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PubMed1977

Genetic deficiency of the fourth component of complement (C4) in Wistar rats.

A chance observation has led to the discovery of single component complement deficiency in Wistar rats. During serial total haemolytic activity (CH50) determinations on 10 male rats, 2 were consistently found to have values 20% or less than that of the others. An additional 30 males (200--220 g) and 20 females (180--200 g) were screened for CH50 and the defect was found in 10 of the males but none of the females. Mixtures of sera of high and low haemolytic activity gave intermediate values between the two populations arguing against the presence of an inhibitor of the complement system. Single component analysis revealed the defect to reside in the fourth component of complement (C4). Highly purified human C4 completely reconstituted the haemolytic activity of the complement deficient rat serum. A linear relationship between C4 and CH50 titres was observed. Data from preliminary selective breeding experiments point toward an autosomal recessive mode of inheritance. Animals with intermediate values were observed indicating a gene dosage effect with which the heterozygote may be recognized.

Animals↗
PubMed1989

Biosynthesis of complement C4 messenger RNA in normal human kidney.

Complementary DNA (cDNA) probes were used to investigate the extrahepatic production of the major histocompatibility complex (MHC)-linked complement components C4, factor B and C2 in various normal human tissues. The presence of the corresponding messenger RNA (mRNA) was tested by Northern blot analysis. Complement C4 mRNA was found in liver, and with high intensity also in normal kidneys. In contrast, no C2 mRNA and only very low amounts of factor B mRNA could be detected in the kidney. Slot blot hybridization was performed to quantitate the amount of C4 mRNA, and the intensity of C4 mRNA hybridization in the kidney samples was about 25% compared with liver RNA. C4-specific transcripts were not present in isolated glomeruli but in the renal interstitium. Other human tissues, such as tonsil, spleen, thymus, brain, lung and peripheral mononuclear cells, contained no C4 mRNA. Low amounts of C4 mRNA were found in colon, thyroid gland, lymph node and breast carcinoma. The results obtained with lung, where C2 mRNA was found but no C4 mRNA, further indicate an independent, tissue-specific regulation of the class III gene expression. The results, showing that the complement C4 genes are transcribed very efficiently in normal human kidney, suggest a direct role of complement C4 in renal pathogenesis.

Adult↗
PubMed1992

Family studies of the steroid 21-hydroxylase and complement C4 genes define 11 haplotypes in classical congenital adrenal hyperplasia in The Netherlands.

Two steroid 21-hydroxylase genes are normally present within the human major histocompatibility complex near the genes encoding the fourth component of complement (C4A and C4B). Steroid 21-hydroxylase is encoded by the CYP21 gene, while the highly homologous CYP21P gene is a pseudogene. We studied steroid 21-hydroxylase and complement C4 haplotypes in 33 Dutch patients (29 families) suffering form classical congenital adrenal hyperplasia (CAH) and in their 80 family members, and also in 55 unrelated healthy controls, using 21-hydroxylase and complement C4 cDNA probes. Eleven different haplotypes, defined in terms of gene deletions, gene duplications, conversions of CYP21 to CYP21P, and "long" and "short" C4 genes, were found. In 23% of the patients' haplotypes, the CYP21 gene was deleted; in 12%, it was converted into a CYP21P pseudogene. In the remaining 65%, the defect was apparently caused by a mutation not detectable by this method. The most common haplotype (with one CYP21 and one CYP21P gene) was significantly more often observed in patients with simple virilizing CAH than in those with salt-losing CAH. Comparison of the 21-hydroxylase haplotypes found in CAH patients from several countries shows evidence for considerable genetic variation between the groups studied.

Adrenal Hyperplasia, Congenital↗
PubMed1983

[B, C2 and C4 complement factors, the HLA system and diseases. Genetic relation].

Close linkage of the complement factor loci C2, C4 and Bf to HLA loci has been firmly documented. A review of the literature was made about genetic defects of these components associated with a variety of disorders, especially immunologic diseases. Some allotypes of these factors are also closely linked to several diseases. Relationship between these diseases and the genes controlling the synthesis of C2, C4 and Bf and their allelic variants is not yet known but this association suggested several pathogenic hypotheses.

Complement C2↗
PubMed1992

Genetic polymorphisms in the fourth component of complement (C4) and in properdin factor B (BF) in Japanese patients with palmoplantar pustulosis.

Genetic polymorphisms in the fourth component of complement (C4) and in properdin factor B (BF) were investigated in 49 and 32 Japanese patients with palmoplantar pustulosis (PPP), respectively. C4B2 was significantly increased in frequency, whereas no significant deviations were detected in BF compared with the controls. These results may indicate that complement polymorphisms are involved in the pathogenesis of PPP.

