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PubMed1982

Distribution of complement factors Bf, C2 and C6 in the Western Pacific.

Complement components Bf, C2 and C6 have been typed in various Micronesian, Polynesian, Melanesian and Indian populations of the Western Pacific. BfS and BfF gene frequencies are heterogeneous throughout the region but the number of alleles in the Bf system is restricted. C2 is also restricted with the C22 gene frequency from 0-1.3% in all groups except Fijian Indians where it is 4.8%. The C6A and C6B frequencies of Polynesians, Melanesians and Fijian Indians are within the narrow range of frequencies reported for these alleles from other parts of the world. In the Micronesians of Nauru, a third polymorphic allele (C6Nauru) occurs together with a number of rare alleles (C6R). The Nauruan C6 gene frequencies are C6A 44.6%, C6B 45.2%, C6Nauru 6.7% and C6R 3.5% C6Nauri is present in low frequencies in most other Western Pacific populations and C6R variants occur in Polynesians.

Alleles↗
PubMed1996

Characterization of the human C6 promoter: requirement of the CCAAT enhancer binding protein binding site for C6 gene promoter activity.

The sixth complement component (C6) is a late-acting complement protein that participates in the assembly of the membrane attack complex. C6 and most of the complement proteins are mainly synthesized in the liver. However, the human hepatoma-derived cell line Hep-G2, which produces the majority of complement proteins, synthesizes traces of C6. Here, we have isolated and characterized the human C6 promoter. Approximately 1 kb of C6 upstream sequence is shown to be sufficient to achieve tissue-specific expression of a luciferase reporter gene in two hepatic (Hep-G2 and Hep-3B) and two extrahepatic cell lines (fibroblast M1 and HeLa) in a manner similar to endogenous C6. There are wide differences in C6 mRNA expression among the four cell lines, whereas Hep-3B expresses high levels of C6, Hep-G2 and M1 poorly synthesize C6, and HeLa completely lacks C6 expression. Deletional and mutational analysis demonstrates that a C/EBP (CCAAT/enhancer binding protein) site located at -67 is required for C6 expression in Hep-3B cells, but it has little effect in M1 and Hep-G2 cells. Electrophoretic mobility shift assays show that this sequence binds to a C/EBP alpha using Hep-3B nuclear extract, but a negligible activity is detected using a Hep-G2 extract. To further investigate whether C/EBP alpha is the limiting factor for C6 expression, we have transfected a C/EBP alpha expression vector into Hep-G2 and Ml cells. C/EBP alpha expression vector dramatically trans-activates the luciferase reporter gene controlled by the C6 promoter, and it partially restores C6 mRNA expression in Hep-G2 cells.

Animals↗
PubMed1979

Structural similarities between C6 and C7 of human complement.

A new method for the isolation of C6 and C7 by affinity chromatography of human serum with anti-C6 and anti-C7 coupled to Sepharose is described. C6 and C7 prepared by this method are hemolytically fully active, homogeneous proteins obtained in 25% yield. A comparison of the properties of isolated C6 and C7 gave the following results: The amino acid composition of the two proteins is very similar. The m.w. calculated from the amino acid content is 124,800 for C6 and 120,800 for C7. Both components are single chain glycoproteins migrating upon electrophoresis at pH 8.6 as beta 2-globulins, Both proteins are polymorphic as detected by isoelectrofocusing in polyacrylamide gels and range in their isoelectric points from pH 6.15 to 6.7. The UV spectra reveal only minor differences; the extinction coefficients are: EC6 = 1.71 cm2 X mg-1 and EC7 = 1.92 cm2 X mg-1. CD-spectra show 8% alpha-helix and 10% beta-structure for C6 and 10% alpha-helix and 14% beta-structure for C7. The structural similarities of C6 and C7 suggest their evolution from a common ancestral gene.

Chemical Phenomena↗
PubMed1995

Human polymorphonuclear leukocytes store large amounts of terminal complement components C7 and C6, which may be released on stimulation.

