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PubMed1990

Human major histocompatibility complex contains a new cluster of genes between the HLA-D and complement C4 loci.

A new cluster of genes has been defined in the human Major Histocompatibility Complex class III region. The seven novel genes, G12 to G18, are localised in a 160 kb segment of DNA extending from the complement gene cluster towards HLA-DR. The genes were identified by isolation of cDNA clones using cosmid genomic inserts as hybridisation probes, and by the detection of the corresponding transcripts in Northern blot analysis. Characterisation of the cosmid genomic DNA inserts, in conjunction with pulsed field gel electrophoresis analysis of uncloned DNA, for the presence of clustered sites for infrequently cutting restriction endonucleases has revealed that at least 5 of the 7 genes are associated with HTF-islands. These unmethylated CpG-rich sequences are frequently found at the 5' ends of ubiquitously expressed genes. Together with previously published data 36 genes have now been defined in a 680kb stretch of DNA within the MHC. With one gene approximately every 20kb of DNA this represents the most densely packed region of the human genome so far characterised, and is of major significance in relation to the mapping and sequence analysis of the rest of the genome.

Blotting, Northern↗
PubMed1992

Prolonged clinically asymptomatic evolution after HIV-1 infection is marked by the absence of complement C4 null alleles at the MHC.

The length of time after which persons infected with HIV-1 progress to AIDS is variable. Certain alleles at the MHC have been shown to influence negatively the clinical outcome of HIV-1-infected persons and to be associated with special clinical manifestations. We investigated the MHC class I, class II and class III antigens in 54 Caucasian HIV-1-infected persons. The MHC profile of individuals with a prolonged period before AIDS is marked by a lower frequency of C4 null alleles.

Acquired Immunodeficiency Syndrome↗
PubMed1981

Family studies of complement C4 and HLA in man.

At least 12 different C4 gene products with a three band pattern have been identified after electrophoresis of sera pretreated with neuraminidase. Segregation analysis showed at least 12 different C4 haplotypes (or supergenes), of which five represent a single gene product and seven are duplications each composed of an F and an S gene. The data analyzed with respect to linkage showed one recombinant between the C4 and HLAB loci in 154 meioses giving a map distance of C4 HLAB of 0.6 cM. Another recombinant between the C4 and the HLAD loci was found in 101 meioses giving a map distance of C4 HLAD of 1.0 cM. Linkage disequilibrium was found between at least eight C4 haplotypes and certain alleles at the HLAB as well as the HLAD loci. Examinations of 15 families selected through a proband with HLAA 25, HLAB 18 and C2Q0 showed that in almost all cases a slight variant of the C4 supergene F3S2 followed the haplotype HLAA25 HLAB18 C2Q0. No associations were found between the two duplications of C4F3 C4S2 and C4F3 C4S1 and the loci. These findings may indicate that these C4 haplotypes were the original ones preceding the other C4 haplotypes.

Adult↗
PubMed1984

Determination of circulating immune complexes, C3 and C4 complement components and anti-DNA antibody in different classes of lupus nephritis.

Circulating immune complexes (CIC) were measured in 237 sera from children who underwent a renal biopsy during the course of systemic lupus erythematosus. CIC-positive sera contained a lower mean level of C3 but not C4. Anti-DNA antibody was similar in CIC-positive and negative sera. The World Health Organization classification of lupus nephritis was used to categorize the biopsies. CIC, C3, C4 and anti-DNA antibody were determined to assess whether they correlated with the severity of renal lesions. Of 25 sera obtained at renal biopsy from patients with classes 2, 3 and 4, 16 were positive for CIC. C3 was significantly lower in classes 3 and 4 than in class 2. C4 was reduced and anti-DNA antibody was present in classes 2, 3 and 4. Determination of the level of C3 but not C4, CIC or anti-DNA antibody correlates with the severity of lupus nephritis seen on renal biopsies. Nevertheless, performance of a renal biopsy is preferred.

Antibodies, Anti-Idiotypic↗
PubMed1979

Genetic studies of complement C4 in man.

A C4 variant found in about 5% of the population is described. The fast-moving part of this variant is governed by an allele (Fx) codominant to F. The Fx allele is in very strong linkage disequilibrium with HLA-B17 as the linkage disequilibrium parameter accounted for nearly 100% of the haplotype frequency of B17,Fx. The strong association is also evidenced by the study of 11 families segregating for the Fx allele. There was no instance of recombination between C4 and HLA in 36 informative meioses.

Adult↗
PubMed1994

Deficiency of the fourth component of complement (C4): a family case.

