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PubMed1986

Cloning and sequencing of full-length cDNA encoding the precursor of human complement component C1r.

The sequencing of human liver cDNA clones encoding the entire C1r precursor protein has confirmed the previously determined peptide sequence and has shown that there is a leader peptide which is 17 amino acids long. A residue tentatively identified as beta-hydroxyaspartic acid [Arlaud, Willis & Gagnon (1986) Biochem. J., in the press] located in the C1r A-chain, within an epidermal-growth-factor consensus sequence, was found to be encoded as asparagine. Two sequence elements, tandemly located in the A-chain, are related to a sequence widespread among proteins which interact with C3b or C4b. Structural comparisons between different clones indicate that multiple polyadenylation sites are responsible for the length heterogeneity observed for C1r mRNA from liver and Hep G2 cells.

Base Sequence↗
PubMedDate not supplied

Bf S gene frequency in Nigerians with HIV infection.

Complement immunogenetic susceptibility to human immunodeficiency virus (HIV) infection was examined in 40 Nigerians with serological and/or clinical evidence of the infection. A mild increase in C4A null alleles (C4AQO) frequency was observed in the patient group compared to a group of healthy subjects (25 per cent vs 17 per cent) but overall the HIV infected and the reference groups did not differ significantly in the frequency of alleles of C4A or C4B. In contrast, properdin factor B (Bf) S gene frequency was significantly higher in the patients with HIV infection (p less than 0.025). There was a concomitant decrease in Bf F allele and gene frequencies (p less than 0.01, and p less than 0.05), respectively. Furthermore, blank Bf allotypes due to excessive complement consumption were detected in two asymptomatic patients. These findings suggest that Major Histocompatibility Complex (MHC) located complement genes may be important HIV infection. In particular Bf S gene or even C4AQO alleles may be permissive or influence outcome of infection with HIV.

Adult↗
PubMed1985

Polymorphism of human complement component C4.

An assessment has been made of the polymorphism of human complement component C4 by comparing derived amino acid sequences of cDNA and genomic DNA with limited amino acid sequences. In all, one complete and six partial sequences have been obtained from material from three individuals and include two C4A and two C4B alleles. Differences were found between the 4 alleles from 2 loci in only 15 of the 1722 amino acid residues, and 12 lie within one section of 230 residues, which in 1 allele also contains a 3-residue deletion. In three variable positions, an allelic difference in one C4 type was common to the other types. Three nucleotide differences were found in four introns. In spite of marked differences in their chemical reactivity, the many allelic forms appear to differ in less than 1% of their amino acid residue positions. This unusual pattern of polymorphism may be due to recent duplication of the C4 gene, or may have arisen by selection as a result of the biological role of C4, which interacts in the complement sequence with nine other proteins necessitating conservation of much of the surface structure.

Amino Acid Sequence↗
PubMed1988

Polymorphism of MHC class III genes: definition of restriction fragment linkage groups and evidence for frequent deletions and duplications.

The loci for the complement proteins BF and C2 and the two loci for C4 are closely linked to one another, as are the duplicated steroid 21 hydroxylase (21-OHase) genes to the C4A and C4B loci. The alleles of these four loci occur in specific combinations termed "complotypes". We have studied the gene frequencies of their different products in the Lebanese population and compared these values with those found in other populations. We observed a novel complotype (S B 4 6) in one family and a complotype with a so far undescribed variant of the C4A locus. Using several restriction fragment length polymorphisms (RFLPs), we have defined restriction fragment linkage groups. The combined use of C4 and 21-OHase probes allowed us to detect different types of deletions and duplications at these loci in the Lebanese population.

Chromosome Deletion↗
PubMed1997

The internal thioester and the covalent binding properties of the complement proteins C3 and C4.

The covalent binding of complement components C3 and C4 is critical for their activities. This reaction is made possible by the presence of an internal thioester in the native protein. Upon activation, which involves a conformational change initiated by the cleavage of a single peptide bond, the thioester becomes available to react with molecules with nucleophilic groups. This description is probably sufficient to account for the binding of the C4A isotype of human C4 to amino nucleophiles. The binding of the C4B isotype, and most likely C3, to hydroxyl nucleophiles, however, involves a histidine residue, which attacks the thioester to form an intramolecular acyl-imidazole bond. The released thiolate anion then acts as a base to catalyze the binding of hydroxyl nucleophiles, including water, to the acyl function. This mechanism allows the complement proteins to bind to the hydroxyl groups of carbohydrates found on all biological surfaces, including the components of bacterial cell walls. In addition, the fast hydrolysis of the thioester provides a means to contain this very damaging reaction to the immediate proximity of the site of activation.

