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PubMed1980

Complement activating property of the protein-rich endotoxin (OEP) of Pseudomonas aeruginosa. I. Activation of both the classical and the alternative pathways of guinea pig complement.

Complement activating property of the protein-rich endotoxin (OEP) of Pseudomonas aeruginosa was investigated. The ability of OEP to consume the hemolytic complement (CH50) of guinea pig serum (GPS) was relatively lower than zymosan, a potent activator of the alternative pathway (AP). The profiles of the complement consumption with OEP in GPS suggested that classical pathway (CP) activation seems to occur in addition to the AP-activation, because the consumption of the C3-C9, i.e., C3 total was relatively higher than those of C1, C4 and C2. Further results stated below is confirmed this. OEP consumed complement in certain extent in C4-deficient GPS and also in factor B- or D-depleted GPS. In these sera either pathway of the AP or the CP was operated. However, OEP consumed complement quite in full extent in the EGTA-chelated serum, in which AP-activation took place in normal level. OEP was therefore found in this experiment to activate only the AP. The conversion of C3 in immunoelectrophoresis which is a evidence of the CP-and/or AP-activation was observed with OEP. It was suggested that the antibody against OEP did not participate in the consumption of complement, because the GPS priorly absorbed with OEP-coated sheep RBC, was retained fully to react with OEP. It was discussed that the active site of OEP as to the complement activation located on the LPS portion of OEP.

Animals↗
PubMed1997

Differential cytokine regulation of complement proteins in human glomerular epithelial cells.

We have previously shown in inbred strains of mice which naturally develop systemic lupus erythematosus that kidney C3, C2, C4 and factor B gene expression increases coincidently with the occurrence of glomerulonephritis, suggesting that local tissue complement gene expression could contribute to the pathogenesis of immune complex injury. In this study, we investigated the synthesis of complement proteins in glomerular epithelial cells (GECs) and its regulation. Using biosynthetic labelling, immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis, we demonstrated that GECs synthesized C1r, C1s, C1 inhibitor, C3, C2 and factor B. Interferon-gamma induced increases in the synthesis of all these proteins. Both factor B and C3 proteins were increased following addition of either IL-1beta, IL-6 or TNF-alpha to GEC cultures; however, these cytokines did not increase either C2, C1r, C1s or C1-inhibitor biosynthesis. Lipopolysaccharide affected the biosynthesis of these proteins in a similar way. A semiquantitative analysis of the mRNA expression of some of these proteins by reverse-transcriptase polymerase chain reaction showed that these cytokine effects were pretranslational as there was enhancement of factor B mRNA expression by IL-1, TNF-alpha, IFN-gamma, IL-6 and endotoxin, but only IFN-gamma enhanced C1-inhibitor and C4 mRNA expression. These results may be of significance in the immunopathogenesis of glomerulonephritis, where it is likely that local complement production in GECs is independently regulated by cytokines, derived from resident glomerular mesangial cells or infiltrating monocyte/macrophages and T cells.

Animals↗
PubMed1989

Distribution of complement in the sclera.

In the present study, we compared hemolytic activities of C1, C4, C2, C3, C5, C6 and C7 in the anterior and posterior sclera. Additionally, we used radial immunodiffusion to measure levels of Factor B, IgG, IgA and albumin in the anterior and posterior sclera. Except for C1, complement levels were significantly higher in the posterior than anterior sclera. Additionally, levels of immunoglobulins as well as albumin were significantly higher in the posterior than anterior sclera. These results suggest that the posterior sclera has a better adjacent vascular supply than the anterior sclera. On the other hand, the results of this study show that the anterior sclera has more C1, the recognition unit of the classical pathway, than the posterior sclera. Because there is nearly twice as much C1 in the anterior sclera, it may be easier for antigen-antibody complexes, whether formed in the sclera itself or derived from the neighboring vessels, to set off the complement cascade in the anterior sclera. This finding may help explain why scleritis associated with immune complex disease is more common in the anterior than posterior sclera.

Adult↗
PubMed1986

Alternative complement pathway activation by C4b deposited during classical pathway activation.

