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PubMed1997

Relationship between protein complotypes and DNA variant haplotypes: complotype-RFLP constellations (CRC).

From the study of 52 families and 15 homozygous typing cells, 234 MHC complement haplotypes were characterized for features in the DNA of the complotype region: C2/Sst I (2.75, 2.70, 2.65, and 2.40 kb), BF/Taq I (6.6 and 4.5 kb), C4 5'/Bgl II (15 and 4.5 kb), C4 5'/Taq I (7.0, 6.4, 6.0 and 5.4 kb) and C4 3'/Xba I/BamH I (11 and 4 + 7 kb) restriction fragment length polymorphisms (RFLP's), by the presence or absence of C4A, C4B, CYP21A and CYP21B genes and by duplications. Nineteen (of over 1000 theoretically possible) complotype-RFLP constellations (CRC's) were found. The 9 CRC's with two C4 and CYP21 genes were designated A through I. CRC's Bdup and Ddup were like B and D but had duplicated C4B-CYP21B genes. The remaining CRC's had deletions of C4 and/or CYP21 genes and were designated Bdel, Cdel and the like. Individual complement alleles and complotypes were nor randomly distributed among the CRC's. Some complotypes, such as SC01, SC02 and FIC30, were restricted to only 1 CRC; others, such as SC31, FC31, and SC30, were found in several CRC's. Some of the CRC's contained a single complotype, others contained several. Remarkably, there are about 30 CRC-specified complotypes with frequencies of .01 or higher and 14 of .02 or higher. A number of evolutionary origins of complement alleles and complotypes are suggested by the relationships among CRC's. Approximate normal frequencies of the undeleted CRC's were A = .27, B = .19, Bdup = .02, C = .17, D = .07, Ddup = .02, E = .06, F = .05, and G = .02. Thus, CRC's without deletions accounted for 88% of normal complotypes. Since the frequency of Bdel, with a deletion of C4A, was .12, 10 CRC's accounted for all observed normal caucasian MHC haplotypes.

Chromosome Mapping↗

PubMed1995

Serum concentrations of C4 isotypes and factor B in type I C2 deficiency suggest haplotype-dependent quantitative expression of MHC class III complement genes.

The complement protein C4 exists as two isotypes, C4A and C4B, encoded by genes in the major histocompatibility complex (MHC) class III region. The serum concentrations of C4A4 were lower than those of C4B2 in serum from 19 individuals homozygous for type I C2 deficiency (p < 0.0002). These individuals all had the S042 complotype and most of them were homozygous for the haplotype HLA-B18,S042,DR2. In 14 individuals heterozygous for the C2Q0 gene and with the C4A4, C4B2 phenotype and in 51 individuals with the C4A3, C4B1 phenotype, the isotype concentrations were equal. Factor B concentrations in the C2-deficient individuals were lower than those in individuals with the C4A3, C4B1 phenotype (p < 0.0001). The findings strongly suggest that the quantitative expression of C4 isotypes and factor B is MHC haplotype dependent. C4 null alleles cannot be accurately determined by measuring relative C4 isotype serum concentrations.

Complement C2↗

PubMed1992

Complement activation during storage of blood under normal blood bank conditions. Effects of proteinase inhibitors and leukocyte depletion.

During storage of CPD-A1 preserved whole blood factors of the complement cascade become activated, as evidenced by a rapid increase in the concentrations of C3a-desArg and C4a-desArg. After 10 to 14 days of whole blood storage, the elevations of C3a and C4a levels were highly significant. This increase was paralleled by an increase in the concentration of the lysosomal proteinase elastase from polymorphonuclear (PMN) granulocytes. By contrast, the concentration of the C3 activator complex C4b2b remained unchanged even after 3 weeks of storage. The supplementation of the anticoagulant CPD-A1 with the polyvalent-proteinase-inhibitor aprotinin and the specific elastase-inhibitor eglin C failed to inhibit complement activation, whereas leukocyte depletion could partially abolish the increase of the concentration of C4a, but had no effect on C3a concentrations. These observations support the notion that cleavage of C4 during storage of whole blood is partially leukocyte dependent, whereas the activation of C3 is possibly caused by the activation of the alternate pathway of the complement system by contact of plasma with plastic surfaces.

