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PubMed1998

C1q knock-out mice for the study of complement deficiency in autoimmune disease.

In humans, homozygous deficiency of the first component of the classical pathway of complement, C1q, is a powerful disease susceptibility factor for the development of systemic lupus erythematosus (SLE). This strong association indicates that a functional activity of C1q protects from the development of SLE. Studies in vitro have shown that C1q can bind apoptotic keratinocytes suggesting that it may have an important role in the clearance of apoptotic cells. C1q-deficient mice, generated by gene targeting, showed an increased mortality and 25% of the mice had histological evidence of glomerulonephritis characterised by multiple apoptotic cell bodies and immune deposits, assessed by immunofluorescence and electron microscopy. These observations are compatible with the hypothesis that C1q deficiency causes autoimmunity by an impaired clearance of apoptotic cells.

Animals↗
PubMed2006

Anti-complementary activity of ursane-type triterpenoids from Weigela subsessilis.

A new ursane-type triterpenoid, weigelic acid (1), and seven known compounds, ursolic acid (2), ilekudinol A (3), corosolic acid (4), ilekudinol B (5), esculentic acid (6), pomolic acid (7), and asiatic acid (8) were isolated from the leaf and stem of Weigela subsessilis. The structure of the new triterpenoid was established as 1beta,2alpha,3alpha,23-tetrahydroxyurs-12-en-28-oic acid on the basis of spectroscopic analyses. In addition, the isolated compounds were evaluated for their anti-complement activity against the classical pathway of the complement system. Of these, compounds 1-2 and 4-8 exhibited anti-complement activity with IC50 values of 152, 90, 130, 51, 56, 4, and 163 microM, respectively, whereas 3 was inactive. This shows that a carboxylic group of ursane-type triterpenoids seems to play an important role in inhibiting the hemolytic activity of human serum against erythrocytes.

Animals↗
PubMed1999

Heparin-coated cardiopulmonary bypass equipment. II. Mechanisms for reduced complement activation in vivo.

OBJECTIVE: Our objective was to study mechanisms for reduced complement activation by heparin coating of cardiopulmonary bypass equipment in clinical heart surgery. METHODS: Adults undergoing elective coronary artery bypass grafting were randomized to cardiopulmonary bypass with Duraflo II heparin-coated (n = 15) or uncoated (n = 14) sets (Duraflo coating surface; Baxter International, Inc, Deerfield, Ill). Blood samples were analyzed with the use of enzyme immunoassays for C1rs-C1 inhibitor complexes and the activation products Bb, C4bc, C3bc, C5a-desArg, and the terminal complement complex. Data were compared by repeated-measures analysis of variance. RESULTS: C1 was activated during bypass, and increases in C1rs-C1 inhibitor complexes were larger with heparin coating (P =.03). C4bc increased after administration of protamine, without intergroup differences (P =.69). Bb (P =.22) and C5a-desArg (P =.13) tended to increase less with heparin coating. Formation of C3bc (P =.03) and the terminal complement complex (P <.01) was significantly reduced with heparin coating. C5a-desArg increased 2-fold during bypass, whereas the terminal complement complex increased 10- to 20-fold. Maximal terminal complement complex concentrations were significantly correlated to maximal Bb and C3bc (R = 0.6, P <.001), but not to C1rs-C1 inhibitor complexes or C4bc (R < 0.05, P >.8). CONCLUSIONS: C1 activation during bypass was increased by heparin coating, but further classical pathway activation was held in check until administration of protamine. Heparin coating significantly inhibited C3bc and terminal complement complex formation. Terminal complement complex concentrations were related to alternative pathway activation and may be useful for evaluation of differences in bypass circuitry. Increases and intergroup differences in terminal complement complex concentrations were much larger than those in C5a-desArg.

Anticoagulants↗
PubMed1981

Cold dependent activation of complement in systemic lupus erythematosus. A unique cause for a discrepancy between clinical and laboratory parameters.

A 31-year-old woman with systemic lupus erythematosus (SLE) was studied because she developed markedly reduced total hemolytic complement activity at a time when her disease was clinically inactive. Functional assays demonstrated reduced activities of C1, C4, and C2, but normal concentrations of C3 and the terminal (C5-9) components were present. Antigenic concentrations of C1, C4, and C2 were normal. Plasma or serum obtained from blood allowed to clot at 37 degrees C had normal complement activity. Complement activity was depleted when the patient's serum was incubated in the cold. At reduced temperatures, the patient's serum (or purified IgG) depleted complement activity of normal human sera. A second patient with SLE was also demonstrated to have this same phenomenon. Cryoglobulins were not detectable in these patients. These data indicate that in vivo the patients' complement was normal and that the observed in vitro reduction was caused by cold dependent activation of the classical pathway.