Adult↗
PubMed1999

Sodium butyrate blocks interferon-gamma (IFN-gamma)-induced biosynthesis of MHC class III gene products (complement C4 and factor B) in human fetal intestinal epithelial cells.

Human intestinal epithelial cells have been established as local sites for complement biosynthesis. In this study, we investigated the effects of IFN-gamma and sodium butyrate on biosynthesis of MHC class III gene products (complement C4 and factor B) in the human fetal intestinal epithelial cell line INT-407. IFN-gamma induced a dose- and time-dependent increase in C4 and factor B secretion. However, sodium butyrate dose-dependently inhibited IFN-gamma-induced C4 and factor B secretion. These effects were also observed at the mRNA level. Immunoblotting indicated that IFN-gamma induced a rapid activation of Stat1alpha, and fluorescence immunohistochemistry detected a translocation of Stat1alpha into the nucleus within 1 h. However, the translocation of Stat1alpha was not affected by the addition of sodium butyrate. Nuclear run-on assay indicated that IFN-gamma induced a weak increase in the transcription rate of factor B gene, and sodium butyrate did not affect this response. IFN-gamma and sodium butyrate induced a counter-regulatory effect on C4 and factor B secretion: IFN-gamma acted as a potent inducer, but sodium butyrate potently abrogated these responses. These are mainly regulated through the post-transcriptional mechanism.

Blotting, Northern↗
PubMed1991

Changes in plasma complement C4 and factor B allotypes after liver transplantation.

Plasma complement allotypes for C4 and factor B were determined in 21 patients before and after liver transplantation together with donor typing. In 17 transplantations allelic differences between the patient and the donor could be shown. In all cases the patient's C4 and factor-B types converted to that of the donor, showing that the liver is the major source of plasma complement C4 and factor B.

Adult↗
PubMed1977

Cell-free synthesis of the fourth component of guinea pig complement (C4): identification of a precursor of serum C4 (pro-C4).

Polysomes (S-20) from homogenates of guinea pig liver synthesized serum albumin and a precursor of the fourth component of guinea pig complement (C4) in vitro. The C4 precursor (pro-C4) accounted for approximately 0.2% and albumin 4% of the radiolabeled protein precipitable by trichloroacetic acid and not bound to polysomes. Pro-C4 is a single polypeptide chain (molecular weight 200,000) which is then converted to C4, a three-chain (molecular weights 95,000, 78,000 and 31,000) structure linked by interchain disulfide bridges. Pro-C4 was also detected intracellularly in short-term tissue cultures of guinea pig liver. C4 was found in the medium harvested from these cultures.

Animals↗
PubMed1990

Post-transcriptional regulation of complement C4 in low C4-producing strain of mouse.

The expression of the fourth component of complement (C4) of the mouse can differ 20-fold and is determined by C4-high (C4h) or C4-low (C4l) alleles. To investigate the molecular mechanisms underlying the differences in C4 expression, we compared the transcriptional activity of the C4 genes between high and low C4-producer strains of mice (B10 and FM vs B10.BR) using nuclear transcriptional and chloramphenicol acetyltransferase (CAT) assays. We also compared the level of C4-specific RNA in total and nuclear RNA of the liver. The results revealed no significant difference in transcriptional activity between C4h and C4l genes. However, the steady-state levels of C4 mRNA are ten times lower in C4l strains than in C4h strains, suggesting that the major regulation of C4 plasma levels occurs at the post-transcriptional level.

Animals↗
PubMed1987

Synthesis and regulation of the two human complement C4 genes in stable transfected mouse fibroblasts.

The major histocompatibility complex-linked human complement C4 genes are highly homologous in primary structure but give rise to products which differ in complement-activating function. In order to examine the synthesis, function, and regulation of these two genes independently, cloned C4A and C4B genes were transfected into mouse fibroblast L-cells. In the stable transfected cell lines, C4A and C4B are synthesized, undergo a complex series of post-translational modifications, and each functions appropriately in activation of the classical complement pathway. A marked difference in the kinetics of complement component C1-mediated cleavage of the C4A- and C4B-alpha chains was demonstrated in the transfectants and may contribute to the differences in the intrinsic functional activity of the two C4 isotypes. In contrast to the expression of other complement genes which are affected during the hepatic "acute phase response" (factor B, C3), the expression of C4 was not regulated by interleukin-1 or tumor necrosis factor. Interferon-gamma, however, mediated a dose- and time-dependent increase in the expression of the C4 genes. Moreover, interferon had a significantly greater and longer-lasting effect on the synthesis of C4A than that of C4B. Differences in the expression and regulation of these two genes provide insight into the control of complement activation during inflammation.

