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PubMed1990

[Studies on polymorphism of C6 in Han nationality of China].

The polymorphism of C6 in three groups of Han nationality was investigated by using polyacrylamide gel isoelectric focusing and immunoblotting technique. The gene frequencies obtained are as follows: Zhangzhou City (Fujiang Province) C6*A:0.4634, C6*B:0.5000, C6*R:0.0366 (C6*B2:0.0317); Chendu City (Sichuan Province) C6*A:0.4975, C6*B:0.4480, C6*R:0.0545 (C6*B2:0.0396); Harbin City (Heilongjiang Province) C6*A:0.4708, C6*B:0.5219, C6*R:0.0073 (C6*B2:0.0073). The frequency of C6*A in Mongoloid populations is usually lower than 0.5, while that of black people ranges between 0.5 and 0.6 and that of white people is higher than 0.6. The other difference between Caucasian and Mongoloid is that the former has very few C6*B2 while the frequency of C6*B2 in the latter ranges from 0.03 to 0.07.

Asian People↗
PubMed1995

Extrahepatic synthesis of C6 in the rat is sufficient for complement-mediated hyperacute rejection of a guinea pig cardiac xenograft.

The liver is the major source of complement (C) components, but extrahepatic sources of C, such as macrophages and endothelial cells, have been hypothesized to contribute to inflammation. Our experiments demonstrate that extrahepatically produced C6 can contribute to hyperacute rejection. PVG (RT1c) rats with normal C activity (PVG (C+)) reject guinea pig cardiac xenografts in 0.5 +/- 0.2 hr, but fully C6-deficient PVG (RT1c) rats (PVG (C-)) reject guinea pig cardiac xenografts in 45 +/- 9 hr. PVG (C+) rats, which received liver transplants from PVG (C-) rats and retained all extrahepatic sources of C6, rejected guinea pig cardiac xenografts in 0.6 +/- 0.03 hr (n = 3). PVG (C-) rats, which received bone marrow transplants from PVG (C+) rats, had C6 levels restored to 10% of that of the donor and rejected guinea pig cardiac xenografts in 9 +/- 3.2 hr (n = 5). Thus, extrahepatic sources of C6 can contribute to xenograft rejection.

Animals↗
PubMed1993

Role of late complement components in experimental autoimmune thyroiditis.

Availability of a line of rabbits deficient in the sixth complement component (C6-D) made it possible to evaluate the role of the terminal complement complex (TCC) in the development of experimental autoimmune thyroiditis (EAT) of the rabbit. Immunization with saline extract of homologous thyroid, known to be composed predominantly of thyroglobulin, led in normocomplementemic (NC) rabbits to severe thyroiditis, with cellular infiltrates occupying 50-95% of the thyroid, and to minimal or moderate thyroiditis, with 1-35% of thyroids infiltrated in C6-D rabbits. Cellular infiltrates consisted predominantly of mononuclear cells with appreciable numbers of granulocytes. Destruction of thyroid follicles was extensive and diffuse in NC rabbits, but it was only minimal and focal in C6-D rabbits. Immunohistology revealed in both groups of rabbits deposits of IgG and C3 along follicular basal laminae. In addition, NC rabbits showed deposition of C6 and MAC in thyroid follicles. These results suggested that TCC is necessary for the development of fully expressed, severe EAT; simultaneously, however, they showed that a significantly reduced EAT can develop without TCC. Administration of NC but not of C6-D rabbit serum to C6-D rabbits resulted in a significant increase in the severity of EAT. It was also shown that C6-D rabbits have "normal" T-cell activity, since they developed experimental autoallergic encephalomyelitis as readily as NC rabbits. Therefore, it is likely that development of EAT is indeed impaired by the C6 deficiency in rabbits. The requirement for TCC observed in this study may be relevant to the understanding of the pathogenesis of Hashimoto's thyroiditis, in which thyroid tissue was recently shown to contain TCC deposits.

Animals↗
PubMed1989

Relative contributions of chemo-attractant and terminal components of complement to anti-glomerular basement membrane (GBM) glomerulonephritis.