Sheep erythrocytes (E) sensitized with anti-E antibody (A) were reacted with guinea pig C1 (C1gp) and human C4 (C4hu) or guinea pig C4 (C4gp) to prepare EAC1, 4b. Treatment of the EAC1, 4b with a buffer containing EDTA removes C1rgp and C1sgp, resulting in the formation of EAC4b. EAC4b prepared in this way were found to be lysed by human or guinea pig serum in a gelatin Veronal-buffered saline containing 2 mM MgCl2 and 8 mM EGTA (Mg-EGTA-GVB). In the hemolytic sensitivity of EAC4bhu, essentially no difference was noted whether IgG or IgM antibodies were used for preparation of EAC4bhu. The extent of the hemolysis of EAC4bhu was dependent on the dose of C4bhu. Because EAC4bhu were lysed even by C2-deficient human serum, C3 convertase of the classical complement pathway would not be involved in the hemolysis of EAC4bhu. Furthermore, the reactivity of EAC4bhu with serum in Mg-EGTA-GVB remained even after treatment of the intermediate cells with 1 mM PMSF, indicating that any remaining C1gp was not responsible for the hemolysis. Therefore, the hemolysis of EAC4b by sera in Mg-EGTA-GVB was considered to be mediated via activation of the alternative complement pathway (ACP). Pretreatment of EAC4bhu with anti-C4hu antibody or C4-binding protein suppressed the hemolysis of EAC4bhu via the ACP activation. Furthermore, EAC4bhu were more sensitive to hemolysis by the reaction with a mixture of C3, B, D, and H followed by rat serum in EDTA-GVB than EAC1qgp were. These results indicate that C4b molecules on the cell membrane participate in the activation of ACP.

Animals↗
PubMed1983

Gene order and gene distances in the HLA region studied by the haplotype method.

The present report describes a method to establish gene order and gene distances in chromosomal regions where several genes are located closely together. The method is applied to the study of the complement loci in the HLA complex on chromosome 6 in man. The method is based on allelic association, i.e. alleles of closely linked loci are nonrandomly associated on haplotypes. A haplotype which yields information has a frequency higher than would be expected from the frequencies of each of its alleles. They occur, moreover, with a frequency which makes them the main source of the least frequent of the alleles in the combinations. Other haplotype combinations involving this allele (these alleles) are most likely the results of recombinational events involving a main haplotype. Such crossovers may therefore, on certain conditions, be used for gene mapping purposes. Some basic rules for the use of the method are given. A total of 701 haplotypes involving the short arm of chromosome 6 have been studied. Typings have been performed with regard to HLA-A, -B, -C, -D/-DR, C4, C2 and Bf. The study confirms previous localization of the complement loci between HLA-D and -B. The investigation suggests the order HLA-D-Bf-C4-C2-HLA-B. There is, moreover, slight evidence in favour of a localization of the C4A gene on the HLA-B side of C4B. Given an HLA-A-HLA-B distance of 0.8 cM, suggested relative distances are: HLA-D-Bf:0.44 cM, Bf-C4:0.04 cM, C4-C2:0.11 cM, and C2-HLA-B:0.12 cM.

Alleles↗
PubMed1985

Activation of complement by 405-nm light in serum from porphyria cutanea tarda.

Sera from three patients with porphyria cutanea tarda (PCT) were examined for evidence of complement activation. The irradiation of sera in vitro with 405-nm light resulted in a dose-dependent diminution of total hemolytic complement activity and the hemolytic titers of C1, C4, C2, C3, and C5. Furthermore, such irradiated sera showed immunoelectrophoretical C3 conversion, chemotactic activity for rat polymorphonuclear leukocytes inhibited by incubation with anti-C5 antisera but not anti-C3 antisera, and C5a generation as measured by radioimmunoassay. Factor-B conversion did not occur in such irradiated sera. Using Sephadex G-75 chromatography, the irradiated sera showed a multiphasic elution profile of chemotactic activity similar to that of zymosan-activated serum. The generation of C5a even occurred in factor-B-depleted serum. These studies indicate that the irradiation of PCT serum with 405-nm light induces the activation of the complement system via the classical pathway, resulting in the development of a chemotactic factor.

Chemotaxis, Leukocyte↗
PubMed1983

Complement components in 100 newborns and their mothers determined by electroimmunoassay.

Samples of blood were obtained from 100 healthy full-term women in labour and, after delivery, from the umbilical cord of their infants. By electroimmunoassay, complement components were quantitated in serum (C1q, C1r, C1s, C1 IA, C2, P, D. I, H, C6 and C7) or in EDTA-plasma (C4, C3, B, C5. and C). The concentrations of C7 in cord serum was twice that found by others using a functional assay. Concentrations of C1r, I and C6 in the cord sample were 50-60 per cent of those in healthy blood donors used as reference, and that of D was about 130 per cent. The cord serum and plasma concentrations of the remaining components agreed with previously reported values. The maternal levels of C2, C4, C3, B, H, C5 were 40-60 per cent higher than those of the reference.