Complement C3↗
PubMed1982

Mechanism of enhanced complement-dependent cytotoxicity of papain-treated lymphocytes: evidence for increased stability of classical pathway C3 convertase.

The mechanisms of enhanced antibody-mediated, complement-dependent cytotoxicity caused by proteolytic treatment of cells was studied in a model system based on HLA microlymphocytotoxicity methods. In this model, papain treatment of lymphocytes resulted in a) no change in antibody binding, b) a slight decrease in initial binding of C4, c) a marked increase in stability of cell-bound C4b, resulting in d) an increase of cell-bound C3, and e) no increase in lytic efficiency of the C5b-9 membrane attack complex. We conclude that the most important step in papain enhancement of lysis of lymphocytes is an increased stability of cell-bound C4b, possibly through decreased surface binding of C4-bp. This mechanism may be relevant to the pathologically increased lysis of cells occurring in patients with hereditary erythroblastic multinuclearity with a positive acidified-serum test (HEM-PAS).

Anemia, Dyserythropoietic, Congenital↗
PubMed2006

Molecular defects of the C7 gene in two patients with complement C7 deficiency.

Different genetic mutations have been described in complement components resulting in total or subtotal deficiency states. In this work we report the genetic basis of C7 deficiency in a previously reported Spanish patient exhibiting a combined total deficiency of C7 and C4B associated with systemic lupus erythematosus. Exon-specific polymerase chain reaction and sequencing revealed a not previously described single base mutation in exon 10 (T1458A) leading to a stop codon that causes the premature truncation of the C7 protein (C464X). Additionally, a C to A transversion at position 1561 (exon 11) was found in the patient resulting in an amino acid change (R499S). This latter mutation has been previously reported in individuals with subtotal C7 deficiency or with combined subtotal C6/C7 deficiency from widely spaced geographical areas. Another novel mutation was found in a second patient with meningococcal meningitis of Bolivian and Czech origin; a 11-base pair deletion of nucleotides 631-641 in exon 6 leading to the generation of a downstream stop codon causing the premature truncation of the C7 protein product (T189 x 193). This patient was found to be a heterozygous compound for another mutation in C7; a two-base pair deletion of nucleotides 1922 and 1923, 1923 and 1924 or 1924 and 1925 in exon 14 (1922delAG/1923delGA/1924delAG), leading again to the generation of a downstream stop codon that provokes the truncation of the C7 protein (S620x630). This latter mutation has been recently reported by our group in another Spanish family. Our results provide more evidences for the heterogeneous molecular basis of C7 deficiency.

Adult↗
PubMed1982

The purification and properties of the second component of guinea-pig complement.

A method has been developed for the purification to homogeneity of guinea-pig complement component C2. Contrary to previous reports, guinea-pig C2 is a single polypeptide chain with apparent mol.wt. of 102000, the same as human C2. It is cleaved by C1s to yield fragments C2a (apparent molwt. 74000) and C2b (apparent mol.wt. 34000). The amino acid composition and N-terminal sequences of these fragments are similar to those of human C2a and C2b. Human and guinea-pig C2 show more extensive sequence homology to Factor B than previously identified. The known homology around the sites of cleavage by C1s and Factor D has now been extended by a stretch of ten identical or conservatively substituted residues. Sequence homology has now been identified at the N-terminal of C2b and Factor Ba. The properties of the classical-pathway C3 convertases assembled from human C4b, C1s and human or guinea-pig C2 have been compared. The rates of cleavage of human and guinea-pig C2 by C1s (and therefore the rates of assembly of the C3 convertases) are similar. The rate of decay of the activity of the C3 convertase formed from guinea-pig C2 is 10-fold lower than for human C2. This greater stability reflects a higher affinity of guinea-pig C2a for human C4b. The presence of C2b is not necessary for C3 convertase activity.

Amino Acid Sequence↗
PubMed1996

C4 phenotypes in IgA nephropathy: disease progression associated with C4A deficiency but not with C4 isotype concentrations.

