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PubMed1990

The binding site of human C4b-binding protein on complement C4 is localized in the alpha'-chain.

C4b-binding protein (C4BP) is a multimeric plasma protein, which regulates the classical pathway of the C system. C4BP functions as a cofactor to factor I in the degradation of C4b and accelerates the decay rate of the C4b2a complex. We now demonstrate that C4b contains a binding site for C4BP, which is localized on the alpha'-chain of C4b. SDS-PAGE of C C4 and C4b both under reducing and nonreducing conditions was followed by a radiolabeled C4BP ligand blotting procedure. It was demonstrated that the C4BP binding site on C4b is localized on the alpha'-chain. In addition, we found C4BP binding to the alpha-chain of C4, which suggests that the binding site for C4BP becomes available after reduction of the C4 molecule. Direct binding of C4BP to the alpha- and alpha'-chains of C4 and C4b was demonstrated in a radio-labeled C4BP binding assay with the reduced and alkylated isolated chains. mAb against the alpha'-chain of C4b were prepared, characterized, and evaluated for their ability to block the binding of 125I-C4BP to C4b. Two mAb specific for the alpha'-chain of C4b were found that completely abolished C4BP binding to intact C4b. Other mAb recognizing both the alpha- and alpha'-chain of C4 and C4b demonstrated only minor inhibitory effect on the binding of C4BP to C4b. In conclusion, we have localized the C4BP binding site on the alpha'-chain of C4b and have demonstrated that this binding can be inhibited by mAb specific for the alpha'-chain.

Antibodies, Monoclonal↗
PubMed1993

HLA antigens and complement C4 allotypes in patients with chronic biologically false positive (CBFP) seroreactions for syphilis: a follow-up study of SLE patients and CBFP reactors.

We report a follow-up of our previous study of HLA markers in 118 unrelated patients: 49 with definite systemic lupus erythematosus (SLE) (group 1), 32 with definite or probable SLE and chronic biologically false positive (CBFP) seroreactions for syphilis (group 2), and 37 CBFP reactors (group 3). Definite SLE was confirmed in 28 (90.3%) of the patients in group 2, equally in HLA B8- and HLA B7-positive patients. Three of the CBFP reactors developed SLE, two (40%) out of five HLA B8-positive as compared to one (6.6%) out of 15 HLA B7-positive CBFP reactors (P = 0.07). Fourteen patients died (groups 1 and 2). Eight of the 24 HLA B8-positive patients died in contrast to one of the 20 HLA B7-positive patients (P < 0.02). Of the CBFP reactors, 70.9% had complement C4 null alleles as compared to 47.9% in controls (P = 0.05) and 50% had C4A null alleles as compared to 17.8% in controls (P < 0.05). C4B null alleles were found in 28.6% (28.6% in controls, P is not significant). The null alleles for C4A were not solely in a linkage disequilibrium with the HLA B8 DR3 haplotype. CBFP reactors with C4A null alleles had a higher risk of developing SLE, lupus-like disease or symptoms such as photosensitivity, cutaneous vasculitis and/or autoantibodies than did those with no C4A null alleles (P < 0.02).

Adolescent↗
PubMed1991

Heat shock protein 70 (HSP70) and complement C4 genotypes in patients with hyperthyroid Graves' disease.

The genetic polymorphisms of the heat shock protein 70 (HSP70) and complement component C4 were investigated in 90 patients with hyperthyroid Graves' disease and 92 normal control subjects. The 8.5-kb PstI HSP70 allele was strongly associated with Graves' disease when compared with controls (P less than 0.001). The presence of the 8.5-kb PstI HSP70 allele was strongly associated with a deletion of the C4A gene in both patients and controls (P less than 0.0003 and P less than 0.00005 respectively). However, in the absence of C4A gene deletion, the frequency of the 8.5-kb PstI HSP70 allele was still significantly higher in patients when compared with controls (P less than 0.04). These results suggest that the HSP70 locus may have an immunological role to play in autoimmune hyperthyroid Graves' disease.

Alleles↗
PubMed1997

Genetic regulation of the impaired immune response to hepatitis-B vaccine associated with low TCR density in end stage renal disease patients: contribution of complement C4 and factor B alleles.