Adolescent↗
PubMed1984

Comparative study of the fluid-phase proteolytic cleavage of human complement subcomponents C4 and C2 by C1s and C1r2-C1s2.

The C3 convertase of the classical pathway of complement is composed of fragments C4b and C2a resulting from cleavage of C4 and C2 by activated C1. The limited proteolysis of these two different substrates by the same protease, C1s, has been studied in the fluid phase using purified proteins. The turnover numbers of C2 and C4 cleavage by C1s were affected to different extents, depending on whether C1s was alone or associated with C1r or with monoclonal antibodies to C1s. The binding of C2 to C4 favours the proteolysis of C2 by C1s, as revealed by the use of I2-treated C2.

Antibodies, Monoclonal↗
PubMed1992

Oligodendrocytes lack glycolipid anchored proteins which protect them against complement lysis. Restoration of resistance to lysis by incorporation of CD59.

Rat oligodendrocytes, which activate the classical pathway of complement in the absence of antibody, are highly sensitive in a reactive lysis assay using human C5b6 and EDTA serum. Oligodendrocytes may be relatively deficient in glycolipid-linked complement regulatory protein(s), since digestion with phosphatidylinositol-specific phospholipase C (PI-PLC) failed to increase their sensitivity to serum, whereas complement-insensitive astrocytes, when treated with PI-PLC, became strikingly sensitive. To test the hypothesis that oligodendrocytes lack terminal complement regulatory molecule(s), human erythrocyte CD59, a recently described complement regulatory protein, was purified to homogeneity. The biological activity of the preparation was confirmed by reincorporating the protein into guinea-pig erythrocytes through its glycolipid anchor, which resulted in dose-dependent protection against human C5b6 and EDTA serum. Incorporation of 10(5) molecules of human CD59 into rat oligodendrocytes resulted in good protection against homologous human complement (76%), and significant protection against rat complement homologous to the cell (36%). Protection could be reversed using an antibody to CD59.

Animals↗
PubMed1991

C1 subcomponent complexes and C2 cleavage in active systemic lupus erythematosus.

We studied the activation and C1 inactivator-dependent dissociation of the first component of complement, the C1q(C1r-C1s)2 complex, in relation to recruitment of the classical activation pathway in the circulation of 24 patients with systemic lupus erythematosus (SLE). The patients were divided into three groups on a clinical basis, and were investigated during flares of disease activity. Group I had mild symptoms, group II major extrarenal manifestations, and group III manifest renal disease. High serum concentrations of trimer complexes containing C1 inactivator, activated C1r and zymogen C1s(C1 IA-C1r-C1s) were found in the majority of the patients. Some patients with high C1 IA-C1r-C1s concentrations showed no evidence of classical pathway activation, indicating that C1 activation was controlled by the action of C1 IA at the C1r level. By contrast, formation in serum of tetramer complexes in which C1 IA was firmly bound to both C1r and C1s (C1 IA-C1r-C1s-C1 IA) was associated with C2 and C3 cleavage in EDTA plasma, and with manifest hypocomplementemia. Low C1 IA-C1r-C1s-C1 IA values were observed in conjunction with substantial C2 cleavage in a few patients. Thus, C1 IA-C1r-C1s-C1 IA may not always be a sensitive indicator of classical pathway activation. Efficient recruitment of the classical pathway was related to disease severity, with some overlap between the clinical groups. In conclusion, C1 dissociation with formation of C1 IA-containing complexes was consistently found in patients with active SLE. The results suggested that C1 IA-dependent control of C1 activation was of biological significance in the disease.

Adolescent↗
PubMed1993

Expression and function of gingival fibroblast C1q receptors are upregulated by interleukin-1 beta and transforming growth factor-beta.

In injury and inflammation, complement (C) component C1q, in addition to its central role in initiation of classical pathway of complement activation, modulates diverse cellular functions by binding to specific cell surface receptors. Interaction of substrate-bound C1q with receptors for the collagen-like domain of C1q (C1qRC) of human gingival fibroblasts (HGF) promotes cell attachment. We investigated modulation of the adhesive function and expression of C1qRC by interleukin-1 beta (IL-1 beta) and transforming growth factor-beta (TGF-beta). Confluent fibroblast monolayers were incubated under standard culture conditions with or without cytokines. C1qRC function was measured by attachment assays. IL-1 beta and TGF-beta increased fibroblast adhesion to C1q to 146% and 131% of controls, respectively. Cytokine enhancement of HGF adhesion was concentration-dependent, saturable (20 ng/ml IL-1 beta; 1 ng/ml TGF-beta) and time-dependent (IL-1 beta 12-hr peak; TGF-beta 24-hr peak). Effect of IL-1 beta and TGF-beta on C1qRC expression was assessed by flow cytometry measurements of fluorescence intensity of cells stained with C1q and FITC anti-C1q antibody, and by binding studies with 125I-C1q. Cells treated with cytokines displayed a two- to four-fold increased fluorescence of cell-bound C1q compared to controls. Binding studies indicated the increased fluorescence correlated with increase in number of C1qRC in both IL-1 beta (4.7 x 10(6)/cell) and TGF-beta (3.9 x 10(6)/cell)-treated cells, compared to control (3.0 x 10(6)/cell), but had no effect on binding affinity. Rates of internalization of receptor-bound C1q were similar in cytokine-treated cells and controls. We propose from these data that IL-1 beta and TGF-beta have the ability to upregulate C1qRC expression, and this effect contributes to increased adhesion of HGF to substrate-bound C1q.