IgA nephropathy (IgAN) is a common glomerular disease and is thought to have an immunological origin which may involve complement-mediated pathogenic mechanisms. We performed C4 phenotyping and C4 isotype quantification in 93 IgAN patients in Southern Sweden. Phenotype frequencies did not deviate from those of healthy controls. However, three patients had homozygous C4A deficiency and these all belonged to a group of fifteen patients with end-stage renal failure (p < 0.0035). Progression to end-stage renal failure did not appear to be faster than in other IgAN patients. Both C4A and C4B concentrations were raised in the IgAN patients, but the C4A/C4B concentration ratios did not deviate from those of healthy controls. This indicated that heterozygosity for C4A or C4B deficiency or other reasons for the relatively low concentrations of the protein were not associated with disease susceptibility. There was no correlation between low C4A/C4B ratio and poor prognosis. In conclusion, the findings suggested that homozygous C4A deficiency predisposes to development of end-stage renal failure. The question if this is due to complement dysfunction or to linked genetic factors remains to be elucidated.

Adolescent↗
PubMed1987

Purification and characterisation of the fourth component of bovine complement.

A relatively rapid method for the isolation of complement protein C4 from bovine plasma is described. The method consists of DEAE Sephacel anion exchange chromatography of plasminogen-depleted bovine plasma followed by cation exchange chromatography on CM Sepharose and finally gel filtration on a TSK G3000 SW column. A yield of approximately 20% was obtained. Conventional SDS-PAGE of purified bovine C4 showed the presence of alpha, beta and gamma polypeptide chains, the molecular weights of which were determined from Ferguson plots to be 95,000 +/- 2,500, 80,500 +/- 2,000 and 30,000 +/- 500 daltons, respectively. SDS-PAGE of C4 immunoprecipitated from the plasma of individual cattle in gels with a reduced proportion of crosslinker showed size polymorphism of the alpha chain. The presence of dual alpha chains was confirmed by radiolabelling their reactive thiol ester moiety with 14C methylamine. The difference in size of the two bovine alpha chains is approximately 1,800 daltons. On activation of bovine C4 both alpha chains were cleaved into alpha' chains (87,000 and 85,000 daltons) characteristic of C4b.

Animals↗
PubMed1992

Membrane cofactor protein (CD46) protects cells from complement-mediated attack by an intrinsic mechanism.

The cleavage of C3 is a critical step for complement (C) activation in the classical and alternative pathways. This reaction is controlled by the regulators of C activation protein family. Membrane cofactor protein (MCP) is a cofactor for the factor I-mediated inactivation of C3b and C4b. As a widely distributed membrane protein, MCP may protect host cells from inadvertent C activation. Human MCP has recently been shown to protect transfected rodent cells from human C-mediated lysis. In this report the relationship of MCP expression to C3b deposition and cytoprotection was examined using NIH/3T3 cells transfected with human MCP and exposed to human serum as a source of C and naturally occurring anti-mouse antibody. MCP inhibited C3b deposition in a dose-dependent fashion and inhibited lysis of the mouse cells expressing it. MCP did not inhibit lysis on bystander cells. These results demonstrate the protective role of MCP, at the cellular level, by an intrinsic mechanism.

3T3 Cells↗
PubMed2002

Enhancement of complement activation and opsonophagocytosis by complexes of mannose-binding lectin with mannose-binding lectin-associated serine protease after binding to Staphylococcus aureus.

Human mannose-binding lectin (MBL) is a serum protein of the innate immune system that circulates as a complex with a group of so-called MBL-associated serine proteases (MASP-1, MASP-2, and MASP-3). Complexes of MBL-MASP2 are able to activate the complement system in an Ab and C1-independent fashion after binding of the lectin to appropriate microbial sugar arrays. We have evaluated the additive effect of the lectin pathway relative to other complement activation pathways and the subsequent effect on neutrophil phagocytosis. Complement activation in the sera of MBL-deficient individuals was studied with and without the addition of exogenous MBL-MASP. Flow cytometry was used to measure the deposition of C4, factor B, C3b, and iC3b on Staphylococcus aureus. Deposition of the first cleavage product of the lectin pathway, C4b, was increased using the sera of three different MBL-deficient individuals when exogenous MBL-MASP was added. Factor B was deposited in association with C4, but there was no evidence of independent alternative pathway activation. Similar enhancement of C3b deposition was also observed, with evidence of elevated amounts of C3b processed to iC3b. The increase in opsonic C3 fragments mediated by MBL was associated with a significant increase in the uptake of organisms by neutrophils. We also observed significant increases in phagocytosis with MBL-MASPs that were independent of complement activation. We conclude that MBL-MASP makes a major contribution to complement-mediated host defense mechanisms.