Aprotinin↗

PubMed1981

Quantitation of human complement fragment C4ai in physiological fluids by competitive inhibition radioimmune assay.

A method is described to quantitate complement fragment C4ai in human plasma, synovial fluid, and urine. Samples are first precipitated with 50% saturated (NH4)2SO4 to remove cross-reactive macromolecules C4 and pro-C4. Whereas greater than 97% of C4 is removed by this precipitation step, 88% of C4ai remains in solution. Second, the concentration of C4ai in supernatant fractions is determined by double antibody competitive inhibition radioimmunoassay. C4a was recently completely sequenced (Moon et al., 1981) and is readily available as a pure standard. Examination of the specificity of this method confirmed it was indeed specific for C4a antigenicity. Immunochemically depleted C4-deficient plasma and inulin-activated reconstituted C4-deficient plasma exhibited less than 0.1% of the immunoreactivity of untreated plasma. In addition, good agreement was observed in analyses of aggregated IgG activated serum between the experimentally determined concentration of C4ai and that expected from the initial concentration of C4. As a result, recovery and measurement of C4ai in physiological fluids with this method appear both quantitative and specific. Based on results from 17 adult volunteers, the average concentration of C4ai in normal plasma is 488 ng/ml. Interestingly, significant correlation could not be demonstrated between the levels of C4 and C4ai in normal plasma. The mean concentration of C4ai in human urine is 0.5 ng/ml.

Animals↗

PubMed2006

Discovery and identification of potential biomarkers in a prospective study of chronic lymphoid malignancies using SELDI-TOF-MS.

The accurate diagnosis of the different forms of chronic mature B-cell lymphocytic malignancies is of primary importance to determine an appropriate and efficient treatment. Usually, the diagnosis is achieved by morphology and immunophenotyping. Nevertheless, the diagnostic tools available are not able to discriminate pathologies with variable evolution, or to classify some of them. To discover new biomarkers, we used peptide and protein profiling SELDI-TOF-MS, to analyze 39 chronic B-cell malignancies and 20 control serum samples. Markers of interest were subsequently identified and characterized. In the obtained SELDI-MS profiles, most of the differences were observed in three mass ranges (m/z = 13 000; m/z = 9000; m/z < 2000). Identification of these biomarkers was achieved either by direct enrichment on the ProteinChip arrays followed by on-chip-MS/MS or by chromatographic fractionation, 1D-gel followed by nanoLC-MS/MS analysis. An increase of a sulfite form of transthyretin (13,841 Da) was observed in the patient group. A second set of markers at 8.6 and 8.9 kDa was identified as complement related fragment proteins, the C3a and C4a anaphylatoxins. In the low mass range, several peptides originating from N-terminal and C-terminal processing of the C3 alpha and C4 alpha chains were specifically observed in 38% of the patient sera, but in none of the control sera. This study emphasizes the usefulness of mass spectrometry studies in such malignancies.

Amino Acid Sequence↗

PubMed1990

[DNA analysis of HLA class II and III genes in sudden infant death (SIDS)].

In 39 cases of SID we studied the polymorphism of HLA-class II genes DRB and DQB and HLA-class III genes C4 (C4A and C4B, genes encoding the fourth complement component) and 21-hydroxylase (21OH-A and 21OH-B, genes encoding the enzyme 21-hydroxylase of the cortisol pathway) by DNA analysis. This study was performed in cooperation with the Institute of Legal Medicine, University of Munich. Compared to healthy controls the percentage of C4B gene deletions, C4B gene duplications (C4B "short") and 21OH-A gene deletions is increased in SIDS. The deviations are statistically not significant. The analysis of the HLA-DR alleles revealed a significant decrease of HLA-DR2 in SIDS compared to controls (p = 0.0016, pc = 0.016). The results of this study indicate a possible role of C4B/21OH-A gene defects as a risk factor in a subgroup of SID cases. This hypothesis has to be confirmed by studying further cases.

Chromosome Aberrations↗

PubMed1989

Molecular genetics of C4B deficiency in IgA nephropathy.

