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PubMed2004

Protective function of complement against alcohol-induced rat liver damage.

The complement system can promote tissue damage or play a homeostatic role in the clearance and disposal of damaged tissue. We assessed the role of the terminal complement pathway in alcohol-induced liver damage in complement C6 (C6-/-) genetically deficient rats. C6-/- and corresponding C6+/+ rats were continuously exposed to ethanol by feeding ethanol-supplemented liquid diet for six weeks. Liver samples were analyzed for histopathology and complement component deposition by immunofluorescence microscopy. Prostaglandin E receptors and cytokine mRNA levels were analyzed by RT-PCR and plasma cytokines by ELISA. Deposition of complement components C1, C3, C8 and C9 was observed in C6+/+ rats, but not in C6-/- animals. The histopathological changes, the liver weight increase and the elevation of the plasma pro-/anti-inflammatory TNF-alpha/IL-10 ratio were, on the other hand, more marked in C6-/- rats. Furthermore, ethanol enhanced the hepatic mRNA expression of the prostaglandin E receptors EP2R and EP4R exclusively in the C6-/- rats. Our results indicate that a deficient terminal complement pathway predisposes to tissue injury and promotes a pro-inflammatory cytokine response. This suggests that an intact complement system has a protective function in the development of alcoholic liver damage.

Alcoholism↗
PubMed1979

Simultaneous occurrence of hereditary C6 and C2 deficiency in a French-Canadian family.

The sera of four sisters were found to lack the sixth component of complement (C6) and the serum of one was also partially deficient in the second component (C2). Two other blood relatives were found to be heterozygous for both deficiencies, while only one sibling had normal values. The father of these eight siblings was heterozygous for C2D and C6D and in the third generation, six children were heterozygous for C6 deficiency was treated for chronic active brucel-transmitted; the C6 deficiency was not linked to the HLA system, while the C2-deficiency segregated with the haplotype A10,B18. The proband, homozygous for C6 deficiency was treated for chronic active Brucellosis and in another sibling with C6 deficiency, toxoplasmosis was diagnosed. Neither bleeding disorders nor a tendency to collagen diseases have been observed and the opsonic activity was normal in the sera of all family members.

Adult↗
PubMed1986

Family study on the polymorphisms of the sixth and seventh components (C6 and C7) of human complement: linkage and haplotype analyses.

Genetic polymorphisms of the sixth and seventh complement components (C6 and C7) have been studied in Japanese family material using polyacrylamide gel isoelectric focusing followed by immunoblotting. Three common and four rare alleles were observed at the locus for C6. Inheritance of the two rare C6 variants, M11 and B3, was first confirmed. Three common C7 allotypes were classified as C7 1, C7 2, and C7 4, respectively. Linkage analysis confirmed the close linkage between the loci for C6 and C7. The maximum lod score was 8.43 at phi = 0 (95% confidence limits: phi = 0 and phi = .07). No significant linkage disequilibrium was found between C6 and C7 in directly determined haplotypes of unrelated parents.

Alleles↗
PubMed1985

C6 polymorphism in Japanese: typing by agarose gel isoelectric focusing-immunofixation.

Agarose gel isoelectric focusing was used to investigate the genetic polymorphism of the sixth component of complement (C6) in Japanese. C6 patterns were visualized by the immunofixation procedure. The allele frequencies calculated from 135 individuals were as follows: C6*A = 0.467, C6*B = 0.481, C6*B2 = 0.037, and C6*B3 = 0.015. It is suggested that C6*B3 is the fourth common allele characterizing the Japanese population.

Adult↗
PubMed1999

The terminal sequence of complement plays an essential role in antibody-mediated renal cell apoptosis.