Adjuvants, Immunologic↗
PubMed1983

Complement receptor expression by neoplastic and normal human cells.

Complement receptor (CR) expression in cell lines derived from Burkitt's lymphoma (BL), Epstein Barr virus-transformed cord blood lymphocytes (CB), and peripheral lymphocytes from patients with infectious mononucleosis (IM) was examined. Red cell intermediates bearing various densities of C4b, C3b, C3bi, or C3d were tested for rosette formation with the cell lines. In addition, a series of studies was performed under conditions that precluded the cleavage of cellbound C3b by Factor I (C3bINA). These conditions did not alter rosetting by the cells that were tested. RAJI cells rosetted with EAC3bi greater than EAC3d greater than EAC3b, but not with EAC4b. EAC3b/RAJI rosette formation required much greater quantities of C3b bound to red cells than did CB and IM lines, which unlike RAJI, also bound EAC4b. All of the BL lines failed to bind EAC4b even at a C4b density of 50,000 molecules/cell, but several lines did form rosettes with EAC3b, and most formed rosettes with EAC3bi and EAC3d. Fluid phase C3b blocked RAJI/EAC3b rosetting while having little effect on RAJI/EAC3bi rosette activity. Moreover, fluid phase C3b, as well as C4b, blocked RAJI/EAC3b rosettes more effectively than CB/EAC3b rosettes. The results indicate that the RAJI cell line has a receptor for C3b, with characteristics that differ markedly from the C3b receptor of cell lines derived from CB lymphocytes and of lymphoblastoid cell lines derived from patients with IM. This receptor is capable of interacting with soluble but not cellbound C4b. In these studies, rosette formation was examined under various ionic conditions. RAJI/EAC3b rosette formation was severely reduced as ionic strength was increased, whereas RAJI/EAC3bi binding was only moderately decreased at physiologic ionic strength. In striking contrast, EAC3bi binding to monocytes, PMN, and human erythrocytes was markedly reduced as ionic strength increased, but EAC3b binding to these cells was less sensitive to changes in ionic strength. Under conditions of physiologic ionic strength, the C3bi receptor of phagocytic cells may be at a functional disadvantage in the binding of C3bi-coated particles. This may have major physiologic implications.

Burkitt Lymphoma↗
PubMed1982

Purification and structural studies on the complement-system control protein beta 1H (Factor H).

An efficient procedure for the isolation of the complement-system control protein beta 1H (Factor H) from human plasma was developed. The chemical composition and physical characteristics of the protein were studied, and a sequence of 17 amino acid residues at the N-terminus was determined. Factor H is a single-polypeptide-chain glycoprotein of mol.wt. 155 000 containing 9.3% carbohydrate. Factor H is cleaved by plasma proteinases to a two-chain form. This cleavage can be mimicked by trypsin, and the two-chain form retains fully the C3b-inactivator cofactor activity of Factor H. The proteolytic fragments of Factor H are compared with those of other proteins (C4b-binding protein and erythrocyte C3b-receptor) that act as cofactors for C3b-inactivator.

Amino Acid Sequence↗
PubMed1993

Complement component C4 deficiencies and gene alterations in patients with systemic lupus erythematosus.