Secretion of the C factors C7, C6, and C3 by human polymorphonuclear leukocytes (PMNs) and PBMCs was studied by ELISA and immunoblot. The release of C7 and C6 by PMNs during 24 h of culture was 16-fold and 6-fold higher, respectively, than the C3 release, with median concentrations of 50.2 ng/ml, 18.3 ng/ml, and 3.1 ng/ml, respectively. In PBMC cultures, C release was considerably lower, and there was a different secretory pattern with a 6-fold higher release of C3 compared with C7 and C6. Stimulation with PMA led to a more rapid and complete secretion of the components to the culture media, whereas treatment with unopsonized Candida species did not affect the release. PMN release of C factors was not dependent on protein biosynthesis, and there was no indication of a selective uptake of C7 from serum as demonstrated by incubating PMNs from a subject with allotype C7 N in C7 M serum. Thus, the C components were probably produced by the PMNs or their bone marrow precursors before ex vivo culture. In cell lysates of freshly isolated cells, median C7, C6, and C3 contents of 1 x 10(7) PMNs were 149.7, 60.1, and 10.4 ng/ml, respectively, whereas the corresponding values for 1 x 10(7) PBMCs were 3.2, 2.6, and 14.6 ng/ml, respectively. The C6 and C7 were shown to incorporate into the terminal complement complex, and their molecular integrity was supported by identical m.w. to C6 and C7 present in normal serum. PMNs may represent a major source of C7 and C6 and may be more important than monocytes or macrophages in contributing terminal C components at a site of inflammation. This suggests a new role for the PMN as a C membrane attack modulator.

Candida↗
PubMed2002

C6-like and C3-like molecules from the cephalochordate, amphioxus, suggest a cytolytic complement system in invertebrates.

The mammalian immune system has cytotoxic mechanisms, both cellular and humoral, that destroy the membrane integrity of target cells. The main effector molecules of these cytolytic mechanisms-perforin, used by killer lymphocytes, and the membrane attack complex (MAC) components of the complement system-share a unique module called the MAC/perforin module. Until now, both immunological cytotoxicity and the MAC/perforin module have been reported only in jawed vertebrates. Here, we report the identification of a protein containing the MAC/perforin module from the invertebrate cephalochordate, amphioxus ( Branchiostoma belcheri), using expressed sequence tag (EST) analysis of the notochord. The deduced amino acid sequence of this molecule is most similar to the primary structure of human complement component C6 and is designated AmphiC6. AmphiC6 shares a unique modular structure, including the MAC/perforin module, with human C6 and other MAC components. Another EST clone predicts the presence of a thioester-containing protein with the closest structural similarity to vertebrate C3 (therefore designated AmphiC3). AmphiC3 retains most of the functionally important residues of vertebrate C3 and is shown by phylogenetic analysis to be derived directly from the common ancestor of vertebrate C3, C4, and C5. Only opsonic activity has been assigned to the invertebrate complement system until now. Therefore, this is the first molecular evidence for complement-mediated immunological cytotoxicity in invertebrates.

Amino Acid Sequence↗
PubMed1976

Purification of the sixth and seventh component of human complement without loss of hemolytic activity.

Procedures for the isolation of the human complement proteins C6 and C7 have been described. These procedures allow isolation of the two proteins without any loss of hemolytic activity. Apparent activity gains of 160% and 140% were observed for C6 and C7, respectively, when the activity of the isolated proteins was compared with their activity in serum. The recovery of C6 was 3.5 to 11% and that of C7 was 7 to 13% of the amount present in serum. C6 has a m.w.of 128,000 and an electrophoretic mobility at pH 8.6 of -2.6 times 10(-5) cm2 s-1 v-1. C7 has a m.w. of 121,000 and an identical electrophoretic mobility. With 3 times 10(7) assay cells, 63% hemolysis was achieved with 1 ng of C6 and 3.8 ng C7. On polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate and after reduction with mercaptoethanol, C6 and C7 behaved as single polypeptide chain proteins.

Complement C6↗
PubMed1983

Functional identification of serum complement components following electrophoresis in polyacrylamide gels containing sodium dodecyl sulphate.