Complement C4↗
PubMed1985

The modulation of immune complex aggregation by classical pathway-mediated reactions.

Classical pathway (CP)-triggered reactions of complement-modulated immune complex (IC) aggregation (tetanus toxoid/human anti-tetanus toxoid-IgG; ICs of equivalence) were investigated turbidimetrically during the early stages of reaction. Monospecific Fab'- or Fab-fragments (rabbit) directed against certain complement components were used to block the complement function in normal human serum (NHS). Additionally, parts of the reactions were studied using purified complement components. C1q in serum generated by the addition of EDTA as well as purified C1q were found to increase the IC aggregation. In contrast to C1q, macromolecular C1 is able to inhibit IC aggregation, whereas additional participation of C-1 INH reversed this process. The cooperation of the remaining CP proteins (C4, C2, C4bp, and I) reconstituted the inhibition capacity of the complement. Whereas C3 supported significantly inhibition, a significant influence of other effector pathway (EP) components (C5-C9) was not detectable turbidimetrically.

Antigen-Antibody Complex↗
PubMed1980

Receptors on guinea-pig erythrocytes specific for cell-bound fourth component of human complement (C4).

Guinea-pig erythrocytes have receptors for heterologous (human and rabbit) complement activated by the classical pathway on cell surfaces. This was shown in the present study by rosette-forming reactions of guinea-pig erythrocytes and human lymphocytes or sheep erythrocytes pre-treated with antibody and human R3 complement. The binding is temperature-dependent and is enhanced by treating the guinea-pig erythrocytes with neuraminidase. The receptors were shown to be specific for C4 by inhibition tests employing a range of anti-human complement antibodies (including anti-Clq, -Cl inhibitor, -C4, -C2, -C3 and -C3b inactivator). Of these reagents, only anti-C4 inhibited the receptor activity, indicating that the guinea-pig erythrocyte C4-receptors differ from those on lymphocytes, monocytes, polymorphonuclear leucocytes and human erythrocytes which are reported to react with both C3b and C4b. In contrast to the strong affinity observed for heterologous C4, guinea-pig erythrocytes appear to react very weakly, if at all, with homologous C4.

Animals↗
PubMed2000

Expression of complement messenger RNAs by human endothelial cells.

This study evaluated complement mRNA expression in human brain microvessel endothelial cells (HBMEC), human umbilical vein endothelial cells (HUVEC), and cells of the human derived ECV304 line. Cerebral endothelial cells and HUVEC expressed detectable levels of complement gene mRNAs for the C1q B-chain, C1r, C1s, C2, C3, C4, C5, C7, C8 gamma-subunit and C9. In addition to C6 mRNA, C1q and C9 were not detected in ECV304 cells. These results indicate that endothelial cells may be a source of complement proteins in brain and other organs of the body.

Cell Line↗
PubMed1985

C1-inhibitor--biochemical properties and clinical applications.

C1-inhibitor (C1-INH) is an alpha-2-neuraminoglycoprotein with a molecular weight of 105,000 daltons. It has a broad spectrum control of the many blood cascades including the complement system. Inherited deficiency of this molecule has been associated with the development of hereditary angioneurotic edema (HANE), a dominant genetic disorder. The liver and monocytes are the primary sites of C1-INH synthesis. The genetic basis of dysfunctional C1-INH is a defect at the structural locus for one C1-INH gene; both the dysfunctional C1-INH gene and the normal C1-INH gene products are present in the plasma of the affected person. The absence of C1-INH permits spontaneous activation of the first component of the complement system (C1); this, in turn, activates C4 and C2. A kinin derived from C2 may be elaborated, which then increases vascular permeability. However, recent investigations have indicated that kinin activity generated from C1-INH-depleted plasma is not derived from C2 but implicates kallikrein, an enzyme which is also controlled by C1-INH, in the formation of a kinin which is most probably bradykinin. A number of therapeutic approaches have been used to treat HANE patients, including antifribrinolytic drugs such as tranexamic acid, plasma infusion, and steroids. The anabolic steroids such as danazol and stanazolol have been used widely to treat HANE patients. We discuss in this review the potential mechanisms by which danazol promotes selective synthesis of C1-INH and several other proteins in the liver.

Angioedema↗
PubMed1999

Regulation of complement activation by C-reactive protein.