In this report, an apparently healthy 38-year-old woman with a remarkably low serum C4 value is described together with other family members who had moderately low serum C4. Plasma C4 typing disclosed that the proband inherited two C4B "null" haplotypes. In addition, Southern blot analysis of the C4 gene indicated that the C4A gene was partially deleted on one of these two haplotypes in the proband. We thus concluded that a de novo deletion on the inherited half-null haplotype was the likeliest cause of the low C4 level.

Adult↗
PubMed1984

Genetic polymorphism of complement C4 in the dog.

Plasma samples from 129 dogs have been typed using an immunofixation technique to define the polymorphism of canine C4. The mode of inheritance was inferred by study of four large pedigrees. In contrast to the situation in man, canine C4 may be encoded by a single locus. At least five different co-dominant structural alleles have been detected. A deficiency allele has not been found as yet. Because there are associations between C4 allotypes and spontaneous autoimmune disease in man, the well defined polymorphism of canine C4 may provide an excellent model for understanding of the pathogenetic mechanisms of autoimmune disease.

Alleles↗
PubMed1986

[Hereditary deficiency of the 4th component of complement (C4) associated with a lupic syndrome].

A 2 year-old girl presented with bacterial meningitis followed by a lupus erythematosus syndrome consisting of erythematous rash, Raynaud's phenomenon and mutilating cicatricia atrophy; high speckled antinuclear antibodies and anti-Sm and anti-Ro antibodies titers; a selective absence of C4; moderate mesangial proliferation with IgM and C1q mesangial deposits. Study of the family revealed a linkage of C4 deficiency with the HLA A1 B17/BfF haplotype.

Antibodies, Antinuclear↗
PubMed1997

Evidence for increased synthesis of complement C4 in the renal epithelium of rats with passive Heymann nephritis.

Passive Heymann nephritis (PHN) is a complement-dependent model of immune complex glomerulonephritis. This study investigated the contribution of local complement synthesis by studying gene expression of the classical pathway component C4 in relation to the site of the tissue injury and the development of proteinuria induced by the pathogenic antibody (sheep anti-GP330). This study, using in situ hybridization, found that C4 mRNA expression was increased in the glomerular epithelium and the proximal renal tubular epithelium in a distribution similar to that of the targeted GP330 antigen. The total cortical C4 mRNA expression assessed by semiquantitative polymerase chain reaction (PCR) increased in a time-dependent manner (P < 0.05), coincident with the onset and progression of proteinuria, and peaking 11 to 14 days after the induction of the disease. These data suggest a link, in place and time, between local complement gene expression and glomerular barrier dysfunction induced by anti-GP330. It is postulated that increased epithelial synthesis of C4 stimulated by the engagement of GP330 enhances the formation of the membrane attack complex of complement through its classical pathway, and, hence, the formation of complement-mediated injury.

Animals↗
PubMed1993

IFN-gamma mediates stimulation of complement C4 biosynthesis in human proximal tubular epithelial cells.

The liver has been presumed to be the main source of complement deposited in inflammatory lesions such as in glomerulonephritis. In a previous study, however, it was demonstrated that renal tubular cells synthesize C3 in vitro. Furthermore, it was shown by others that C4 gene transcripts were detectable in situ in renal tubular cells. Therefore studies were initiated to investigate the synthesis of C4 by proximal tubular epithelial cells (PTEC) in vitro. Biosynthetic labeling experiments showed de novo synthesis of C4 by PTEC. The synthesis of C4 by PTEC and its regulation by IFN-gamma was fully inhibitable by the addition of cycloheximide, indicating that protein synthesis is required for an increase in C4 secretion. Addition of increasing concentrations of IFN-gamma enhanced the production of C4 by PTEC in a dose dependent fashion, with a 2.5-fold maximum. Kinetic experiments demonstrated higher levels of C4 production when stimulated with IFN-gamma for up to 72 hours. The hemolytic activity of C4 present in culture supernatants of PTEC decreased during the culture period as assessed by hemolytic titration. Northern blot analysis showed no enhancement of C4 mRNA in IFN-gamma treated PTEC, indicating that IFN-gamma regulates C4 production at a post-transcriptional level. Antibody blocking experiments confirmed that regulation of C4 production was directly mediated by IFN-gamma. From this study it was concluded that renal cells are able to synthesize complement components that could possibly play a role in inflammatory responses evolving in the kidney.

Cells, Cultured↗
PubMed1989

Direct observation of the gene organization of the complement C4 and 21-hydroxylase loci by pulsed field gel electrophoresis.