The fourth component of complement (C4) occurs in two functionally distinct isotypes, C4A and C4B. The two closely linked genes are located on chromosome 6p, between HLA-B and -DR. Several reports have established complete C4B deficiency as the major genetic risk factor for IgA nephropathy (RR = 6.5; p = 0.0004). It is not clear whether this association derives from immune dysfunction related to the absent isotype or from another disease susceptibility gene closely linked to C4B. To help distinguish between these mechanisms, we examined the molecular basis of complete C4B deficiency in five patients with IgA nephropathy and eight healthy individuals. C4 and Bf protein typing were performed by immunofixation electrophoresis of plasma. Genomic DNA was digested with several restriction enzymes, chosen to produce informative restriction fragment length polymorphisms (RFLPs). After electrophoresis and Southern blotting, digests were hybridized to a series of cDNA probes specific to the 5' and 3' ends of the C4 genes, the C4d region, and the adjacent 21-hydroxylase genes. Availability of DNA from family members allowed assignment of RFLPs to specific haplotypes. The 10 C4B-deficient IgA nephropathy-associated haplotypes displayed seven different protein phenotype/RFLP patterns. Three haplotypes consisted of the common C4B/21-hydroxylase deletion on the Bf*S, C4A*3, C4B*Q0 complotype. Two haplotypes were characterized by the C4A*3,2 duplication, with two C4 genes present but a C4A protein being produced by the gene at the usual C4B locus. All of the remaining haplotypes had unique Bf, C4, and 21-hydroxylase patterns. C4B-deficient IgA nephropathy patients display a variety of molecular genetic bases for their protein deficiency. This observation speaks against linkage of C4B deficiency with a locus encoding disease susceptibility and supports a primary role for the complement abnormality in this disease.

Child↗

PubMed1991

Complement activation in diabetes mellitus.

To see whether or not there is complement activation in patients with diabetes mellitus, we investigated the plasma concentrations of C4, C3, C4a, C3a and SC5b-9 in either juvenile or adult onset insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients at least 2 years after diagnosis. C4, C3, SC5b-9 plasma levels were not significantly different in IDDM and NIDDM patients than in age-matched controls. Anaphylatoxin peptide conversion product C4a, but not C3a, was found significantly higher in adult-onset IDDM patients than in patients with juvenile onset IDDM, NIDDM patients and age-matched controls. Complement activation did not appear to be correlated with the metabolic control, nor the duration of disease nor the presence of circulating antibodies (including islet cells (ICA), insulin (IA), thyroid microsomal (TMA), and thyroglobulin (TGA)). Although there are many factors that may trigger complement activation, we found the highest levels of C4a in elderly subjects (both diabetics and control subjects) and particularly in those who had clinically detectable vascular complications.

Adolescent↗

PubMed2003

Molecular cloning of C4 gene and identification of the class III complement region in the shark MHC.

To clarify the evolutionary origin of the linkage of the MHC class III complement genes with the MHC class I and II genes, we isolated C4 cDNA from the banded hound shark (Triakis scyllium). Upon phylogenetic tree analysis, shark C4 formed a well-supported cluster with C4 of higher vertebrates, indicating that the C3/C4 gene duplication predated the divergence of cartilaginous fish from the main line of vertebrate evolution. The deduced amino acid sequence predicted the typical C4 three-subunits chain structure, but without the histidine residue catalytic for the thioester bond, suggesting the human C4A-like specificity. The linkage analysis of the complement genes, one C4 and two factor B (Bf) genes, to the shark MHC was performed using 56 siblings from two typing panels of T. scyllium and Ginglymostoma cirratum. The C4 and one of two Bf genes showed a perfect cosegregation with the class I and II genes, whereas two recombinants were identified for the other Bf gene. These results indicate that the linkage between the complement C4 and Bf genes, as well as the linkage between these complement genes and the MHC class I and II genes were established before the emergence of cartilaginous fish >460 million years ago.

Amino Acid Sequence↗

PubMed2000

Frequencies of certain complement protein alleles and serum levels of anti-heat-shock protein antibodies in cerebrovascular diseases.