Mesangial cell (MC) injury is a characteristic feature in the early phase of Thy.1 nephritis. The present study investigates the contribution of complement to MC apoptosis in this experimental model of kidney disease in rats. Thy.1 nephritis was induced by injection of mouse anti-Thy.1 monoclonal antibody (ER4G). To assess the contribution of the terminal sequence of complement on apoptosis, the studies were performed in complement-sufficient PVG/c (PVG/c+) rats and in rats deficient in complement C6 (PVG/c-). Apoptosis was monitored by assessment of the number of condensed nuclei in kidney sections stained with periodic acid-Schiff (PAS) and by the terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) method and expressed as number of apoptotic cells per 50 glomerular cross sections. In the PAS method, 1 h after intravenous injection of ER4G, PVG/c+ rats exhibited 160.9 +/- 49.5 apoptotic cells, whereas PVG/c- rats had only 3.2 +/- 1.4 apoptotic cells. Control rats exhibited 0.9 +/- 0.6 apoptotic cells. These findings were confirmed with the TUNEL method. In PVG/c- rats, a maximum number of 8.8 +/- 3.1 TUNEL-positive (TUNEL+) cells was found at 6 h followed by a decline thereafter. In PVG/c+ rats, apoptosis was associated with deposition of C6 and C5b-9. Restoration of the complement system of PVG/c- rats with purified human C6 resulted in an increase of apoptosis at 1 h after injection of ER4G from minimal numbers to 239.9 +/- 52.4 TUNEL+ cells. These studies appear to indicate for the first time that the terminal sequence of complement is involved in induction of apoptosis.

Analysis of Variance↗
PubMed1995

Importance of the third thrombospondin repeat of C6 for terminal complement complex assembly.

The anti-C6 monoclonal antibody WU 6-4 was shown to be unequivocally native restricted since it neither binds to the terminal complement complex (TCC) nor to C5b6. In addition, it was shown to inhibit TCC formation by interfering with C5b6 generation. Using the pUEX expression system and C6 cDNA the WU 6-4 epitope was mapped to the third thrombospondin repeat of C6. This protein domain may therefore contribute to the C5 binding site of C6 and be involved in terminal complement complex assembly. The presence of the epitope in rabbit C6 indicates a useful model for studying inhibition of TCC formation in vivo.

Animals↗
PubMed1979

Recurrent meningococcal meningitis with absence of the sixth component of complement: an evaluation of underlying immunologic mechanisms.

A 51/2-year-old black girl with recurrent meningococcal meningitis and absence of the sixth component of complement (C6) is reported. To explore the pathogenesis of recurrent neisserial infections in C6 deficiency, a detailed analysis of her immune competence was conducted. Her serum had normal chemotactic, opsonic, alternative complement pathway, and specific antibody activity, but lacked complement-mediated bacteriolytic activity. In addition, her C6-deficient serum was indistinguishable from normal serum in a complement-dependent assay of phagocyte bactericidal activity. Absent bacteriolysis remains the only consistent defect associated with recurrent neisserial infections and absence of one of the late-acting complement components.

Blood Bactericidal Activity↗
PubMed1990

Prophylaxis against Neisseria meningitidis infections and antibody responses in patients with deficiency of the sixth component of complement.

Forty South African patients with homozygous deficiency of the sixth component of complement (C6) have been identified in an area where group B meningococcal meningitis is endemic; 22 of the 24 proband cases presented with recurrent meningococcal meningitis. In a 2- to 4-year prospective study, patients with recurrent infections who received monthly prophylactic long-acting penicillin were significantly protected from subsequent neisserial infection compared with those who did not receive penicillin (P = .02, Fisher's exact test). Heterogeneous susceptibility to neisserial infection was confirmed by following C6-deficient patients who presented with one or no Neisseria meningitidis infections. These patients, on no prophylaxis, had significantly fewer infections (P = .004) than did patients who presented with recurrent disease. Functional C6 activity was restored by transfusion of fresh frozen plasma in a C6-deficient patient resistant to conventional antibiotic treatment. Antibody levels to the serotype 2 outer membrane proteins were significantly elevated in C6-deficient patients compared with control groups (P = .001).

Antibodies, Bacterial↗
PubMed1974

Hereditary deficiency of the sixth component of complement in man. I. Immunochemical, biologic, and family studies.