Pulsed field gel electrophoresis and enzymes that cut genomic DNA infrequently have been used to define large RFLPs at the human C4 loci. With the enzymes BssH II or Sac II, and C4 or 21-hydroxylase DNA probes, it has been possible to observe directly the number of C4 genes present on a haplotype, and also whether the C4 genes are long (6-7-kb intron present) or short (6-7-kb intron absent). Haplotypes that have either two long C4 genes or one long and one short C4 gene generate BssH II fragments of approximately 115 or approximately 105 kb, respectively. Haplotypes that have either a single long or a single short C4 gene generate BssH II fragments of approximately 80 or approximately 70 kb, respectively. This technique has been used to analyze the DNA isolated from PBMC and allows the complete definition of the C4 gene organization of an individual without the need for family studies.

Cell Line↗
PubMed1992

Analysis of complement C4 loci in Caucasoids and Japanese with idiopathic membranous nephropathy.

Deletion of the HLA class III complement gene, C4A, has been linked with susceptibility to a number of autoimmune diseases. In this study, we show a strong positive association between C4A gene deletion and development of idiopathic membranous nephropathy (IMN) in European Caucasoids [patients, 17/27 (63%); healthy controls, 13/65 (20%); RR 6.8; P = 0.003]. To clarify whether C4A deletion is an independent risk factor for IMN or is increased secondarily to the Caucasoid HLA A1, B8, DR3 extended haplotype, we examined the frequency of C4A deletion in Japanese patients, in whom the disease is associated with another HLA haplotype (DR2-DQw1). Analysis of 31 Japanese patients and 46 healthy controls showed that C4A deletion was present in only one patient (3%) and one control (2%). In addition, examination of the C4B locus in Japanese patients showed that there was no significant increase in the estimated frequency of C4B deletion in patients against controls (31 vs. 27%) and no difference in the frequency of the C4B long gene (73 vs. 87%) or C4B short gene (77 vs. 78%). We conclude that although C4A deletion confers significant risk of IMN in Caucasoids, there is no significant association between C4 polymorphism, as detected here, and risk of IMN in Japanese. This suggests that either C4A deletion is irrelevant to the pathogenesis of IMN or that more than one genetic mechanism is involved.

Asian People↗
PubMed1984

Gene and haplotype frequencies of the fourth component of complement (C4) in type 1 diabetics and normal controls.

C4 gene and haplotype frequencies were calculated from phenotype data of 380 unrelated Caucasian patients with insulin dependent (type 1) diabetes mellitus and were compared with analogous frequencies of 382 unrelated healthy Caucasian individuals. In diabetics, a significantly increased frequency of the rare allele C4B 3 (p less than 10(-7] and of the silent alleles C4A Q0 (p less than 10(-7] and B Q0 (p less than 0.002) was observed. Accordingly, insulin dependent diabetes is associated with partial C4 deficiency, which may contribute to the pathogenesis of the disease.

Alleles↗
PubMed1988

C4 complement allotypes in juvenile dermatomyositis.

Twenty probands with juvenile dermatomyositis and their relatives were studied to determine the inherited segregation patterns of class I, II, and III HLA region markers including C4A, C4B, Bf, and C2 complement polymorphisms. The extended haplotype B8, DR3, C4A*Q0, C4B*1, C2*C, and Bf*S was present in 13 of the 20 probands. Three other probands also carried a haplotype with a null allele for C4A and two further probands carried a null allele for C4B; only two probands had no detectable C4 null allele. These data confirm previous studies showing high frequencies of B8 and DR3 in patients with juvenile dermatomyositis, but show that there is a higher association with null alleles of C4. This suggests that the C4 genes are either themselves the disease-susceptibility genes or are in very strong linkage disequilibrium with such genes.

Adolescent↗
PubMed1985

Complement C4 allotype association with and serum C4 concentration in an autoimmune disease in the dog.

Serum C4 concentrations and C4 allotypes were determined wherever possible on eight dogs with an autoimmune disorder characterized by antinuclear antibody (ANA) positivity, pyrexia, and seronegative arthritis. Three of the six dogs tested serially showed hypocomplementemia at disease onset with return to normal concentrations with clinical remission following steroid therapy. All five dogs C4 allotyped were phenotypically identical. The phenotype (C4-4) was significantly increased in the diseased dogs. Thus C4 allotype may provide a marker for susceptibility to development of an autoimmune disorder in the dog. Serum C4 concentrations may help in disease diagnosis and monitoring the effectiveness of therapy.

Animals↗