BACKGROUND AND PURPOSE: A strong correlation exists between the intensity of atherosclerotic alterations in different arteries. Marked differences exist, however, in the age and sex distribution and risk factors for coronary heart disease (CHD) and cerebrovascular disease (CVD). We therefore performed genetic and immunologic studies in patients with CVD. METHODS: We studied 292 patients with CVD (stroke or transient ischemic attack) and as control either 198 healthy blood donors and 485 healthy elderly (aged >60 years) people (genetic study) or 94 blood donors aged 45 to 60 years and 49 healthy elderly (aged >60 years) people (anti-heat-shock protein [hsp] measurements). Allele frequencies of 3 genes (C4A, C4B, and C3) encoding proteins of the complement system were determined by electrophoresis and immunofixation. Serum concentration of autoantibodies against 60-kDa heat-shock protein (anti-hsp60) was measured by the enzyme-linked immunosorbent assay method. RESULTS: Marked differences were observed between CVD patients and controls in the genetic studies. In the CVD patients aged >60 years, the frequency (11.3%) of the deficient allele of the C4B gene (C4B*Q0) was significantly (P:=0.0003) higher than that of the healthy controls (5.4%). By contrast, in the group aged 45 to 60 years, the frequency of the C4B*Q0 allele was lower in patients than in controls. Serum concentration of anti-hsp60 in the CVD patients did not differ from control values. CONCLUSIONS: In previous studies C4B*Q0 frequency was reported to be higher in CHD patients aged 45 to 60 years than in aged-matched controls. Moreover, high anti-hsp60 levels were found in CHD patients. These findings contrast with our present report of lower frequency of C4B*Q0 in CVD patients. Therefore, genetic and immunologic factors may at least partly explain the differences between the natural history and risk factors of CHD and CVD.

Cerebrovascular Disorders↗

PubMed1992

C4 genes of the chimpanzee, gorilla, and orang-utan: evidence for extensive homogenization.

The human complement component 4 is encoded in two genes, C4A and C4B, residing between the class I and class II genes of the major histocompatibility complex. The C4A and C4B molecules differ in their biological activity, the former binding more efficiently to proteins than to carbohydrates while for the latter, the opposite holds true. To shed light on the origin of the C4 genes we isolated cosmid clones bearing the C4 genes of a chimpanzee, a gorilla, and an orang-utan. From the clones, we isolated the fragments coding for the C4d part of the gene (exons and introns) and sequenced them. Altogether we sequenced eight gene fragments: three chimpanzee (Patr-C4-1*01, Patr-C4-1*02, Patr-C4-2*01), two gorilla (Gogo-C4-1*01, Gogo-C4-2*01), and three orang-utan (Popy-C4-1*01, Popy-C4-2*01, Popy-C4-3*01). Comparison of the sequences with each other and with human C4 sequences revealed that in the region believed to be responsible for the functional difference between the C4A and C4B proteins the C4A genes of the different species fell into one group and the C4B genes fell into another. In the rest of the sequence, however, the C4A and C4B genes of each species resembled each other more than they did C4 genes of other species. These results are interpreted as suggesting extensive homogenization (concerted evolution) of the C4 genes in each species, most likely by repeated unequal, homologous, intragenic crossing-over.

Animals↗

PubMed1999

Homozygous deletion of the CYP21A-TNXA-RP2-C4B gene region conferring C4B deficiency associated with recurrent respiratory infections.

The central class III region of the human major histocompatibility complex contains highly polymorphic genes that are associated with immune disorders and may serve as susceptibility factors for viral infections. Many HLA haplotype specific rearrangements, duplications, conversions and deletions, occur frequently in the C4 gene region. Genetic deficiencies of complement components are associated with recurrent occurrence of bacterial infections. We have studied the complement profile and the class III genes 5'-RP1-C4A-CYP21A-TNXA-RP2-C4B-CYP21B-TNXB -3' in a 4-year-old Caucasian patient. He has suffered from several pneumonias caused by respiratory viruses, eight acute otitis media, prolonged respiratory infections and urinary tract infection. Complement C4 was constantly low, but the other complement components, from C1 to C9, C1INH, factor B and properdin, were within normal limits. Immunological evaluation gave normal lymphocyte numbers and functions with the exception of subnormal T cell response to pokeweed mitogen. Molecular studies of the C4 gene region in the patient revealed homozygous deletion of CYP21A-TNXA-RP2-C4B generating total deficiency of C4B and the flanking 5' region up to C4A, and in the father a missing CYP21A gene. Further investigations are needed to elucidate the relationship between C4B deficiency and susceptibility to infections.

