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PubMed1992

The coding sequence of the hemolytically inactive C4A6 allotype of human complement component C4 reveals that a single arginine to tryptophan substitution at beta-chain residue 458 is the likely cause of the defect.

The C4A6 allotype of the human complement component C4 is known to be defective in C5 binding within the C5 convertase. To characterize the position and nature of the molecular defect in the C4A6 allotype we have isolated the C4A6 gene from a cosmid genomic DNA library. Direct sequencing of a 4.4-kb region of the gene covering exons 17 to 31 and encoding the C4d fragment and most of the rest of the alpha chain of C4 revealed that the C4A6 allele encodes the A isotypic residues Pro Cys-Leu Asp at positions 1101, 1102, 1105, and 1106 and the same residues as the C4A3 alpha gene at the polymorphic positions 1054 (Asp), 1157 (Asn), 1182 (Thr), 1188 (Val), 1191 (Leu) and 1267 (Ala). In addition the C4A6 allele was shown to encode a Pro at the previously characterized polymorphic position 707 in the C4a peptide where the C4A3 alpha allele encodes a Leu. The remaining 26 exons of the C4A6 gene were analyzed by detecting nucleotide mismatches in C4A6/C4A3 and C4A6/C4B1 DNA heteroduplexes using the chemical cleavage of mismatch technique. The regions around detected mismatches were sequenced. In total seven nucleotide differences were defined on comparison of the C4A6 and other C4 sequences, of which three were present in exons. Two of these resulted in amino acid changes. One of the amino acid differences is a known polymorphism in C4, a Tyr/Ser substitution at position 328 in the beta-chain. The second amino acid difference caused by a C to T transition in the first base of the codon for amino acid residue 458 was the only one shown to be specific to the C4A6 allotype. The C4A6 allotype contains a Trp residue at this position in the beta-chain instead of the Arg residue found in all other C4A and C4B allotypes so far characterized. We propose that this Arg to Trp substitution at beta-chain residue 458 is responsible for the inability of C4A6 to bind C5 in the C5 convertase.

Alleles↗
PubMed1984

Defective erythrocyte C3b receptor function associated with low serum complement (C3, C4) concentrations in insulin-dependent diabetes mellitus.

An immune adherence haemagglutination (IAHA) method was used to measure erythrocyte C3b receptor (EC3bR) activity in 110 patients with insulin-dependent diabetes mellitus (IDDM) and 223 controls. Results obtained from IDDM were correlated with serum complement concentrations (C3, C4) as well as with HLA types of the patients. We observed an increased frequency of defective EC3bR in IDDM (26.4%) compared to controls (10.8%, P less than 0.0005). Those patients who had defective EC3bR (IAHA negative) also had lower serum C3 and C4 concentrations than those with normal EC3bR function (IAHA positive). HLA-Dw3 positive patients had lower C4 concentrations than HLA-Dw3 negative patients and more often had defective EC3bR activity, although this difference was statistically not significant. Our results may indicate the close relationship between the risk factors which predispose to both IDDM and systemic lupus erythematosus.

Adolescent↗
PubMed1992

Properdin factor B and complement factor C4 allotypes in rheumatoid arthritis: results of a follow-up study.

The association between allotypes of properdin factor B (Bf), the fourth component of complement (C4A and C4B), and rheumatoid arthritis (RA), was investigated in a well-characterized cohort of RA patients who were followed from an early phase of the disease for a mean duration of 6 years. The frequencies of probable heterozygous C4AQ0 and of C4A3 were lower in RA patients compared to controls, irrespective of the presence of DR4 [relative risk (RR): 0.52 and 0.49, respectively, 95% confidence intervals (95% CI): 0.34-0.80 and 0.29-0.82]. The frequency of C4A4 was higher in RA patients compared to controls (RR: 1.86, 95% CI: 1.03-3.35), especially in DR4 positive RA patients compared to DR4 positive controls (RR: 2.58, 95% CI: 1.07-6.25), indicating a positive association of this allotype with RA additional to DR4. Bf and C4B allotypes were comparable in RA patients and controls. We did not find significant differences in Bf and C4 allotype frequencies in RA patients subdivided according to severity of the disease into a mild group and a progressive group. Because of inconsistent results in all studies on Bf and C4 allotypes, we conclude that C4 and Bf allotypes do not seem to have an important independent effect on determining disease susceptibility.

Adult↗
PubMed1996

Allotypes of complement components C4, C3, C2 and BF in the populations of Tasmania and northeast England.