C-reactive protein (CRP) is an acute-phase serum protein and a mediator of innate immunity. CRP binds to microbial polysaccharides and to ligands exposed on damaged cells. Binding of CRP to these substrates activates the classical complement pathway leading to their uptake by phagocytic cells. Complement activation by CRP is restricted to C1, C4, C2 and C3 with little consumption of C5-9. Surface bound CRP reduces deposition of and generation of C5b-9 by the alternative pathway and deposition of C3b and lysis by the lectin pathway. These activities of CRP are the result of recruitment of factor H resulting in regulation of C3b on bacteria or erythrocytes. Evidence is presented for direct binding of H to CRP. H binding to CRP or C3b immobilized on microtiter wells was demonstrated by ELISA. Attachment of CRP to a surface was required for H binding. H binding to CRP was not inhibited by EDTA or phosphocholine, which inhibit ligand binding, but was inhibited by a 13 amino acid CRP peptide. The peptide sequence was identical to the region of CRP that showed the best alignment to H binding peptides from Streptococcus pyogenes (M6) and Neisseria gonorrhoeae (Por1A). The results suggest that CRP bound to a surface provides secondary binding sites for H resulting in greater regulation of alternative pathway amplification and C5 convertases. Complement activation by CRP may help limit the inflammatory response by providing opsonization with minimal generation of C5a and C5b-9.

Amino Acid Sequence↗
PubMed1989

Mediator-induced activation of xanthine oxidase in endothelial cells.

Rat pulmonary artery endothelial cells incubated with human serum that has been complement-activated by addition of cobra venom factor reveal a pronounced conversion of xanthine dehydrogenase to xanthine oxidase. This process requires the availability of the fifth component of complement (C5) but not the presence of other components (C2 and C6-C9). The phenomenon can be reproduced by addition to endothelial cells of purified human recombinant C5a but not C5a desArg or C3a. The enzyme conversion process is relatively rapid (occurring within 5-10 min), requires the presence of intact endothelial cells, and does not require protein synthesis. Similar effects on endothelial cells have been obtained with human recombinant tumor necrosis factor alpha and the chemotactic peptide N-formyl-Met-Leu-Phe. In contrast, bradykinin, recombinant human interleukin 1 beta, and phorbol ester lack this biological activity. These findings suggest novel effects of inflammatory mediators on endothelial cells.

Animals↗
PubMed1975

Activated guinea-pig C3 and the immune adherence receptor (a complement receptor) on cell membranes.

By treating C3 with purified C1, C4 and C2 in the fluid phase, haemolytically inactive C3 was prepared. This was shown to bind to human erythrocytes by use of radio-labelled (Fab')2 antibody to guinea-pig C3. The activated C3 preparation inhibited immune adherence between EAC43 and human erythrocytes. These findings indicate that the activated C3 attaches to the immune adherence receptor on human erythrocytes. In addition the fluid-phase activated C3 adhered to thymus cells and sheep erythrocytes, whereas EAC43 did not. Thus the immune adherence receptor may be present on so called immune adherence-negative cells, but in insufficient concentration to form rosettes with EAC43.

Animals↗
PubMed1981

Interactions of human, cultured kidney cells with the complement system.

When heat-killed, cultured human kidney cells were incubated with normal human serum, complement (C) activation occurred with moderate consumption of C4, C2, C3, and C5 hemolytic activity. No loss of C1 activity and no, or only slight, reduction in C6 activity was detectable until high cell concentrations were reached. C4 and C2 consumption could not be prevented by blocking the primary C pathway through prior EGTA chelation of the serum. Both living and heat-killed kidney cells were incubated with normal serum and examined for surface-bound C components using immunofluorescent techniques. Heat-killed kidney cells were strongly positive for C3, which was distributed in a diffuse, speckled pattern over the entire cell surface. These cells were also weakly positive for IgG and Clq immunofluorescence, but were negative for surface albumin, C5, and beta 1H. In contrast, living cell suspensions showed only occasional cells positive for C3, IgG, or Clq and all cells were negative for albumin, C5, and beta 1H. Viability staining revealed that the few C3 positive cells in living cell suspensions belonged to a small, nonviable subpopulation. These data indicate that dead cells can initiate limited C activation, which can result in binding of C3 to the cell surface.

Cells, Cultured↗
PubMed2004

Proteases of the complement system.