An 18-yr-old black woman in good general health was found to lack serum hemolytic complement activity. The sixth component of complement (C6) was undetectable by functional assay of serum or plasma and by immunoprecipitin analysis of serum. Functional titers of all other complement components were normal. The absence of C6 in the patient's serum could not be accounted for by a circulating C6 inhibitor, and addition of functionally pure C6 to the patient's serum restored hemolytic activity to normal. Both parents of the proband and five of six available siblings had approximately half the normal levels of functional C6. The other sibling had a normal C6 level. These data suggest that both parents and five siblings are heterozygous for C6 deficiency, while the proband is homozygous and one sibling is normal. Thus, C6 deficiency appears to follow classic mendelian inheritance, with all three possible genotypes recognizable within the family. Functional properties of the proband's C6-deficient serum included total absence of bactericidal activity against Salmonella typhi 0 901 and Hemophilus influenzae, type b, and inability to mediate lysis of red blood cells from patients with paroxysmal nocturnal hemoglobinuria in either the acidified serum or "sugar water" tests. The proband's serum did, however, exhibit a normal capacity (a) to generate chemotactic activity during incubation with bacterial endotoxin or aggregated IgG, (b) to mediate the immune adherence phenomenon, and (c) to coat human red blood cells, sensitized by cold agglutinins, with C4 and C3.

Adolescent↗
PubMed1974

Hereditary deficiency of the sixth component of complement in man. II. Studies of hemostasis.

Prompted by previous observations of defective blood clotting in rabbits deficient in the sixth component of complement (C6), an evaluation was made of the hemostatic functions of the homozygous proband of a newly recognized human kindred with hereditary C6 deficiency. This human subject, who had no clinical evidence of a bleeding disorder, exhibited a total lack of C6 by functional and immunoprecipitin assays of serum or plasma. Standard tests of hemostatic function were normal; however, when the whole blood clotting time was measured at 25 degrees C in plastic tubes, it was at the upper range of our normal values. In confirmation of this observation, prothrombin consumption, when performed at 37 degrees C in plastic tubes, was at the lower range of normal. Inulin and endotoxin, in concentrations shown to cause activation of human complement, had little or no effect on clotting times or prothrombin consumption of normal or C6-deficient human blood. These observations indicate that absence of C6 does not have a significant effect on hemostatic function in man. In the light of other investigations, the observed differences in clotting function between C6-deficient human blood and C6-deficient rabbit blood could be due to species differences governing the susceptibility of platelets to complement activation.

Complement C6↗
PubMed2001

Detection of mRNA for the terminal complement components C5, C6, C8 and C9 in human umbilical vein endothelial cells in vitro.

Human umbilical vein endothelial cells (HUVEC) have previously been shown to synthesize the functional terminal pathway of complement based on the detection by radioimmunoassay of the terminal complement complex (TCC) on coincubated agarose beads. In addition, C7 secretion by these cells in amounts comparable to C3, as well as C7 mRNA, has recently been demonstrated. However, it has not been possible to detect C5-6 and C8 in the fluid phase, and only trace amounts of soluble C9. Against this background we examined whether mRNA for the remaining terminal complement factors was present in HUVEC. By the use of reverse transcription (RT)-polymerase chain reaction (PCR) and Northern blot the presence of mRNA for complement factors C5, C6, C8 and C9 was demonstrated.

Base Sequence↗
PubMed1971

Blood coagulation initiation by a complement-mediated pathway.

A variety of complement-activating substances, including inulin, immunoglobulin aggregates, bacterial endotoxins, and staphylococcal protein A, were found to initiate blood coagulation through a complement-mediated pathway. These substances markedly accelerated blood coagulation in normal rabbit blood. That this clot-promoting activity requires an intact complement system was demonstrated by an almost total lack of effect on blood from rabbits with an inherited deficiency of the sixth component of complement (C6). Small amounts of isolated C6 conferred to C6-deficient blood the ability to respond with accelerated coagulation upon activation of the complement system. In addition, it was determined that activation of complement through the previously described C3 activator system resulted in the initiation of blood coagulation. The participation of C1, C2, and C4 was not necessary.

Animals↗
PubMed1992

[Genetic polymorphism of complement component six (C6) in five Han subpopulations].

By using polyacrylamide gel isoelectric focusing followed by immunoassay, the polymorphism of Complement Component Six (C6) was investigated in five Han subpopulations in China. The following gene frequencies were obtained Zhengzhou Han: C6*A 0.4521, C6*B 0.5228, C 6*B2 0.0183, C6*R 0.0068; Lanzhou Han: C6*A 0.4612, C6*B 0.5218, C6*B2 0.0170; Huhhot Han: C6*A 0.4452, C6*B 0.5286, C6*B2 0.0214, C6*R 0.0048; Xi'an Han: C6*A 0.4899, C6*B 0.4874, C6*B2 0.0126, C6*R 0.0101; Hakka of Meizhou, Guangdong Province: C6*A 0.4569, C6*B 0.5152, C6*B 0.0279 (C6*R is the frequency of rare alleles).