The distribution of four serum complement component polymorphisms (BF, C2, C3 and C4) were examined in two geographically separated populations, one from Tasmania (Australia) and the other from northeast England. The differences in genotypic frequencies between them at all 4 loci are not statistically significant (p > 0.05). When C4 haplotypes were investigated, only one (C4A4-C4B2) exhibited significant linkage disequilibrium (p = 0.0006 after correction, p = 0.01), and this was only observed in Tasmanians. The English population exhibited a larger number of alleles across the four loci used in this study than the Tasmanian, and this may well reflect a bottle-neck effect and the greater relative isolation of the population of the island State of Australia. Overall, the findings confirm the close relationship between immigrants from the British Isles to Tasmania.

Complement C2↗
PubMed1986

Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein.

Two of four siblings expressed the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) and had identical human lymphocyte antigen (HLA) and complement C4 (fourth component of complement) types (HLA-A3,C4,B35,C4A3,C4BQO,DR1/A2,C-,B18,C4A3, C4BQO,DR6). The father and one unaffected sibling were heterozygous carriers of CAH, as determined by a 30-min iv ACTH stimulation test and HLA typing. In addition, the iv ACTH stimulation test revealed that the mother and the other unaffected sibling also carried an allele for an attenuated form of CAH. Restriction endonuclease digests of genomic DNA obtained from members of this family and from normal unrelated subjects were hybridized with cDNA probes encoding human 21-hydroxylase and C4. With the 21-hydroxylase probe, Southern blots prepared from control DNA samples revealed two major restriction fragments in each of four restriction endonuclease digests; TaqI produced major bands at 3.7 and 3.2 kilobases (kb), KpnI at 4.0 and 2.9 kb, EcoRI at 18 and 13 kb, and BglII at 15 and 12.5 kb. Southern blots prepared from DNA of the two patients lacked the 3.7-kb TaqI and 2.9-kb KpnI fragments, but had increased hybridization intensity (relative to control DNA samples) in the 3.2-kb TaqI and 4.0-kb KpnI fragments. By contrast, blots with EcoRI or BglII had two large hybridization fragments not different from control DNA samples. These data indicate the presence of two different 21-hydroxylase genes. Additional mapping studies revealed that the two genes had the restriction pattern of the inactive 21-hydroxylase gene. When genomic DNA that had been isolated from all members of this family and from normal subjects was hybridized with the human C4 cDNA probe, the restriction fragment hybridization patterns for all four endonuclease digests were similar in the two groups. Hence, our results suggest that the 21-hydroxylase deficiency of our patients is due to conversion of the active 21-hydroxylase gene to the inactive gene. This gene conversion was associated with absence of functional C4B protein, without any detectable alterations in the restriction fragment pattern of the C4 genes.

Adrenal Hyperplasia, Congenital↗
PubMed1997

A dysfunctional allele of the mannose binding protein gene associates with systemic lupus erythematosus in a Spanish population.

OBJECTIVE: To determine dysfunctional mannose binding protein (MBP) status of Spanish patients with systemic lupus erythematosus (SLE) and to determine whether MBP and complement C4 null alleles contribute in an additive way to SLE susceptibility. METHODS: The frequencies of MBP alleles (characterized by polymorphisms at codon 54 and codon 57 of exon 1) were determined by the amplification refractory mutation system-polymerase chain reaction in 50 Spanish patients with SLE and 49 matched controls. Mutant genotypes for the codon 54 mutation were confirmed using a Ban I restriction enzyme digest method. Complement C4 allotyping was achieved by agarose gel electrophoresis of neuraminidase/carboxypeptidase B digested plasma samples followed by immunofixation and staining. RESULTS: At least one dysfunctional MBP allele, unable to activate complement, was present in 52% of patients with SLE and in 31% of controls (OR = 2.4, 95% CI 1.1-5.6). Complement C4 null alleles (either C4A or C4B) were present in 61% of patients and 43% of controls (OR = 2.1, 95% CI 0.9-4.9). A dysfunctional MBP allele and C4 null allele were present in 41% of patients and 16% of controls (OR = 3.2, 95% CI 1.2-8.1). CONCLUSION: The presence of a dysfunctional MBP allele is a risk factor for developing SLE in this Spanish population and may affect susceptibility in an additive way with C4 null alleles.

Acute-Phase Proteins↗
PubMed2003

Association of serum complement (C3, C4) and immunoglobulin (IgG, IgM) levels with hormone replacement therapy in healthy post-menopausal women.

BACKGROUND: Recently published data suggest that hormone replacement therapy (HRT) may increase cardiovascular risk during the early months of therapy. Activation of the immune system is known to be involved in several types of cardiovascular disease. In this cross-sectional study, serum C3, C4, IgG and IgM levels were evaluated in healthy post-menopausal women receiving two different short-term HRT regimens, and in untreated women. METHODS: Serum C3, C4, IgM and IgG levels were assessed in 18 women receiving transdermal 17beta-estradiol (50 micro g/day) + continuous oral medroxyprogesterone acetate (MPA; 2.5 mg/day), in 56 women taking oral conjugated equine estrogen (CEE; 0.625 mg/day) + continuous MPA, and in 80 control women not receiving HRT. RESULTS: The mean serum C3 level was significantly higher in women using oral CEE + MPA than in women receiving transdermal 17beta-estradiol + MPA, and those not on HRT (P = 0.02 and P < 0.001 respectively). Furthermore, women taking oral CEE + MPA had significantly higher mean levels of C4 compared with untreated women (P < 0.01). IgG and IgM levels were similar among women either of the two HRT regimens and between women not on HRT. CONCLUSIONS: Oral HRT may be involved in the development of cardiovascular disease through inflammatory mechanisms, as suggested by increased serum levels of C3 and C4.