We have studied the relationship between T-cell receptor (TCR) density, genetic factors and the specific immune response in 153 end stage renal disease (ESRD) patients on haemodialysis immunised with HBsAg vaccine. One-hundred and nineteen patients raised a protective (> 10 U/ml) antibody response to hepatitis-B vaccination (responder, R), while 34 patients were found to be non-responders (NR). The density of the T-cell receptors was determined by flow cytometry. Proliferation of the T-cells induced by autologous monocytes presenting HBsAg was also measured and expressed as a stimulation index (SI). MHC class I, II and III alleles of the patients were also determined. The densities of TCR/CD3 receptors in NR patients were found to be significantly decreased as compared to the R patients (189 +/- 22 vs. 282 +/- 58 arbitrary units, P = 1.3 x 10(-7). TCR/CD3 receptor densities were found to be strongly associated (Spearman correlation coefficient: 0.84, P < 0.000001) with the SI values. Both parameters were found to be under dual genetic control: (a) very low density of the TCR/CD3 receptors and very low SI were found mainly in NR patients carrying HLA-A1, HLA-B8 and HLA-DR3 alleles; and (b) TCR/CD3 densities and function in R group were found to be significantly lower in carriers than in non-carriers of two MHC class III complement protein alleles: C4A*6, and Bf*F. Non-responsiveness to hepatitis-B vaccination was found to be associated with extremely increased neopterin levels. These findings indicate that both genetic and acquired factors contribute to the hepatitis-B vaccination failure in ESRD patients.

Alleles↗
PubMed1996

Visual demonstration of the organization of the human complement C4 and 21-hydroxylase genes by high-resolution fluorescence in situ hybridization.

We analyzed the gene organization in the complement component C4 and 21-hydroxylase (21OH) gene region of the human major histocompatibility complex using visual mapping of stretched DNA by multicolor fluorescence in situ hybridization (FISH). Normally, this region contains a duplicated 21OH-C4 gene cluster (21OHB-C4B-21OHA-C4A). Duplication and deletion of one or more copies of the 21OH-C4 gene unit are known to occur frequently. Biotin-labeled cDNA of the C4 gene and digoxigenin-labeled cDNA of the 21OH gene were hybridized to decondensed nuclei of peripheral blood lymphocytes obtained from individuals with various 21OH-C4 haplotypes. Hybridization signals of the C4 and 21OH probes were detected with fluorescein isothiocyanate (green) and rhodamine (red), respectively. Two linear green and red signal clusters were observed in each nucleus showing the normal haplotype. Gene duplication and deletion were visualized as addition and deletion of the signal cluster, respectively. The DNA types of the 21OH-C4 region determined by FISH were concordant with the results previously obtained by conventional molecular studies. Our high-resolution FISH technique is found to be useful for screening gene duplications and deletions.

Complement C4↗
PubMed1989

HLA and complement C4 antigens in polyarticular onset seronegative juvenile chronic arthritis: association of early onset with HLA-DRw8.

HLA-A,B,C,DR and DQ antigens were tested in 53 British Caucasian patients with polyarticular onset seronegative juvenile chronic arthritis (JCA); C4 allotypes were also tested in 46. A strong association with HLA-DRw8 was found (RR = 6.1, Fp = 7.6 x 10(-5)), with increased -B5(51) and C4A QO, and decreased -DR7 frequencies. DRw8 incidence correlated with an onset under 5 years, 9 of 12 DRw8+ cases being in this subgroup (Fp = less than 0.06), whereas B5 and C4A QO were prevalent in late onset (greater than or equal to 5 years). Erosions after 5 years associated with HLA-DRw6, and their absence with -Cw1 and -DR5. Genetic susceptibility factors and a further subdivision by onset age are thus demonstrated in this disease. Comparative data suggest that the genetic basis of susceptibility to early onset disease is similar to that of pauciarticular JCA.

Adolescent↗
PubMed1991

[Problems in the determination of immunocomplexes. VI. Changes in the levels of C4 complement and IgG in the precipitation of immunocomplexes using polyethylene glycol].

The authors modified the method for the assessment of circulating immunocomplexes by assessing changes in the concentration of IgG and C4 components of complement in the precipitate after adding polyethylene glycol. The method was tested on a series of samples, the scatter of values for the healthy population was assessed and the results were compared with the PEG method elaborated in the Institute for Clinical and Experimental Medicine.

Antigen-Antibody Complex↗
PubMed2002

Complement C4 is protective for lupus disease independent of C3.

The role of complement C3 in mediating systemic lupus erythematosus (SLE) was examined using a double-knockout C3(null)C4(null) Fas (CD95)-deficient mouse model. Results from this study reveal significant lymphadenopathy, splenomegaly, elevated titers of anti-nuclear Abs and anti-dsDNA Abs, an increased number of anti-dsDNA-producing cells in ELISPOT assay, as well as severe glomerulonephritis in the double-deficient mice. Based on these clinical, serological, and histological parameters, we find that autoimmune disease in the double-knockout group is similar in severity to that in C4(null) lpr mice, but not to that in C3(null) lpr mice. The development of severe SLE in the absence of both classical and alternative complement pathways suggests that it is the absence of C4, and not the presence of C3, that is critical in SLE pathogenesis. Thus, complement C4 provides an important protective role against the development of SLE.