Animals↗
PubMed1996

Complement C4 phenotypes in patients with end-stage renal disease.

The phenotypes of complement C4 were determined by agarose gel electrophoresis in 130 patients with end-stage renal failure of various causes and compared with those of 140 healthy controls. C4 allotype frequencies did not differ between patients and controls. Null alleles of both isotypes C4A and C4B were increased, but also without reaching significance. In type 1 diabetics an increased frequency of C4AQ0 (25 vs. 11.8%, p < 0.05) was found. Patients with two null alleles were far more frequent in the group with insulin-dependent diabetes mellitus (25 vs. 3.6%, p < 0.01). We confirmed the presence of a previously described uremic variant of C4B1. Additional uremic variants of C4 were detected in uremic patients homozygous for C4A3, B2 and B3. The relative electrophoretic migration values of the uremic variants of C4A3, B1, B2 and B3 were 132.1 +/- 2.9, 35.8 +/- 1.5, 70.4 and 73.9. These variants appear early in the course of chronic renal failure and disappear after successful renal transplantation. Uremic variants are the only acquired C4 phenotypes known so far. How uremia causes these variants remains unclear, but probably involves carbamylation of the C4 molecule.

Alleles↗
PubMed1980

Acute aflatoxicosis in guinea pigs: sequential changes in serum proteins, complement, C4, and liver enzymes and histopathologic changes.

Guinea pigs were fed a single toxic but sublethal dose of aflatoxin. Serum proteins, complement activity, fourth component of complement (C4), and liver enzymes (ornithine carbamoyltransferase and sorbitol dehydrogenase) as well as microscopic changes in liver tissue, were studied to correlate structural and functional abnormalities. There were no significant changes in serum proteins, but complement activity and C4 were depressed maximally 7 days after aflatoxin was given. The greatest activity of the liver enzymes in plasmas occurred at 3 days, although sorbitol dehydrogenase activity still was elevated significantly on the 7th day. Microscopic changes in the liver were maximum at 3 days with gradual recovery at 7, 10, and through 14 days.

Aflatoxins↗
PubMed1989

Regulation of plasma complement C4 and factor b levels in murine systemic lupus erythematosus.

We have investigated plasma concentrations of complement C4 and Factor B in three murine models of systemic lupus erythematosus, MRL-lpr/lpr (H-2k), BXSB (H-2b) and NZB/W (H-2d/z) mice. Levels of C4 and Factor B were also determined in the following control strains: C57BL/6 (H-2b), BALB/c (H-2d) and MRL-+/+ (H-2k). Although complement levels varied independent of disease activity, strain-dependent and intra-strain gender-dependent differences, were detected. Male BXSB mice exhibited significantly lower C4 levels than male C57BL/6 mice from 2.5-5.5 months of age but Factor B levels were not significantly different. Female BXSB, which do not exhibit early disease, had Factor B and C4 levels very similar to C57BL/6 mice. Male and female MRL-lpr/lpr mice, with active disease, had levels of C4 and Factor B which were not significantly different from those in age matched MRL-+/+ mice. While not significantly different from control, several female MRL-lpr/lpr mice with active disease had elevated C4 levels and normal Factor B levels. Male NZB/W, without disease, exhibited an age-dependent decline in plasma C4 but no decline in Factor B levels. In contrast, NZB/W females, with evidence of disease, exhibited age-dependent increases in C4 and Factor B. Interestingly, some animals with elevated C4 had normal Factor B levels and vice-versa. These observations suggest that complement levels do not necessarily reflect disease activity or morbidity patterns in murine lupus and therefore suggest caution in the interpretation of complement levels in the human counterpart of the disease.

Age Factors↗
PubMed1986

A new serological reaction in patients with polymyalgia rheumatica and/or giant cell (temporal) arteritis: deposition of complement C4 and C3 components on rat kidney structures detected by indirect immunofluorescence.

Using indirect immunofluorescence deposition of complement C4 and C3 components to rat kidney medullary structures was demonstrated. This serological reaction (C4/C3-IFT) is regularly obtained with fresh sera of patients suffering from active polymyalgia rheumatica (PMR) and/or giant cell (temporal) arteritis (GCA). Sera of normal controls and of steroid-treated PMR and/or GCA patients in clinical remission have a negative C4/C3-IFT reaction. A positive conversion of the test in steroid-treated patients indicates enhanced disease activity. Because of its technical simplicity, C4/C3-IFT can be routinely used first, as a reliable serological marker in the primary diagnosis of PMR and/or GCA and second, as a sensitive criterion of disease activity in these patients. C4/C3-IFT reactivity is, however, not specific for GCA and/or PMR. Various systemic inflammatory diseases may have a positive reaction as well (e.g., certain viral and bacterial infections, malignant tumors, vasculitides, inflammatory joint diseases of different etiology). Recent experimental findings suggest that C-reactive protein (CRP) in patients' sera mediates an activation of the classical complement pathway resulting in a deposition of C4 and C3 complement components to certain rat kidney structures.