Adult↗

PubMed1989

Molecular basis of complete C4 deficiency. A study of three patients.

The highly polymorphic fourth component of human complement (C4) is usually encoded by two genes, C4A and C4B, adjacent to the 21-hydroxylase (21-OH) genes and is also remarkable by the high frequency of the null alleles, C4A*Q0 and C4B*Q0. Complete C4 deficiency is exceptional because this condition appears only in homozygotes for the very rare double-null haplotype C4AQ0,BQ0. This condition in most cases gives rise to systemic lupus erythematosus and an increased susceptibility to infections. The molecular basis for complete C4 deficiency has not yet been established. Therefore we studied the DNA of three previously described C4 deficient patients belonging to unrelated families by restriction fragment length polymorphism analysis using C4 and 21-OH probes. These studies revealed a deletion of the C4B and 21-OHA genes in two patients and no deletion at all in the third patient. Therefore, complete C4 deficiency as a result of homozygosity for the C4AQ0, BQ0 haplotype is not a consequence of a deletion of the C4 genes. The molecular basis of this genetic abnormality is certainly very complex and may vary also from one case to another.

Alleles↗

PubMed1988

C4 null phenotypes among lupus erythematosus patients are predominantly the result of deletions covering C4 and closely linked 21-hydroxylase A genes.

Two genes, C4A and C4B, encoding the fourth component of the complement system are linked to the HLA complex. C4 defects or C4 'null' genes can predispose to an autoimmune disease, lupus erythematosus (LE). We have used Southern blotting techniques to analyse genomic DNA from 23 patients with LE and from healthy controls, to evaluate the molecular basis of the C4 null phenotypes. In addition to the high frequencies of C4 null phenotypes and HLA-B8. DR3 antigens, confirming earlier results, we observed that among the patients both the C4A and C4B null phenotypes mostly resulted from gene deletions. Among the controls only the C4A null phenotypes were predominantly the result of gene deletions. In all cases these C4 gene deletions also extended to a closely linked pseudogene, 21-hydroxylase A (21-OHA). Altogether, 52% of the patients and 26% of the controls carried a C4/21-OHA deletion.

Chromosome Deletion↗

PubMedDate not supplied

Autoimmune hepatitis.

Autoimmune hepatitis is an inflammatory liver disease in which the immune system is believed to orchestrate an immune attack onto the liver cell. Current knowledge suggests that both T helper 1 (TH1) and TH2 programmes are involved in the generation of the liver damage. Release of TH2 cytokines leads to the production of autoantibodies to the hepatocyte membrane that recruit killer cells. TH1 cytokines induce macrophage activation which contributes to hepatocyte destruction. Patients commonly possess the "autoimmune" HLA A1/B8/DR3 haplotype and a silent gene at the C4A locus with consequent partial deficiency of the complement component C4. Two main types of autoimmune hepatitis are recognised according to the presence of circulating non-organ specific autoantibodies. Patients with smooth muscle antibody and/or antinuclear antibody may be adults or children, while patients with antiliver kidney microsomal type 1 (LKM1) antibody are usually children or very young adults. In both types there is a preponderance of females. LKM1 antibody is also present in a proportion of adult patients, mainly male, with chronic hepatitis C virus infection. This observation originally led to the suggestion that hepatitis C virus may be the cause of this form of autoimmune hepatitis, but several studies have shown that the epitopes target of the LKM1 antibody in autoimmune hepatitis and chronic hepatitis C virus infection differ. Although autoimmune hepatitis responds satisfactorily to immunosuppression in the short term, progression to cirrhosis is frequent. It is hoped that ongoing research will provide a better understanding of the pathogenic mechanisms of liver damage leading to a more effective and specific mode of treatment.

Autoantibodies↗

PubMed1988

Molecular heterogeneity of complement component C4-null and 21-hydroxylase genes in systemic lupus erythematosus.