Animals↗
PubMed1992

Molecular heterogeneity of the fourth component of complement (C4) and its genes in vitiligo.

In view of evidence suggesting vitiligo is an autoimmune disease, we investigated whether vitiligo is associated with inherited deficiencies of the fourth (C4) and second (C2) component of complement and with certain human leukocyte antigens (HLA). Analysis of functional activities of C4 and C2 in sera of patients with vitiligo (n = 42) showed that 17% of them had a heterozygous C4 deficiency and 5% had a heterozygous C2 deficiency. In the normal control group (n = 30), 3% had a heterozygous C4 deficiency and none had a C2 deficiency. C4 typing by Western blot analysis showed the frequency of the C4A*Q0 allele in the vitiligo patient group to be close to normal. However, the frequency of one C4B*Q0 allele was three times higher, and that of two C4B*Q0 alleles five times higher in the vitiligo patient group than the reported frequencies in normal control groups. Southern blot analysis of Taq1 digests of DNA using C4 and 21-hydroxylase probes showed that two patients with two C4B*Q0 alleles had a deletion of a 21-OHA-C4B segment. In the other patients, having one or two C4B*Q0 alleles, these null alleles probably occurred due to a loss of C4 gene expression. HLA analysis did not show any allelic association of C4A*Q0 or C4B*Q0 with any HLA antigen in vitiligo, but confirmed the previous findings of a negative association with HLA-DR3 and a positive association with HLA-DR4. These results suggest that abnormalities of the C4B gene and the above-mentioned associations with HLA antigens may be some of the risk factors in vitiligo.

Adrenal Hyperplasia, Congenital↗
PubMed1980

Structural studies on the murine fourth component of complement (C4). IV. Demonstration that C4 and Slp are encoded by separate loci.

The S region of the murine major histocompatibility complex (MHC) encodes the structural gene for the fourth complement component (C4) and controls C4 serum levels and expression of the sex-limited protein (Slp). Although Slp was first throught to be an allele of C4, more recent studies have suggested that Slp is either a modified product of the C4 locus or is encoded at a separate locus. By using a sensitive peptide analysis technique, each of the three constitutive polypeptide chains of C4 and Slp was compared, and multiple distinct peptides as well as several shared peptides were detected. These results demonstrate that although C4 and Slp undoubtedly share a common genetic origin, they are encoded by separate structural genes.

Alleles↗
PubMed1990

Importance of the alpha 3-fragment of complement C4 for the binding with C4b-binding protein.

The human regulatory complement component C4b-binding protein (C4BP) is a multimeric plasma protein, which regulates the classical pathway of the complement system. C4BP functions as a cofactor to factor 1 in the degradation of C4b and accelerates the decay rate of the C4b2a complex. Previously, we have demonstrated that monoclonal antibodies (C4-2 and 9) directed against the alpha'-chain of C4b inhibit the binding of C4b to C4BP. In order to identify the structural domain of C4b that binds C4BP, proteolytic fragments of C4 were generated with trypsin and Staphylococcus aureus V8 protease. Sodium dodecyl sulfate polyacrylamide gel electrophoresis, immunoblotting and amino acid sequence analysis of the proteolytic fragments reactive with the anti-C4 mAb's revealed that the residues Ala738-Arg826 of the alpha 3-fragment of C4b are important for the interaction with C4BP.

Amino Acid Sequence↗
PubMed1994

Promoter elements of the mouse complement C4 gene critical for transcription activation and start site location.

We have explored the template and factor requirements for transcription of the gene encoding the murine complement component C4, expressed predominantly but not exclusively in liver and mononuclear phagocytes. Competition experiments in transcription assays with liver nuclear extracts show that the regions upstream of the transcription initiation site are largely dispensable for obtaining basal levels of accurately initiated transcription. Activated transcription, however, depends on three upstream regulatory factors, two of which interact with target sites seemingly related to NF-1 (region -112/-87) and USF (region -85/-64), respectively. A third upstream regulatory factor has been detected by the surprising finding that double-stranded oligomers covering sequences proximal to the cap site (position -48 to -7) stimulate transcription from the C4 promoter specifically. Results of nucleotide deletions and site-directed mutations argue that the C4 initiator, that is, the most critical element for basal and accurate transcription of the gene, overlaps the cap site and extends into the transcribed sequences (-1 to +12). Immediately downstream of this region lies a last regulatory element (within the +5 to +43 boundaries) indispensable for high levels of transcription. These data assume wider interest because the C4 promoter does not contain TATA or CAAT boxes and does not feature any of the elements characteristic of the TATA-less genes so far reported.