China↗
PubMed1974

Complement-dependent stimulation of prostaglandin synthesis and bone resorption.

Complement-sufficient heterologous serum induced prostaglandin synthesis and resultant resorption in cultures of fetal rat long bones. Bone resorption was enhanced with unheated normal rabbit serum as compared to heated serum or serum from rabbits lacking the sixth component of complement (C6). Addition of functionally purified C6 restored resorptive activity in C6-deficient serum. Concentrations of prostaglandin E were increased in the culture media of bones incubated with complement-sufficient serum. The resorptive effects of active serum as well as the appearance of prostaglandin E in the media were inhibited by indomethacin.

Animals↗
PubMed1991

Functional and structural domains of the sixth component (C6) of human complement.

The effects of serine protease inhibitors, diisopropyl fluorophosphate (DFP) and phenylmethanesulfonyl fluoride (PMSF), on hemolytic activity of C6 were reinvestigated. C6 was inactivated in a range of 1-10 mM by both of the inhibitors as previously reported. Limited proteolytic digestion was also studied to elucidate the functional and structural domains of C6. The major fragments produced by trypsin, plasmin, or lysyl endopeptidase could not be separated unless disulfide bonds were disrupted, but Staphylococcus aureus V8 protease yielded several fragments, each of which was not linked by disulfide bond. When C6 labeled with [3H]DFP was subjected to limited digestion with V8 protease, a fragment with a molecular weight of 38 kilodaltons (kDa) was mainly labeled and other fragments of 53 kDa and 26.4 kDa were also faintly labeled, while fragment 35 kDa wasn't labeled, indicating specific domains reactive with DFP. On the other hand, when C6 with or without DFP treatment was digested with V8 protease and those fragments were incubated with C5 and subjected to sucrose density ultracentrifugation, fragments 53, 38, 35 and 27.5 kDa interacted with C5 in both cases. These results suggest that C6 modified by DFP can interact with C5, and the amino-terminal sequences of fragment 38 and 35 kDa suggest the binding domain of C6 with C5 takes place within the two short consensus repeats.

Complement C6↗
PubMed1986

Synthesis of complement components C5, C6, C7, C8 and C9 in vitro by human monocytes and assembly of the terminal complement complex.

Monocytes cultured under serum-free conditions secreted protein which bound covalently and non-covalently to agarose beads, an activator of the alternative pathway of complement. There was a significantly binding of monoclonal anti-C3c antibodies, polyclonal anti-C5, anti-C6, anti-C7, anti-C8, and anti-C9 antibodies, and of a monoclonal antibody against a neoantigen of polymerized C9 to agarose beads incubated with the monocytes for 24, 48, 72 or 96 h. From these results, we conclude that monocytes produce C5, C6, C7, C8 and C9 that assemble as the terminal complement complex on the surface of the agarose beads. Activation by agarose of the alternative pathway with generation of particle bound C3 and C5 convertases is a prerequisite for the subsequent formation of the terminal complement complex. Whether SC5b-9 or the membrane attack of complement (C5b-9) is formed on the beads will be examined.

Antibodies, Monoclonal↗
PubMed2001

Reduction in the local expression of complement component 6 (C6) and 7 (C7) mRNAs in oesophageal carcinoma.

Differential displays of tumour/normal pair specimens of human oesophagus identified complement component 7 (C7) as being enhanced in normal tissues, but remarkably reduced in carcinoma tissues. In situ hybridisation confirmed the localisation of C7 mRNA in normal oesophageal epithelial cells and its disappearance in tumour cells. When mRNA expressions of other components were examined by means of semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in 10 tumour/normal pair specimens, significant reductions in C6 and C7 mRNAs were observed, while C3 and C5 mRNAs were enhanced in both normal and tumour tissues. A similar reduction was observed in colon and kidney cancers using the tumour/normal expression array analysis. Gene deletion of C7 was not found in the cell lines by Southern blot analysis. Our findings suggest a possible relationship between oesophageal tumorigenesis and reduced expression of C6 and C7 mRNAs, which is probably caused by a change in gene expression regulation and not by genetic loss of the locus.

Animals↗