A method is described for detecting the active complement components C6 and C7 after polyacrylamide gel electrophoresis (PAGE) of whole serum in the presence of sodium dodecyl sulphate (SDS). The method involves the removal of SDS by washing with non-ionic detergent followed by the application of an erythrocyte/agarose gel to detect haemolytic activity. Two forms of human C6 with apparent molecular weights of approximately 121,000 daltons and 114,000 daltons were observed. Major activity resided in the 121,000 dalton species. The 2 forms of human C6 were not related to known genetic polymorphisms for this component. Analysis of sera from different animal species showed that not all possessed the 2 forms of C6 and that there were interspecies differences in C6 molecular weights. These are most marked in the case of human and murine C6; the major form of murine C6 had a molecular weight approximately 20,000 daltons less than the major human form. One form of human C7 with an apparent molecular weight of 104,000 daltons was seen. The molecular weights of C7 from the various animal sera tested did not differ significantly from this. Studies with reducing agents and metabolic inhibitors showed that both C6 and C7 required intact disulphide bonds and sulphydral groups for functional activity.

Animals↗
PubMed1983

The genetics of the sixth and seventh components of complement in the dog: polymorphism, linkage, locus duplication, and silent alleles.

The complement components C6 and C7 exhibit genetic polymorphism in the domestic dog. In the case of C6, there is a single locus with a null allele and two structural alleles; in the case of C7, there are two linked loci, each with three structural alleles. There is a null allele or locus deletion at one of these loci. In all cases, inheritance is autosomal and codominant. The C7 loci are closely linked to each other and to C6. This complex is not close to the dog major histocompatibility complex (MHC) locus.

Alleles↗
PubMed1987

Terminal complement components play a role in the expression of C5a.

This study examined the expression of C5a detected antigenically (RIA) and functionally (PMN-myeloperoxidase release) consequent to classical or alternative pathway convertase cleavage. Maximal C5a expression occurred when C5 was cleaved in the presence of the later-acting complement components, C6, C7, and C8. This effect was detected by using both purified components and normal human serum immunochemically depleted of C7 or C8 and reconstituted with the purified component. C6 alone was not sufficient to augment C5a expression. Subsequent incubation of C6 and C7 with C5 cleaved in the absence of the terminal components was not sufficient for C5a release. Repeated freezing and thawing of C5 cleaved in the absence of C6 and C7 produced C5a equivalent to that detected when convertase cleavage occurred in the presence of the terminal components. Mild detergent treatment of convertase-cleaved C5 was not sufficient for C5a release. We believe that these data indicate a role for the terminal complement components in the expression of both C5a antigen and function. The mechanism for this effect is not known, but it may involve conformational changes in the C5 molecule that occur during membrane attack complex formation.

Complement C5↗
PubMed1997

Factors involved in rejection of concordant xenografts in complement-deficient rats.

BACKGROUND: Factors that contribute to xenograft (Xg) rejection were investigated in complement C6-deficient (C-) PVG rats. METHODS: First and second hamster hearts were transplanted in C6-deficient and C6-sufficient PVG rats. Xenoantibody (XAb) formation, hemolytic C (CH50) activity and immunohistochemistry were studied. RESULTS: PVG C6-deficient rats rejected Xgs 3 days later than PVG C6-sufficient rats. Surprisingly, C activation participated in the rejection in PVG C- rats, as shown by partially recovered serum CH50 levels and deposition of C factors in the Xgs. As we found that cultured endothelial cells produced C6 in vitro, we hypothesized that Xg endothelial cells corrected the C6 defect in PVG C- rats. This was probably induced by IgM XAbs as: (1) it did not occur in immunosuppressed PVG C- rats in which XAb formation was prevented, and (2) transfer of IgM XAbs to naive, xenotransplanted PVG C- rats accelerated the recovery of CH50 and concomitantly Xg rejection. Thirty days after rejection of a first Xg, when no IgM XAbs or CH50 activity but high levels of IgG XAbs were detected in PVG C- rats, second Xgs underwent a hyperacute rejection. This time, complement was not involved, as no serum CH50 nor C deposition was found in the Xg. Instead, IgG antibody-dependent cellular cytotoxicity was involved as: (1) IgG XAbs were deposited in the Xg and (2) hyperacute rejection was induced in naive PVG C- rats by transfer of IgG XAbs, and (3) this rejection was delayed to 5+/-3 days if the adoptive hosts were first irradiated. CONCLUSIONS: In the face of a defect of host C factors, IgM XAb may induce cells of the Xg to secrete C factors which may correct the C defect of the host. Even if activation of lytic C can be prevented, IgG XAb may still provoke an acute Xg rejection by antibody-dependent cellular cytotoxicity.