Adult↗
PubMed1985

Complete nucleotide and derived amino acid sequences of the fourth component of mouse complement (C4). Evolutionary aspects.

The nucleotide sequence coding for the fourth component of mouse complement (C4) has been determined from a cloned genomic DNA fragment and a cloned cDNA fragment. The amino acid sequence of the protein was deduced. The single chain precursor protein (pro-C4) consists of 1719 amino acid residues. The mature beta, alpha, and gamma subunits contain 654, 766, and 291 amino acids, respectively. One potential carbohydrate attachment site is predicted for the beta chain, three for the alpha chain, and none for the gamma chain. From a comparison with human C4 cDNA sequence an extensive overall sequence homology, 79% in nucleotides and 76% in amino acids, is observed. There is conservation in both the position and number of cysteine residues in human and mouse C4. We compared the mouse C4 amino acid sequences with those of mouse C3 and human alpha 2-macroglobulin and the evolutionary relationship among these three proteins is discussed.

Amino Acid Sequence↗
PubMed1987

Association between restriction fragment length variants of the complement C4 genes and MHC haplotypes.

DNA polymorphism of the human major histocompatibility complex (MHC)-linked complement C4 genes was studied using restriction enzymes XbaI and TaqI, and Southern hybridization. The results show that some, but not all, C4 phenotypes can be divided into subtypes. Analysis of MHC haplotypes indicates that in each extended MHC haplotype, i.e. in the haplotypes having a particular combination of HLA and complotype phenotypes in significant linkage disequilibrium, the C4 genes always produce just one 'conserved' restriction enzyme fragment pattern, while in the other haplotypes the C4 genes are more heterogeneous. Furthermore, the findings provide preliminary evidence for a C4B gene duplication, and suggest that the C4 genes may often be 'corrected' alike.

Chromosome Mapping↗
PubMed1980

Activation of the fourth component of complement (C4): assessment by rocket immunoelectrophoresis and correlation with the metabolism of C4.

The classical pathway of complement (C) is activated in several diseases, and this activation characteristically involves the activation of C4, the fourth component of C. Since activation of C4 ultimately produces the polypeptide fragment C4d, we have applied immunoelectrophoresis in gels containing antibodies that precipitate C4d and C4 (rocket immunoelectrophoresis) as a means of detecting and quantitating C4 activation. Plasma C4 produced a single precipitin line after rocket immunoelectrophoresis, whereas plasma containing C4d produced two precipitin lines corresponding to C4d and C4. The areas enclosed by the respective precipitin line(s) were quantitated by planimetry and approximated the amounts of C4d and C4 present in the specimen. The ratio of the areas of C4d/C4 as measured in this analysis correlated significantly with the in vivo metabolism of radiolabeled C4. Our method detected C4d in the plasmas of some patients with rheumatoid arthritis, hereditary angioedema, systemic lupus erythematosus, or chronic urticaria with hypocomplementemia. These studies indicated that determination of the C4d/C4 ratio is useful in the evaluation of in vivo C activation and also may be applicable to the study and management of diseases associated with C activation.

Angioedema↗
PubMed1985

Deletion of complement C4 and steroid 21-hydroxylase genes in the HLA class III region.

Molecular maps have been prepared of the HLA region on human chromosome 6 that includes the complement C4 and steroid 21-hydroxylase genes (21-OH), using DNA of individuals deficient (QO) in either of the two forms C4A or C4B. In all, 18 haplotypes with C4A QO were examined by Southern analysis and two had deletions of 28-30 kb that included both the C4A and 21-OHA genes. Of six C4B QO haplotypes, one had a deletion that included both the C4B and 21-OHA genes. Thus, some of the C4 null alleles are due to deletion of the gene but the majority in this sample are not. Deletion occurred in two common haplotypes suggesting that in the population as a whole, C4A deficiency is due to deletion in about one-half the C4A QO haplotypes. As duplication of C4A or C4B genes does occur, the possibility that unequal cross-over could explain the C4 deletion was examined by preparing cosmid clones from the DNA of an individual typed C4A QO. A cloned genomic fragment containing the single C4B gene was isolated and found to be similar to the homologous region of a cosmid from a normal individual carrying a C4A gene. This suggests that if a cross-over has occurred it is in a region where the two genes are identical. The biological significance of the rather frequent occurrence in the population of haplotypes with C4A or C4B deletion together with the accompanying deletion of the 21-OHA gene is discussed.

Alleles↗