The relative contributions of chemo-attractant and terminal components of complement to heterologous phase glomerular injury was studied in anti-GBM glomerulonephritis in rabbits. Normal rabbits (complement intact) were given anti-GBM antibody at a dose which resulted in 140 micrograms specific kidney-fixed antibody per gram of renal cortex, and developed significant proteinuria (1910 +/- 327 mg/24 h; control 18.2 +/- 6.1 mg/24 h; P less than 0.01). Leucocyte depletion significantly reduced but did not abolish proteinuria (574 +/- 186 mg/24 h, P less than 0.05). Complement depletion of neutrophil-depleted rabbits resulted in a further significant reduction in proteinuria 50.1 +/- 12.2 mg/24 h, P less than 0.05; versus neutrophil-depleted, complement-intact rabbits), indicating that both neutrophil accumulation and complement activation independent of neutrophils contribute to injury in this model. Rabbits congenitally deficient in the sixth component of complement (C6D) developed similar levels of proteinuria (2099 +/- 796 mg/24 h) to normal rabbits given an identical dose of antibody. However, after leucocyte depletion, C6D rabbits developed significantly less proteinuria (135 +/- 56 mg/24 h) than did leucocyte-depleted, complement-intact rabbits (P less than 0.05). These studies show that terminal complement components are not necessary for the full expression of acute anti-GBM antibody-initiated injury in leucocyte-intact rabbits. However, in the absence of leucocytes, C6 and the terminal complement components are apparently responsible for the majority of the complement-dependent glomerular injury.

Animals↗
PubMed1979

[C6-polymorphism of the sixth component of complement: application to paternity cases (author's transl)].

The results of a study of the polymorphism of the sixth component of human complement by means of isoelectric focusing in polyacrylamide gels with subsequent C-dependent lysis in an agarose overlay containing C6 deficient rabbit serum are reported. The allele frequencies obtained (C6A = 0.613, C6B = 0.379, C6R = 0.008) are in good agreement with those previously published. The mode of inheritance in 47 families with 173 offspring as well as 26 mother-child combinations is in agreement with a formal genetical model: "C6A, C6B, C6A1 and C6B1 at an autosomal locus". The inclusion of this system into a blood group expertise in Germany can be recommended.

Adult↗
PubMed1975

On the mechanism of cytolysis by complement: evidence on insertion of C5b and C7 subunits of the C5b,6,7 complex into phospholipid bilayers of erythrocyte membranes.

The doughnut hypothesis of cytolysis by complement [Mayer, M. M. (1972) Proc. Nat. Acad. Sci. USA 69, 2954-2958] describes an annular structure made up of C5b-9 (complement factors C5b, C6, C7, C8, and C9) which becomes inserted in the lipid bilayer of the cell membrane, thus creating a hole. We now present initial explorations of this hypothesis. EAC1-6 and EAC1-7 (sheep erythrocytes carrying rabbit antibody and complement factors C1 through C6 or C1 through C7, respectively), prepared with either 125I-C3 or 125I-C5 were incubated with trypsin and the release of bound 125I was measured. In the case of 125I-C3, all of the radioactivity was released by trypsin from both intermediates. With 125I-C5, trypsin released all of the 125I from EAC1-6, but only 40-55% from EAC1-7. Possible reasons for resistance of the C5b subunit in EAC1-7 to tryptic digestion are discussed; in terms of the doughnut hypothesis it would be due to shielding by lipid molecules as a consequence of insertion into the lipid bilayer. In accord with this interpretation we have also found that C5b in EAC1-7, but not in EAC1-6, resists elution by 0.3 M NaC1. Similarly, we have found that 125I-C7 in EAC1-7 resists stripping by trypsin. Hence, we now propose the hypothesis that hydrophobic polypeptide chains from the C5b and the C7 subunits of C5b,6,7 complex become inserted in the phospholipid bilayer and that subsequent reactions with C8 and C9 open a channel across the membrane.

Animals↗
PubMed1997

Complement activation in vitro by the red cell substitute, liposome-encapsulated hemoglobin: mechanism of activation and inhibition by soluble complement receptor type 1.

BACKGROUND: Liposome-encapsulated hemoglobin (LEH) has been developed as an emergency blood substitute, yet its effect on human complement has never been explored. Considering that complement activation is a major pathogenic factor in the respiratory distress syndrome that often develops in trauma and shock, LEH-induced complement activation may be a critical safety issue. STUDY DESIGN AND METHODS: Various LEH and corresponding empty liposomes were incubated with normal human sera, and various markers of complement activation (serum levels of C4d, Bb, SC5b-9, and CH50; C5a-induced granulocyte aggregation; membrane deposition of C3b) were measured. Incubations were also performed in the presence of (ethylene-bis[oxyethylenenitrilo]tetraacetic acid) (EGTA) and Mg++ (EGTA/Mg++) and soluble complement receptor type 1. RESULTS: LEH and liposomes activated human complement, as indicated by significant changes in one or more markers. The effect was primarily due to the presence of the phospholipid vehicle; small, unilamellar, highly homodispersed vesicles induced the greatest degree of complement activation. Complement activation was partially inhibited by EGTA/Mg++. The latter finding, together with the parallel increases in serum C4d and Bb, suggests activation of both the classical and alternative pathways. Soluble complement receptor type 1 (0.05-20 micrograms/mL) efficiently inhibited all vesicle-induced complement activation. CONCLUSION: Because of complement activation, the use of LEH for transfusion may require careful evaluation of safety. Soluble complement receptor type 1 may be useful as a prophylactic agent for complement activation-related complications of liposome infusions.