Carrier Proteins↗
PubMed1988

Activation of human complement by rat peritoneal mast cells and its inhibition by a rat serum factor.

The effects of normal sera from humans, rats, and guinea pigs on unsensitized rat peritoneal mast cells were studied in vitro. Five to 20% fresh human sera induced mast cell death and substantial histamine release. The factor was heat labile. Neither hereditary C3-deficient sera nor experimentally C1q-depleted sera showed cytotoxicity. The CH50 activity of human serum was decreased to about one half after a 15-min incubation with 2 X 10(6) mast cells/ml at 37 degrees C. The cytotoxic activity and CH50 reduction were completely eliminated by an addition of 10 mM Mg-EGTA to the serum. These data demonstrated that unsensitized rat mast cells served as both the initiator and target of complement activity when human serum was used as a complement source. Requirements of both Ca++ and C1q suggested the activation of the classical pathway of complement. Fresh 5-20% sera from rats and guinea pigs, on the other hand, showed neither cytotoxicity nor CH50 reduction. Furthermore, these sera strongly inhibited the human serum-induced reaction. The latter results indicated the presence of a modulating factor in rat and guinea pig sera, which inhibits mast cell associated complement activation.

Animals↗
PubMed1986

Interaction of complement-solubilized immune complexes with CR1 receptors on human erythrocytes. The binding reaction.

The binding of complement (C)-solubilized 125I bovine serum albumin (BSA) anti-BSA immune complexes (IC) to CR1 receptors on human red blood cells (RBC-CR1) was studied. The binding of IC to CR1 was strongly dependent on the molar antigen to antibody ratio, and IC formed in moderate antigen excess showed no binding. IC solubilized in 50% human serum in the presence of autologous RBC bound rapidly to RBC-CR1, with maximal binding within less than 1 min at 37 degrees C. Release of CR1-bound IC under these conditions occurred slowly, requiring more than 30 min. Only binding of 'partially' solubilized, e.g., anti C3c (C4c), and conglutinin-reactive IC occurred, whereas fully solubilized complexes (IC-C3dg, C4d) showed virtually no binding. Solubilization of IC in the presence of Mg-EGTA or in C2-deficient serum resulted in a markedly delayed binding of IC to RBC, indicating the importance of an intact classical pathway in preparing the IC for binding to RBC-CR1. C-solubilized IC could be absorbed to solid-phase conglutinin or antibody to C3c and C4c, and these ligands were able to inhibit the binding of solubilized IC to RBC. Heparin also exerted a marked, dose-dependent inhibitory effect on the binding of presolubilized IC to RBC-CR1, whereas the binding was unaffected by the addition of monosaccharides or by the concentration of Ca2+ or Mg2+ ions.

Animals↗
PubMed1984

Activation of complement system by porins extracted from Salmonella typhimurium.

The effect of porins purified from Salmonella typhimurium on the complement system was investigated both in vitro and in vivo. Incubation of porins with either human or guinea pig serum resulted in the consumption of the total complement activity when an amount of porins ranging from 8 to 10 micrograms per 100 microliters of serum was used. The activation of the complement system was temperature dependent, suggesting an active process rather than passive adsorption of the complement components by porins. In addition, the activation had a fast kinetic and proceeded mainly through the classical pathway. This conclusion is supported by the consumption of C1s and C4 in normal human serum treated with porins and also by the depletion of C3 activity in the C1s-deficient serum which was marked only when purified C1s was added to the serum before incubation with porins. Injection of 100 micrograms of porins into guinea pigs induced profound complement consumption at 6 h postinjection that persisted up to 12 h. We conclude from this study that porins can effectively contribute to complement activation and to subsequent biological events induced by gram-negative bacteria.

Animals↗
PubMed1991

The inhibitory effect of rosmarinic acid on complement involves the C5 convertase.