C4A-null alleles (C4A*Q0) and hereditary complete C4 deficiency (homozygous C4A*Q0,C4B*Q0) are associated with systemic lupus erythematosus (SLE). Using Southern blot analysis with C4 and 21-hydroxylase (21-OH) DNA probes, we studied SLE patients and normal control subjects with or without C4A*Q0, and 2 C4-deficient SLE patients. A previously reported large C4A,21-OHA gene deletion associated in normal subjects with the HLA-A1;B8;DR3;C4AQ0 haplotype was detected by the appearance of a new C4 Hind III 8.5-kb fragment and disappearance of a 3.2-kb 21-OH Taq I fragment. In 3 SLE patients with homozygous C4A*Q0 and 15 with heterozygous C4A*Q0, this deletion pattern occurred almost exclusively in association with the HLA-B8;DR3;C4A*Q0 phenotype; the one exception was a black SLE patient. Other C4A*Q0-bearing HLA phenotypes in white patients and black patients with SLE, and the 2 completely C4-deficient SLE patients, had normal DNA hybridization to both C4 and 21-OH probes. The genetic basis for C4-null alleles in SLE is heterogeneous. A large C4A,21-OHA deletion occurs mainly on the HLA-B8;DR3;C4AQ0 haplotype in SLE and controls. Other HLA haplotypes bearing C4A*Q0 have normal C4 and 21-OH genes, as demonstrated by Southern blot analysis.

Alleles↗

PubMedDate not supplied

[Genetics of complement: recent aspects (author's transl)].

Genetic deficiencies of complement proteins are now more often recognized and analysed more precisely because the structure of the different complement proteins is better known. Partial defects may be detected in some components by the combined utilization of titration techniques, polymorphism studies and linkage analyses. The partial deficiency in C4 seems to be the most frequent protein deficiency in the human. The complement markers on the short arm of the sixth chromosome in man (BF, C2, C4A and C4B) are located in close proximity to the HLA-D/DR region. The combined study of the complement and HLA markers will probably allow the fine structure of the HLA region to be better defined. The association of some diseases with HLA types will probably also be better specified by the definition of associations not only with HLA-B or HLA-D types but also with the BF, C2 and C4 types.

Animals↗

PubMed1996

Genetic polymorphism of the fourth component of human complement: population study and proposal for a revised nomenclature based on genomic PCR typing of Rodgers and Chido determinants.

The fourth component of human complement (C4) is coded for by two homologous genes, C4A and C4B, located in the class III region of the major histocompatibility complex (MHC). Genetic typing of C4A and B alleles is routinely carried out by high-voltage agarose gel electrophoresis. The electrophoretic C4 polymorphism can be further subdivided by the Rodgers (Rg) and Chido (Ch) blood groups, which are antigenic determinants of the C4A and B alpha-chains, respectively. We have used a recently described direct PCR typing method using sequence-specific primers (PCR-SSP) in combination with electrophoretic C4 typing as well as genomic RFLP analysis to determine the frequency of C4 allotypes, Rg/Ch subtypes and C4A-B haplotypes in a family study of the German population. As the current C4 allele designation does not provide any information about the presence or absence of Rodgers and Chido antigens, we have developed an extension to the existing C4 nomenclature. This revised allele designation combines the existing numerical allotypes defined by electrophoretic mobility with eight subtypes (01-08) based on Rg/Ch PCR genotyping results. Using this approach, most electrophoretic allotypes could be subdivided. Among the C4A allotypes, the most common allele was A*0301 (59.9%), and the most common subtype among all electrophoretic allotypes was 01 (85.1%; = Rg1,2-positive, Ch-negative). For C4B, the most common allele was B*0101 (64.3%), and the most common subtype was 01 (79.6%; = Ch1,2,3,4,5,6-positive, Rg-negative). The subtypes 03, 04, 07 and 08 of the C4A allotypes, and the subtypes 03, 07 and 08 of the C4B allotypes, were not detected in this study. The analysis of duplicated C4 alleles revealed considerable heterogeneity of their subtypes. The results demonstrate that all known C4 allotypes can now be assigned unambiguously, which facilitates the identification of MHC haplotypes relevant for transplantation and disease association studies.

Complement C4↗