Deficiency of complement component C4 is considered playing a role in the genetic predisposition for systemic lupus erythematosus (SLE). The purpose of this study was to characterize the genomic alterations of the C4 and CYP21 genes in 40 caucasoid patients with SLE by C4 allotyping and by RFLP analysis. Nineteen patients (47.5%) carried C4A null alleles and eight patients (20.0%) C4B null alleles. SLE patients had more frequent C4A null alleles (47.5%) than healthy individuals (20%) (chi 2 = 10.75; P < 0.005). The commonest molecular alteration in the patients with C4A null alleles was a large gene deletion affecting both C4A and CYP21A genes. However, among the patients with C4A null alleles, 16.7% persons had no detectable C4A deletion. The non-expression of C4A gene might be due to defects at various levels of gene expression (i.e. transcription and translation). Among the patients with C4B null alleles, 62.5% persons had no detectable gene lesion, whereas 37.5% showed a C4B deletion including both C4B/CYP21A or C4B/CYP21B genes. Duplication of the C4B gene was not rare in SLE patients, as we found 15.0% of the patients with a heterozygous C4B/CY21A gene duplication. The patients typed as having C4B gene homoduplication (B1,1) demonstrated two long C4B loci, whereas heteroduplication (B1,2) displayed two short loci, therefore the type of C4B gene duplication may be related to the gene length. In conclusion, C4 deficiencies observed in 26 of the 40 SLE patients studied were very heterogeneous. In every case, the gene alteration affected both C4 and CYP21 genes.

Alleles↗
PubMed1991

DR3 and nonDR3 associated complement component C4A deficiency in systemic lupus erythematosus.

The molecular basis of complement component C4A deficiency in white U.S. and Mexican patients with systemic lupus erythematosus (SLE) was studied. Genomic DNA from SLE patients and non-SLE controls was analyzed for restriction fragments using HindIII and a 5' C4 cDNA probe. C4A gene deletion was recognized by the loss of a 15-kb restriction fragment and the appearance of a 8.5-kb fragment. Thirty-two selected U.S. SLE patients, 7 nonSLE controls, and 11 Mexican SLE patients and 9 relatives were studied. The deletion was recognized in all of the 14 HLA-B8;DR3 SLE patients with a C4A protein deficiency. Two SLE patients with DR3 but without B8 also had this gene deletion. None of the 3 U.S. SLE nonDR3, C4A protein deficient patients nor 20 C4A protein deficient Mexican individuals (11 SLE patients and 9 relatives; none had B8 and/or DR3) showed this deletion. Thus the C4A gene deletion failed to account for the C4A protein deficiency in all the nonDR3 Mexicans and in some U.S. SLE patients. To determine whether gene conversion at the C4A locus would encode a C4B-like protein and be responsible for the C4A protein deficiency (in nonDR3 patients), the C4d region of the gene was amplified by polymerase chain reaction and subjected to Nla IV digestion, and restriction fragment analysis was performed using a C4d region-specific probe. The resulting restriction fragment length polymorphism pattern revealed no changes in the isotype-specific region of the gene as characterized by C4A-specific 276- and 191-bp fragments in Dr3 or nonDR3 individuals. Thus, homoexpression of C4B at both loci was not responsible for C4A deficiency in nonDR3 SLE patients without C4A gene deletion.

Alleles↗
PubMed1995

The HLA-A3, Cw6,B47,DR7 extended haplotypes in salt losing 21-hydroxylase deficiency and in the Old Order Amish: identical class I antigens and class II alleles with at least two crossover sites in the class III region.

The HLA-B47,DR7 haplotype in congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency contains a deletion of most of the active CYP21 gene and the entire adjacent C4B gene. The C4A gene produces a protein which is electrophoretically C4A but antigenically C4B. In the Old Order Amish, the HLA-B47,DR7 haplotype contains no deletion, but is immunologically identical to the CAH haplotype in both areas flanking the crossover region. We compared some of the genes in the MHC Class II and Class III regions in the Amish and CAH-linked haplotypes to define further the relationships between the two. The complement factor B (Bf) proteins differed, but no Bf RFLPs were identified. The complement factor 2 genes exhibited different BamHI RFLPs. Analyses of the tumor necrosis factor-alpha genes revealed the same NcoI restriction patterns. The RD genes contained microsatellites of the same size. Portions of the MHC Class II DR and DQ, and Class III CYP21 and C4 alleles were sequenced. The exon 2 sequences of DQ2 and DR7 were identical in the two haplotypes. In the Amish haplotype, both CYP21 and C4 gene pairs were present and functionally normal. The CAH haplotype had two sequence crossovers: from CYP21P to CYP21 in the 7th intron, and from C4A to C4B between codons 1106 (exon 26) and 1157 (exon 28). A model is proposed which accounts for the CAH-linked mutant haplotype arising from a nonmutant homologue via three crossings-over.

Adrenal Hyperplasia, Congenital↗