Rosmarinic acid (RA), a naturally occurring extract from Melissa officinalis, inhibits several complement-dependent inflammatory processes and may have potential as a therapeutic agent for the control of complement activation in disease. Rosmarinic acid has been reported to have effects on both the classical pathway C3-convertase and on the cobra venom factor-induced, alternative pathway convertase. In order to define the mechanism of inhibition, the effect of RA on classical and alternative pathway lysis, C1q binding, the classical pathway convertase, the alternative pathway convertase, membrane attack pathway lysis and the generation of fragments of C3 and C5 during activation, was tested in vitro. The results showed that RA inhibited lysis by the classical pathway more than by the alternative pathway. This effect was dose-dependent with maximum inhibition of classical pathway lysis observed at 2.6 mmoles of RA. There was little effect on C1q binding or on the classical and alternative pathway convertases. However, there was highly significant inhibition of lysis of pre-formed EA43b cells by dilutions of human or rabbit serum in the presence of RA (1 mM); this was accompanied by inhibition of C5a generation. We conclude that the inhibitory effect of RA involves the C5 convertase. Such inhibition could be advantageous to the host in disorders where the terminal attack sequence plays a role in pathogenesis.

Animals↗
PubMed2003

A novel murine complement-related gene encoding a C1r-like serum protein.

C1r and C1s are highly specific serine proteases that initiate the classical pathway of complement activation. We recently demonstrated that, in the mouse, the genes encoding these proteins are duplicated. Analysis of the 5'-flanking region of the murine C1rA gene, the homologue of human C1r, revealed the presence of a novel gene encoding a C1r-like protein (c1r-LP). Although this gene carries a large deletion, it shows an overall structure similar to that of c1rA, suggesting that it may have arisen from a duplication of the C1r gene. The c1r-LP gene is expressed primarily in the liver, and is not regulated by lipopolysaccharide. The open reading frame of full-length cDNA clones encodes a pre-protein with a calculated molecular mass of 50.6 kDa which, except for an internal deletion of several modules, has a modular organization similar to that of C1r and shows 51% overall amino acid identity to corresponding regions of C1rA. Western blot analysis demonstrates the presence of C1r-LP in mouse serum. The serine protease domain of C1r-LP displays 60% amino acid residue identity to that of C1rA, however, certain atypical features of the active center, and primarily the absence of the activation/cleavage site, suggest that C1r-LP is either an atypical enzyme, or it lacks proteolytic activity, perhaps serving a regulatory function in the classical pathway.

Amino Acid Sequence↗
PubMed1987

A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map to 1q32.

The alternative or classical pathways for complement system component C3 may be triggered by microorganisms and antigen-antibody complexes. In particular, an activated fragment of C3, C3b, covalently attaches to microorganisms or antigen-antibody complexes, which in turn bind to the C3b receptor, also known as complement receptor 1. The genes encoding the proteins that constitute the C3-activating enzymes have been cloned and mapped to a "complement activation" locus in the major histocompatibility complex, and we demonstrate in this study such a locus on the long arm of chromosome 1 at band 1q32.

Chromosome Mapping↗
PubMed2003

Anti-complement activity in the saliva of phlebotomine sand flies and other haematophagous insects.

The saliva of haematophagous insects has a series of pharmacological activities which may favour blood feeding. In the present study, an inhibitory effect on the complement system was observed in salivary extracts obtained from the phlebotomine sand flies Lutzomyia longipalpis and Lu. migonei. Saliva from Lu. longipalpis was capable of inhibiting both the classical and alternative pathways, while that from Lu. migonei acted only on the former. Other haematophagous insect species were screened for inhibition of the classical pathway. The triatomine bugs Panstrongylus megistus, Triatoma brasiliensis and Rhodnius prolixus were also able to inhibit the classical pathway whereas the mosquito Aedes aegyti and flea Ctenocephalides felis were not. The activity of Lu. longipalpis saliva on the classical pathway was partially characterized. The inhibitor is a protein of Mr 10000-30000 Da, which is very resistant to denaturation by heat. The inhibition of the complement system by phlebotomine sand flies may have a role in the transmission of Leishmania to the vertebrate hosts. The inhibitor molecule is thus a promising component of a vaccine to target salivary immunomodulators.

Animals↗
PubMed1994

Effect of Melia azedarach L. leaf extracts on human complement and polymorphonuclear leukocytes.

The effect of the water extract of Melia azedarach L. (Meliaceae) leaves on human complement and polymorphonuclear leukocytes was investigated. This extract showed a strong anticomplementary activity, which was more pronounced in the classical pathway assay. The extract did not affect the phagocytic activity of polymorphonuclear leukocytes, nor the respiratory burst of these cells as measured by the nitro blue tetrazolium reduction assay.

Cells, Cultured↗