The complement system is a group of about 35 soluble and cell-surface proteins which interact to recognize, opsonize and clear or kill invading micro-organisms or altered host cells (e.g. apoptotic or necrotic cells). Complement is a major part of the innate immune system. Recognition proteins such as C1q, MBL (mannan-binding lectin) and ficolins bind to targets via charge or sugar arrays. Binding causes activation of a series of serine protease proenzymes, such as C1r, C1s and MASP2 (MBL-associated serine protease 2), which in turn activate the atypical serine proteases factor B and C2, which then activate the major opsonin of the system, C3. Activated C3 binds covalently to targets, and is recognized by receptors on phagocytic cells. Two of the complement proteases, factors D and I, circulate not as proenzymes, but in activated form, and they have no natural inhibitors; their substrates are transient protein complexes (e.g. C3bB and C3bH) which form during complement activation. Factor B and C2 also have no natural inhibitor; they are active only when proteolytically cleaved and bound in an unstable, short-lived complex with C3b or C4b. C1r, C1s and the MASPs, in contrast, are regulated more conventionally by the natural serpin, C1-inhibitor. Complement proteases in general have very narrow specificity, and low substrate turnover with both natural and synthetic substrates. Excessive activation of complement is inflammatory, and causes tissue damage (e.g. in rheumatoid arthritis, or in ischaemia/reperfusion injury). Substances that regulate complement activation are likely to be useful in the regulation of inflammation. Complement activation might potentially be controlled at many different steps. Much attention has been focused on controlling the formation or activity of the protease complexes C3bBb and C4b2a (containing activated factor B and C2 respectively), as these generate the inflammatory peptides C3a and C5a.

Complement Activation↗
PubMed2005

A novel human complement-related protein, C1r-like protease (C1r-LP), specifically cleaves pro-C1s.

The availability of the human genome sequence allowed us to identify a human complement-related, C1r-like protease gene (c1r-LP) located 2 kb centromeric of the C1r gene (c1r). Compared with c1r, c1r-LP carries a large deletion corresponding to exons 4-8 of c1r. The open reading frame of the C1r-LP cDNA predicts a 50 kDa modular protein displaying 52% amino acid residue identity with the corresponding regions of C1r and 75% identity with a previously described murine C1r-LP. The serine protease domain of C1r-LP, despite an overall similarity with the AGY group of complement serine proteases, has certain structural features characteristic of C2 and factor B, thus raising interesting evolutionary questions. Northern blotting demonstrated the expression of C1r-LP mRNA mainly in the liver and ELISA demonstrated the presence of the protein in human serum at a concentration of 5.5+/-0.9 microg/ml. Immunoprecipitation experiments failed to demonstrate an association of C1r-LP with the C1 complex in serum. Recombinant C1r-LP exhibits esterolytic activity against peptide thioesters with arginine at the P1 position, but its catalytic efficiency (kcat/K(m)) is lower than that of C1r and C1s. The enzymic activity of C1r-LP is inhibited by di-isopropyl fluorophosphate and also by C1 inhibitor, which forms stable complexes with the protease. Most importantly, C1r-LP also expresses proteolytic activity, cleaving pro-C1s into two fragments of sizes identical with those of the two chains of active C1s. Thus C1r-LP may provide a novel means for the formation of the classical pathway C3/C5 convertase.

Amino Acid Sequence↗
PubMed1976

Hereditary deficiency of the fifth component of complement in man. I. Clinical, immunochemical, and family studies.

The first recognized human kindred with hereditary deficiency of the fifth component of complement (C5) is described. The proband, a 20-year-old black female with systemic lupus erythematosus since age 11, lacked serum hemolytic complement activity, even during remission. C5 was undetectable in her serum by both immunodiffusion and hemolytic assays. Other complement components were normal during remission of lupus, but C1, C4, C2, and C3 levels fell during exacerbations. A younger half-sister, who had no underlying disease, was also found to lack immunochemically detectable C5. By hemolytic assay, she exhibited 1-2% of the normal serum C5 level and normal concentrations of other complement components. C5 levels of other family members were either normal or approximately half-normal, consistent with autosomal codominant inheritance of the gene determining C5 deficiency. Normal hemolytic titers were restored to both homozygous C5-deficient (C5D) sera by addition of highly purified human C5. In specific C5 titrations, however, it was noted that when limited amounts of C5 were assayed in the presence of low dilutions of either C5D serum, curving rather than linear dose-response plots were consistently obtained, suggesting some inhibitory effect. Further studies suggested that low dilutions of C5D serum contain a factor (or factors) interfering at some step in the hemolytic assay of C5, rather than a true C5 inhibitor or inactivator. Of clinical interest are (a) the documentation of membranous glomerulonephritis, vasculitis, and arthritis in an individual lacking C5 (and its biologic functions), and (b) a remarkable propensity to bacterial infections in the proband, even during periods of low-dose or alternate-day corticosteroid therapy. Other observations indicate that the C5D state is compatible with normal coagulation function and the capacity to mount a neutrophilic leukocytosis during pyogenic infection.

Adult↗