Blood Substitutes↗
PubMed1990

C6 reference typing report.

Various C6 protein allotypes were examined using polyacrylamide gel isoelectric focusing followed by immunoblotting or hemolytic overlay. For several 'difficult' allotypes, neuraminidase treatment of samples and long-distance isoelectric focusing gels were applied. Nineteen different allotypes were distinguished besides the two common allotypes C6 A and C6 B. They were designated basically according to the previous statement on C6 nomenclature [Mauff et al., 1980].

Complement C6↗
PubMed1983

The activation of human complement component C5 by a fluid phase C5 convertase.

Complement component C5 is converted to C5a and C5b by the cobra venom factor-dependent C3/C5 convertase CVF,Bb (EC 3.4.21.47). The C5 convertase produces selective proteolytic cleavage of an arginyl-leucine peptide bond at positions 74-75 in the alpha chain of C5. Circular dichroism studies in both the far and near UV regions provide evidence that a conformational change accompanies the C5 activation process. When C5 is activated by CVF,Bb in the presence of complement component C6, the C5b,6 complex is formed. However, when C6 is added after C5 has been converted to C5b, the C5b,6 complex fails to form. Therefore, the activation of C5 results in a transient binding site for C6. Hydrophobic sites are probably exposed upon C5 activation because C5b undergoes aggregation when C5 is converted to C5b in the absence of C6. Transmission electron micrographs of the C5 molecule indicate a multilobal, irregular ultrastructure with estimated dimensions of 104 X 140 X 168 A. Aggregated C5b has the appearance of globular particles with a diameter range of 350-700 A. Although C5 shares a number of features with the third component of complement, including a similar ultrastructure and partial sequence homology, C5 is devoid of the unusual thiol ester linkage found in C3. It is the labile thiol ester that permits covalent attachment between C3 and nucleophilic acceptors. In contrast, interactions between C5 and C6 or C5 and membranes remain noncovalent.

Amino Acids↗
PubMed1979

Linkage studies in hereditary angio-oedema.

The locus for hereditary angio-oedema must lie well outside the limits of the HLA complex. Linkage tests with 16 marker loci gave no hint of linkage. In particular, close linkage is excluded for C6, PGM1 MNSs, Gm, Rh, Km, Hp, and ABO.

Angioedema↗
PubMed1976

Separation of six bovine complement components and one inactivator (1, 2).

Six components (C1, C5, C6, C7, C8 and C9) of bovine complement and one inactivator (C3 in) could be separated from bovine serum. Bovine C1 was separated by precipitation at low molarity (0.03 M of relative salt concentration) other components by DEAE-cellulose chromatography using 0.005 M sodium phosphate buffer, pH 7.5, as a base for solvents having the relative salt concentration adjusted by addition of NaCl from 0.03 to 0.3 M. The separated bovine complement components could be tested using intermediates formed from sheep erythrocytes, rabbit hemolysin, guinea pig C1 and remaining human complement components. C2, C3 and C4 of bovine origin remained undetected either because of incompatibility with the intermediates used or interference of inhibitors or inactivators.

Animals↗
PubMed1998

Molecular cloning of a cDNA encoding a serine protease homologous to complement C1s precursor from rat C6 glial cells and its expression during glial differentiation.

A cDNA of rat C6 cells was cloned, which was considered to be involved in glial cell differentiation induced by dibutyryl cyclic AMP and theophylline. The cDNA fragment of the gene, termed r-gsp, was originally isolated by mRNA fingerprinting using arbitrarily primed polymerase chain reaction, and was homologous to complement C1s precursors of hamster and human. It encodes a protein of 694 amino acids containing a potential signal peptide, an epidermal growth factor-like domain surrounded by two complement C1r/C1s-related repeats, and a putative trypsin-type serine protease domain. Since the hamster and human C1s, and a protein encoded by r-gsp shared high similarity in primary structure, the r-gsp gene could encode a C1s counterpart of the rat. Messenger RNA expression of this gene was markedly increased during cyclic AMP-induced glial cell differentiation. Its expression profile was well correlated with those of glial fibrillary acidic protein (GFAP) and S100B, which are known as glial differentiation markers. It was, moreover, observed that the r-gsp expression in brain increased considerably after birth, like those of S100B and GFAP. The results presented here suggest that the rat C1s gene would be also implicated in glial differentiation besides the complement cascade.

Amino Acid Sequence↗
PubMed1987

Inhibition of the lytic activity of perforin (cytolysin) and of late complement components by proteoglycans.

