubMed2001

A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration.

Components of innate immunity have recently been implicated in the regulation of developmental processes. Most strikingly, complement factors appear to be involved in limb regeneration in certain urodele species. Prompted by these observations and anticipating a conserved role of complement in mammalian regeneration, we have now investigated the involvement of complement component C5 in liver regeneration, using a murine model of CCl(4)-induced liver toxicity and mice genetically deficient in C5. C5-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis after exposure to CCl(4.) In addition, these mice showed a marked delay in the re-entry of hepatocytes into the cell cycle (S phase) and diminished mitotic activity, as demonstrated, respectively, by the absence of 5-bromo-2'-deoxyuridine incorporation in hepatocytes, and the rare occurrence of mitoses in the liver parenchyma. Reconstitution of C5-deficient mice with murine C5 or C5a significantly restored hepatocyte regeneration after toxic injury. Furthermore, blockade of the C5a receptor (C5aR) abrogated the ability of hepatocytes to proliferate in response to liver injury, providing a mechanism by which C5 exerts its function, and establishing a critical role for C5aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis.

Animals↗
PubMed2001

Complement inhibitor, complement receptor 1-related gene/protein y-Ig attenuates intestinal damage after the onset of mesenteric ischemia/reperfusion injury in mice.

Complement receptor 1-related gene/protein y (Crry) is a murine membrane protein that regulates the activity of both classical and alternative complement pathways. We used a recombinant soluble form of Crry fused to the hinge, CH2, and CH3 domains of mouse IgG1 (Crry-Ig) to determine whether inhibition of complement activation prevents and/or reverses mesenteric ischemia/reperfusion-induced injury in mice. Mice were subjected to 30 min of ischemia, followed by 2 h of reperfusion. Crry-Ig was administered either 5 min before or 30 min after initiation of the reperfusion phase. Pretreatment with Crry-Ig reduced local intestinal mucosal injury and decreased generation of leukotriene B(4) (LTB(4)). When given 30 min after the beginning of the reperfusion phase, Crry-Ig resulted in a decrease in ischemia/reperfusion-induced intestinal mucosal injury comparable to that occurring when it was given 5 min before initiation of the reperfusion phase. The beneficial effect of Crry-Ig administered 30 min after the initiation of reperfusion coincided with a decrease in PGE(2) generation despite the fact that it did not prevent local infiltration of neutrophils and did not have a significant effect on LTB(4) production. These data suggest that complement inhibition protects animals from reperfusion-induced intestinal damage even if administered as late as 30 min into reperfusion and that the mechanism of protection is independent of neutrophil infiltration or LTB(4) inhibition.

Animals↗
PubMed2005

Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization.

Choroidal neovascularization (CNV), or choroidal angiogenesis, is the hallmark of age-related macular degeneration and a leading cause of visual loss after age 55. The pathogenesis of new choroidal vessel formation is poorly understood. Although inflammation has been implicated in the development of CNV, the role of complement in CNV has not been explored experimentally. A reliable way to produce CNV in animals is to rupture Bruch's membrane with laser photocoagulation. A murine model of laser-induced CNV in C57BL/6 mice revealed the deposition of C3 and membrane attack complex (MAC) in the neovascular complex. CNV was inhibited by complement depletion using cobra venom factor and did not develop in C3(-/-) mice. Anti-murine C6 Abs in C57BL/6 mice inhibited MAC formation and also resulted in the inhibition of CNV. Vascular endothelial growth factor, TGF-beta2, and beta-fibroblast growth factor were elevated in C57BL/6 mice after laser-induced CNV; complement depletion resulted in a marked reduction in the level of these angiogenic factors. Thus, activation of complement, specifically the formation of MAC, is essential for the development of laser- induced choroidal angiogenesis in mice. It is possible that a similar mechanism may be involved in the pathophysiology of other angiogenesis essential diseases.

Animals↗
PubMed1981

Studies on the possible involvement of complement component C3 in the initiation of acid hydrolase secretion by macrophages. I. Correlation between enzyme-releasing and complement-activating capacities of several secretagogues.

A possible relationship between activation of the alternative pathway of complement and acid hydrolase secretion by macrophages has been investigated in vitro by examining the dose--response characteristics of several immunological and non-immunological stimuli of these two processes. Zymosan particles, insoluble immune complexes, methylamine and several other primary aliphatic monoamines were all found to elicit the selective release of lysosomal enzymes from macrophages by a process that correlated well with the ability of these agents to bring about consumption of haemolytically-active components of the alternative complement pathway. By contrast, substances which failed to activate the alternative complement pathway, i.e. soluble aggregated immunoglobulin and several primary aliphatic diamines, were found to be likewise incapable of inducing the selective release of lysosomal glycosidases from macrophages. These observations are interpreted as further evidence for imputing a role for complement C3 in the initiation of lysosomal enzyme release from macrophages.