Animals↗
PubMed1975

Consumption of classical complement components by heart subcellular membranes in vitro and in patients after acute myocardial infarction.

Experiments were conducted to characterize the antibody-independent activation of complement in human serum by isolated human heart mitochondrial membranes in vitro and to determine whether similar patterns of complement consumption occurred in patients after acute myocardial infarction. Direct evidence for the interaction of C1 and heart mitochondrial membranes was obtained by mitochondria-C1 binding and elution experiments. Exposure of normal human sera to isolated human heart mitochondria at 37 degrees C resulted in the consumption of C1, C4, C2, and C3 without significant consumption of the terminal components of the complement system (C6 through C9). The consumption occurred in the absence of detectable anti-heart mitochondria autoantibody, was demonstrated to be calcium dependent, and was inhibited by either 0.01 M EDTA or ethylene glycol bis(bets-aminoethyl ether) N,N,N',N',-tetraacetic acid (EDTA). Although specific absorption of C1q from human sera inhibited the mitochondria-dependent activation of C4, C3 donsumption was not affected. These data indicate that the consumption of C4 and C2 likely occurred due to the mitochondrial membrane-mediated activation of C1, but that the consumption of the C3 did not necessarily involve either the classical or alternative complement pathways. After the in vitro characterization of the mitochondria-dependent activation of the complement system, additional studies were performed to determine whether similar consumption occurred in patients after acute myocaridal infarction. During a 72-h period after hospital admission significant decreases in C1, C4, and C3 occurred in six patients with recent chest pain but no evidence of acute myocardial infarction. These studies suggest that myocardial cell necrosis results in the release of subcellular membrane constituents capable of activating the complement system in the absence of detectable anti-heart autoantibodies; such activation may be responsible in part for the development of acute inflammation and evolution of the infarct size following coronary artery occulusion.

Autoantibodies↗
PubMed2002

Modulation of leukocyte recruitment and IL-8 expression by the membrane attack complex of complement (C5b-9) in a rabbit model of antigen-induced arthritis.

The complement system is thought to be a major physiological mediator of injury in a number of diseases including rheumatoid arthritis (RA). The membrane attack complex (MAC) of complement has been detected in RA tissue, suggesting that the MAC may be relevant to the pathogenesis of the disease. Deposition of sublytic concentrations of the MAC has been shown to promote the expression of proinflammatory mediators. In the present study, we utilized rabbits deficient in the complement protein C6 to elucidate the role of the MAC in mediating the pathogenesis of antigen-induced arthritis. Swelling, leukocyte accumulation, IL-8 expression, proteoglycan, and hydroxyproline content were assessed. Analysis of synovial tissue demonstrated a significant decrease in leukocyte influx and a parallel decrease in tissue associated IL-8 in joints of C6-deficient animals as compared to C6-sufficient animals. However, this did not correlate with the preservation of connective tissue. The results derived from this study provide evidence that the MAC has an important function in mediating leukocyte recruitment in antigen-induced arthritis but does not play a direct role in connective tissue breakdown.

Animals↗
PubMed2000

[C6 deficiency].

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Autoimmune Diseases↗
PubMed1993

Structure of the human C6 gene.

The terminal components of the complement system (C6-C9) are related proteins, differing in size and complexity. They seem to be typical mosaic proteins, composed of modules which are homologous with parts of other proteins. Individual elements in a mosaic protein are often bounded by introns in the gene, and where they are duplicated within a polypeptide, partial gene duplication within the gene is responsible. It is often found in such genes that the intron/exon boundaries are of the class 1 type. We have examined the boundaries of 17 of the 18 exons of C6 and five of C7. When considered with published data for C9, only one of the protein elements appears to follow the conventional pattern. These data suggest a more complex evolutionary history for the genes of the terminal complement components than had been anticipated and challenge the notions both that discovery of a recognized protein module is of predictive value in relation to gene structure and that these genes evolved from the simple to the complex.

Amino Acid Sequence↗