Animals↗
PubMedDate not supplied

A rare TaqI polymorphism in a human complement C4 gene is caused by an additional restriction site in the first intron.

We studied the configuration of the complement C4/CYP21 (steroid 21-hydroxylase) region of the human major histocompatibility complex in patients suffering from congenital adrenal hyperplasia (CAH) and in the general population in The Netherlands, using C4 and CYP21 probes and the restriction enzymes TaqI and Bg/II. We found a rare TaqI 3.9-kb restriction fragment in the mother of a CAH patient, and present evidence that this polymorphism is caused by an additional restriction site in the first intron of a complement C4 gene.

Adrenal Hyperplasia, Congenital↗
PubMedDate not supplied

HLA and hypocomplementemia: the disadvantage of carrying the HLA-B35 and the silent alleles of the C4 complement component.

Hypocomplementemia is an extremely complex phenomenon: we devoted our attention to its immunogenetic basis, particularly to the HLA haplotypes involved and to the study of C4 polymorphic genes. With this in mind we analyzed a group of unrelated patients with hypocomplementemia and 15 families suffering from specific C4 deficiency. Firstly, we performed a population analysis in order to identify a statistically significant association: HLA-B35 and C4BQ0 alleles, in the total group of hypocomplementemic individuals, seem to be associated with the primary disease. Secondly, we defined HLA haplotypes clear-cut segregation in the hypocomplementemic families and we identified the most common HLA haplotypes carrying B35 and C4 null allele associated with this condition. With the aid of correspondence analysis and the Transmission Disequilibrium Test (TDT), we measured the strength of this association. In this work, mainly through family analysis, we envisaged a potentially interesting genomic trait, within HLA, close to B locus, that seems to be involved in hypocomplementemia itself and perhaps in hypocomplementemia-related disorders.

Algorithms↗
PubMed1980

Receptors on guinea-pig erythrocytes specific for cell-bound fourth component of human complement (C4).

Guinea-pig erythrocytes have receptors for heterologous (human and rabbit) complement activated by the classical pathway on cell surfaces. This was shown in the present study by rosette-forming reactions of guinea-pig erythrocytes and human lymphocytes or sheep erythrocytes pre-treated with antibody and human R3 complement. The binding is temperature-dependent and is enhanced by treating the guinea-pig erythrocytes with neuraminidase. The receptors were shown to be specific for C4 by inhibition tests employing a range of anti-human complement antibodies (including anti-Clq, -Cl inhibitor, -C4, -C2, -C3 and -C3b inactivator). Of these reagents, only anti-C4 inhibited the receptor activity, indicating that the guinea-pig erythrocyte C4-receptors differ from those on lymphocytes, monocytes, polymorphonuclear leucocytes and human erythrocytes which are reported to react with both C3b and C4b. In contrast to the strong affinity observed for heterologous C4, guinea-pig erythrocytes appear to react very weakly, if at all, with homologous C4.

Animals↗
PubMed1978

[Study of C3 and C4 complement components of synovial fluids in connective tissue diseases (author's transl)].

C3 and C4 levels and the relative concentration of C3 degradation products were measured in fifty pairs of synovial fluids and sera of patients who suffered from different connective tissue diseases. Inverse correlation between C4 level and C3 breakdown products were found in synovial fluids of different groups. Compared to the other groups of patients, the highest increase of C3 degradation was found in RA. patients and it occurred in the SF all of these patients. In arthrosis cases we failed to find any degradation of C3. Of the seven investigated ankylosing spondylitis only two showed some degree of activation of C3 in the SF. Our results suggest that the occurrence and degree of degradation of C3 complement component is a valuable laboratory parameter in the study of connective tissue diseases.

Arthritis↗
PubMed1988

Correlation of the activation of the fourth component of complement (C4) with disease activity in systemic lupus erythematosus.

Levels of C4d, a fragment of C4 generated during activation of the classical complement pathway, were measured in the plasma of 48 patients with systemic lupus erythematosus, 11 with inactive (group 1), 23 with mildly active (group 2), 14 with moderately/severely active disease (group 3), and 30 healthy subjects. Levels of C3d, C4, and C3 were also measured and the C4d/C4 and C3d/C3 ratios calculated. C4d levels correlated with the degree of disease activity, being higher in group 3 than in group 2, in group 2 than in group 1, and in group 1 than in controls. C4d/C4 gave a similar result. Activation indices of the common complement pathway, C3d and C3d/C3, also correlated with disease activity, but in a non-linear relationship, failing to discriminate between patient groups. C4 and C3 showed no correlation with disease activity. These results indicate that indices of C4 activation, C4d and C4d/C4, provide a laboratory measure of disease activity in lupus patients, for whom an objective assessment of the severity of the disease is not readily available.

Adult↗