Adult↗
PubMed2000

Complement activation promotes muscle inflammation during modified muscle use.

Modified muscle use can result in muscle inflammation that is triggered by unidentified events. In the present investigation, we tested whether the activation of the complement system is a component of muscle inflammation that results from changes in muscle loading. Modified rat hindlimb muscle loading was achieved by removing weight-bearing from the hindlimbs for 10 days followed by reloading through normal ambulation. Experimental animals were injected with the recombinant, soluble complement receptor sCR1 to inhibit complement activation. Assays for complement C4 or factor B in sera showed that sCR1 produced large reductions in the capacity for activation of the complement system through both the classical and alternative pathways. Analysis of complement C4 concentration in serum in untreated animals showed that the classical pathway was activated during the first 2 hours of reloading. Analysis of factor B concentration in untreated animals showed activation of the alternative pathway at 6 hours of reloading. Administration of sCR1 significantly attenuated the invasion of neutrophils (-49%) and ED1(+) macrophages (-52%) that occurred in nontreated animals after 6 hours of reloading. The presence of sCR1 also reduced significantly the degree of edema by 22% as compared to untreated animals. Together, these data show that increased muscle loading activated the complement system which then briefly contributes to the early recruitment of inflammatory cells during modified muscle loading.

Animals↗
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↗
PubMed1985

Structure and expression of murine fourth complement component (C4) and sex-limited protein (Slp).

During the past 4 years we have used recombinant DNA technology to build upon previous genetic and biochemical studies of the C4 and Slp genes and their products. We have isolated DNA probes specific for C4 and Slp, determined the complete sequences of C4 and Slp molecules, established the role of liver mRNA levels in determining serum C4 and Slp levels identified the C4 and Slp genes in Balb/c mice, and begun to probe the structures of the C4 and Slp genes in a variety of inbred mouse strains. This work has provided the tools and a framework for future studies aimed at understanding the multiple functions of the C4 protein and the regulatory mechanisms controlling the expression of the C4 and Slp genes.

Amino Acid Sequence↗
PubMed1992

Reciprocal changes in serum levels of immunoglobulins (IgG, IgA, IgM) and complements (C3, C4) in normal pregnancy and after delivery.

Sequential changes in serum levels of IgG, IgA, and IgM, and C3 and C4 during and after pregnancy were studied in 8 healthy women. Serum IgG decreased gradually during pregnancy, but increased markedly during the six months following delivery. Serum IgA and IgM levels also showed patterns similar to IgG. In contrast, C3 and C4 levels increased significantly and reached maximum levels in the last trimester during pregnancy, but decreased gradually for six months after delivery. Reciprocal changes between immunoglobulins and complements were clarified for the first time, and were suggestive of a compensatory autoregulatory mechanism in the suppression of the humoral immune system during pregnancy.

Adult↗
PubMed1987

Lethal deletion of the complement component C4 and steroid 21-hydroxylase genes in the mouse H-2 class III region, caused by meiotic recombination.

A recombinant H-2 haplotype, designated aw18, was produced that underwent meiotic recombination in the E alpha (I-E alpha chain)--Slp (sex-limited protein) interval of the H-2 class III region between B10.A (H-2a) and wild-derived B10.MOL-SGR (H-2wm7) strains. It appeared that the H-2aw18 haplotype has a single, recessive, lethal mutation, since homozygotes for H-2aw18 were not detected in progeny generated from the intercross of mice that were heterozygous for this H-2 haplotype. Nine newly established recombinant H-2 haplotypes, which arose from the heterozygous mice that resulted from a cross between common inbred H-2 haplotypes and the aw18 haplotype, allowed us to map the lethal gene to the class III region of the H-2 complex. Southern blot analysis indicated that the aw18 haplotype has a deletion of the C4 gene and a deletion of one of the steroid 21-hydroxylase genes. This result was confirmed by an immunodiffusion test that demonstrated the absence of production of the C4 protein in mice of haplotype H-2aw18. All data that were obtained supported the hypothesis that the meiotic, presumably unequal, recombination between homologous chromosomes of the H-2a and H-2wm7 haplotypes caused the deletion of the C4 and the 21-hydroxylase genes.

Animals↗