The complement components (C6, C7, C8 and C9) implicated in the lysis of target cells and the pore-forming, lytic protein from cytotoxic T-lymphocytes and NK-cells, perforin, contain an amino acid sequence which is highly homologous to a repeat unit identified in the LDL-receptor (Tschopp et al., 1986, Nature, 322, 831-834). The domain of the LDL-receptor, which is thought to interact with a positively charged segment of its ligands apoprotein B and E, is rich in cysteine residues and contains a cluster of negative charges. We show that the negatively charged molecules suramin and glycosaminoglycans, the positively charged peptides protamine and polylysine, all of which are known to abolish binding of LDL to its receptor (Goldstein et al., 1985, A. Rev. cell. Biol., 1, 1-39) inhibit the lytic activities of C6, C7, C8, C9 and perforin. Moreover, these negatively charged molecules are potent inhibitors of cytolytic T-lymphocyte-mediated lysis of target cells, suggesting a functionally crucial role for perforin in cell-mediated cytolysis. We propose that the negatively charged, cysteine-rich domain of these complement proteins and perforin interacts with an as yet unidentified positively charged segment of its ligand in a manner analogous to the LDL-LDL receptor interaction. Homologous cysteine-rich domains in functionally unrelated proteins may therefore be functionally conserved as ideal rigid interaction domains with the conserved cysteine residues as framework. Specificity of the domain for its ligand would be conferred by the non-conserved amino acid residues.

Cell Line↗
PubMed2003

Effect of plasma exchange in combination with deoxyspergualin on the survival of guinea-pig hearts in macrophage-depleted C6-deficient rats.

The present study aimed to evaluate the effect of plasma exchange (PE) in combination with certain immunosuppressive agents on the survival of guinea-pig hearts in C6-deficient (C6-) rats. To deplete macrophages, we gave liposome-encapsulated dichloromethylene diphosphonate (Lip-Cl2MDP) intravenously (i.v.) in a dose of 10 mg/kg on day 2 before transplantation and every 5 days until rejection. Deoxyspergualin (DSG) was also given i.v. in a dose of 10 mg/kg/day from day -2 until rejection. Plasma exchange was performed 1 day before xenografting. All animals were splenectomized just before heart transplantation. Heart xenografts were evaluated twice daily and harvested at the time of rejection. The serum levels of anti-guinea-pig xenoreactive antibody (IgM, IgG) were measured using enzyme-linked immunosorbent assay (ELISA). Graft survival was 2.8 +/- 0.5 days in control rats, and 4.0 +/- 0.3 days with PE alone. A combination of PE with Lip-Cl2MDP or DSG did not improve the results (4.2 +/- 0.6 days vs. 4.8 +/- 0.6 days, respectively). While in rats treated with PE and the combination of Lip-Cl2MDP and DSG, graft survival was significantly prolonged (6.9 +/- 1.1 days, P < 0.01 vs. controls). In untreated control rats, xenoreactive antibody (IgM, IgG) levels decreased immediately after PE, but their levels rapidly returned to normal. In rats treated with DSG or DSG + Lip-Cl2MDP, the IgM levels remained low during the observation period. Immunohistochemistry showed that macrophage infiltration into the graft was suppressed in Lip-Cl2MDP-treated groups at the time of rejection. Our results demonstrate that sustained suppression of antibody levels can be achieved by PE in combination with DSG and xenograft survival is further prolonged in macrophage-depleted C6- rats. These findings suggest that strategies targeting antibody and macrophages may be useful in prolonging xenograft survival.

Animals↗
PubMed1984

The effect of ethylenedinitrilotetraacetic acid (EDTA) on the reaction between the guinea-pig C5 convertase and guinea-pig C5.

Guinea-pig C5 was reacted with EAC1423 in the washed-cell intermediate assay in the presence of glucose gelatin veronal buffer (GGVB), Zn2+-GGVB (0.025 mM), GGVB2+ containing Ca2+ and/or Mg2+ or EDTA (0.013 M)-GGVB. The EDTA inhibited the formation of competent SAC14235, while Ca2+ and/or Mg2+ had a slight enhancing effect compared to GGVB alone and Zn2+ gave a four-fold increase. Similar results were obtained by using human C5 with guinea-pig C5 convertase and functionally pure guinea-pig C6, C7, C8 and C9. When guinea-pig C6 was incorporated into these various reaction mixtures with guinea-pig C5, its addition markedly reduced the inhibition by EDTA, while Zn2+ still showed an enhancing effect. These results demonstrate that EDTA inhibited formation of competent SAC14235 by preventing activation of C5. The association of C6 with C5 can partially overcome the inhibition of C5 conversion by EDTA and may account for C5 activity in reaction mixtures containing C-EDTA.

Animals↗