Animals↗
PubMed1996

[Effect of macrophage colony-stimulating factor on complement receptors and complement regulatory proteins on human peripheral white blood cells].

The effect of M-CSF and C5a on the expression of complement-related membrane proteins on the peripheral white blood cells was investigated. M-CSF or C5a was added into the suspension of the peripheral white blood cells. The expression of the complement receptors, CD35 (CR1) and CD11b/18 (CR3), and inhibitory membrane proteins, DAF and MCP, was measured by flow cytometry. M-CSF increased CR3 on polymorphonuclear cells (PMNs) and CR1, CR3, MCP and DAF on monocytes. C5a increased CR1, CR3 and DAF on PMNs, but did not affect the expression of those on monocytes. It is concluded that M-CSF possessed the activity of increase expression of both complement regulatory proteins and complement receptors of monocytes and C5a selectively affected the expression of those on PMNs.

Adult↗
PubMed2001

Complement 1 inhibitor is a regulator of the alternative complement pathway.

We studied complement 1 inhibitor (C1-INH) as an inhibitor of the alternative complement pathway. C1-INH prevented lysis, induced by the alternative complement pathway, of paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes in human serum. It inhibited the binding of both factors B and C3 to PNH and rabbit erythrocytes and blocked the ability of factor B to restore alternative-pathway function in factor B-depleted serum. C1-INH did not bind to factors B or D but did bind to immobilized C3b and cobra venom factor (CVF), a C3b analogue. C1-INH prevented factor B from binding to CVF-coated beads and dissociated bound factor B from such beads. Factor B and C1-INH showed cross competition in binding to CVF-coated beads. Factor D cleaved factor B into Bb and Ba in the presence of C3b. Cleavage was markedly inhibited when C3b was preincubated with C1-INH. C1-INH inhibited the formation of CVFBb and decreased the C3 cleavage. Removal of C1-INH from serum, in the presence of Mg-EGTA with an anti-C1-INH immunoabsorbant, markedly increased alternative-pathway lysis. C1-INH interacts with C3b to inhibit binding of factor B to C3b. At physiologic concentrations, it is a downregulator of the alternative pathway convertase.

Absorption↗
PubMedDate not supplied

Complement-dependent antibody cytotoxicity test of chicken antibody with duck complement used against cells of a Marek's disease lymphoma-derived cell line (MSB-1).

Complement-dependent antibody cytotoxicity (CDAC) against cells of a lymphoblastoid cell line (MSB-1) derived from Marek's disease lymphoma was investigated in a chicken antibody system using complements from several animal species. Cytotoxicity was seldom observed when rabbit, guinea pig, or chicken complements were used in the presence of hyperimmune chicken serum against MSB-1. With duck complement, however, cytotoxicity was always observed. Therefore, duck complement appears to be suitable for assay of hyperimmune chicken serum against MSB-1 cells by the CDAC test.

Animals↗
PubMed1984

Control of the immune complex-complement interaction by protein H of the alternative complement pathway and the natural inhibitor heparin.

The potential of the negative regulatory protein H of the alternative complement pathway convertase and of heparin in modulating the complement-dependent capacity of fresh serum to inhibit immune complex precipitation (CIICP) between bovine serum albumin (BSA) and rabbit anti-BSA as well as tetanus toxoid (TT) and human anti-TT was assessed. Additions of purified H to serum to increase the intrinsic concentration of this protein by 80% (BSA-anti-BSA system) and 190% (TT-anti-TT system) resulted in an inhibition of CIICP by 50% and 60%, respectively, whereas further increase of the amount of H lead to a decrease of its inhibitory activity. A similar effect was observed with heparin: at a concentration of 400 U/ml a 90% inhibition of CIICP in the TT-anti-TT system was obtained which diminished at higher heparin concentrations. The effect of H on C3 deposition to immune aggregates was assessed through its influence on C3b-mediated immune adherence hemagglutination; factor H dose-dependently suppressed such hemagglutination induced by aggregated human IgG or preformed TT-anti-TT complexes when added to the immune complex-fresh serum mixture at the outset but not after 45 min of the 37 degrees C incubation period which means that H inhibited more likely decoration of immune complexes with C3b than it did inhibit the interaction of C3b-coated immune complexes with erythrocytes. This suppressive effect of H was reversed by the simultaneous addition of the activating protein B. Complement-mediated binding of tritiated C3 to latex-bound human IgG was assessed and H was found to dose-dependently inhibit such binding with a maximal inhibition of 37% at a H concentration of 7 micrograms/ml.

Animals↗
PubMed1977

Complement receptors and cell associated complement components.

Membrane receptors for activated complement components are widely distributed amongst tissue cells of most mammalian species. Common amongst these are receptors for C3b which mediate many of the biological functions of C3. In addition, the genetic control of certain complement components is linked to the genes which code for the major histocompatibility complex. Many of these components are also present on cell surfaces. This suggests that the function of the complement system and the major histocompatibility complex may be related.

Animals↗