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PubMed1991

Monoclonal antipeptide antibodies against amino acid residues 1101-1106 of human C4 distinguish C4A from C4B.

Comparison of amino acid sequences of the alpha-chain fragment of human C4, C4d, has shown C4A- and C4B-specific sequences at residues 1101-1106 in which the aspartic acid-histidine substitution at position 1106 may be related to the amide and ester bond forming properties of these molecules. Peptides containing twelve amino acid residues of the C4A- or C4B-specific sequences were synthesized and injected into female Balb/c mice. Serum from 2 mice, one immunized with the C4A-specific peptide and the other with the C4B-specific peptide, gave strong isotype-specific responses in an enzyme-linked immunosorbent assay against affinity-purified C4A3 and C4B2B1. Spleen cells from these mice were fused with the mouse myeloma SP2/0-Ag 14, and two cloned cell lines, AII-1 and BII-1, were established from hybrids. Enzyme-linked immunosorbent assay and western blotting of monoclonal antibodies AII-1 and BII-1 show that the former reacts with the C4A but not with the C4B alpha-chain and the latter with C4B but not with the C4A alpha-chain. Furthermore, immunoblotting of C4 allelic variants showed that AII-1 reacted with all C4A allotypes tested, including A6, A4, A3 and A2, whereas BII-1 reacted with all C4B allotypes tested, including B5, B3, B2, and B1.

Amino Acid Sequence↗
PubMed1986

Demonstration of anaphylatoxins C3a, C4a and C5a in the scales of psoriasis and inflammatory pustular dermatoses.

Complement components C3a, C4a and C5a were assayed in corneal scale extracts from psoriasis and other dermatoses characterized by sterile subcorneal pustules, using radioimmunoassay. Larger amounts were detected in psoriasis and related pustular dermatoses than in extracts of non-inflammatory stratum corneum. It is concluded that complement is activated via the classical pathway and releases the neutrophil chemotactic fragment C5a.

Anaphylatoxins↗
PubMed1984

Human C4 haplotypes with duplicated C4A or C4B.

In the course of study of families for the sixth chromosome markers HLA-A, C, B, D/DR, BF, and C2, the two loci for C4, C4A, and C4B, and glyoxalase I, we encountered five examples of probable duplication of one or the other of the two loci for C4. In one of these, both parents and one sib expressed two different structural genes for C4B, one sib expressed one, and one sib expressed none, suggesting that two C4B alleles were carried on a single haplotype: HLA-A2, B7, DR3, BFS1, C2C, C4A2, C4B1, C4B2, GLO1. In a second case, two siblings inherited C4B*1 and C4B*2 from one parent and C4B*Q0 from the other. This duplication appeared on the chromosome as HLA-AW33, B14, DR1, BFS, C2C, C4A2, C4B1, C4B2, GLO2. In a third, very large family with 3 generations, a duplication of the C4B locus occurred which was followed in 2 generations. In one individual, there were three C4B alleles and two C4A alleles. One of the C4B alleles had a hemolytically active product with electrophoretic mobility near C4B2 and was designated C4B*22. It segregated with C4B1 in the family studied. The complete haplotype was HLA-A11, CW1, BW56, DR5, BFS, C2C, C4A3, C4B22, C4B1, GLO2. In another family with 12 siblings, one parent and eight children expressed two C4A alleles on the haplotype HLA-AW30, BW38, DR1, BFF, C2C, C4A3, C4A2, C4BQ0, GLO1.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromosome Mapping↗
PubMed2001

Lack of evidence of a specific role for C4A gene deficiency in determining disease susceptibility among C4-deficient patients with systemic lupus erythematosus (SLE).

The aim of the present study was to investigate the prevalence of C4 and C2 deficiencies and to characterize genomic alterations in C4 genes in a large cohort of 125 unselected patients with SLE. We determined the protein concentration and functional activity of C2 and C4, as well as the C4 phenotype. C4 genotyping included Taq 1 restricted fragment lengh polymorphism (RFLP) analysis and polymerase chain reaction using sequence-specific primers (SSP-PCR). Type I C2 deficiency was diagnosed by PCR. Overall, 79.2% of the patients exhibited abnormalities of the C4 genes including deletion, non-expression, gene conversion and duplication. Among C4-deficient patients (n = 66, 52.8% prevalence), 41.0% of the patients exhibited a C4A deficiency and 59.0% a C4B deficiency. Half of the C4 deficiencies were due to a gene deletion. There was a strong association between C4A and C4B gene deletion and the presence of the DRB1*03 allele. Among the silent C4A genes, only two cases were related to a 2-bp insertion in exon 29 of the C4A gene. A gene conversion was demonstrated in eight patients (6.4%). One patient had a homozygous C4A deficiency. Three (2.4%) patients presented with a heterozygous type I C2 deficiency and none with homozygous deficiency. Our results argue against a specific role for C4A gene deficiency in determining disease susceptibility among patients with SLE that are C4-deficient.

Adolescent↗
PubMed1994

Lack of both spinal fluid oligoclonal bands and complement 4A protein in an MS patient.

We report the case of a multiple sclerosis (MS) patient without oligoclonal bands (OCB) in three cerebrospinal fluid samples. Restriction fragment length polymorphism analysis of Class 3 genes with radiolabelled specific cDNA probes showed a homozygous deletion of the complement 4A (C4A) genes. Consequent lack of C4A protein can alter the development of humoral immune response probably preventing OCB production. Our observation may suggest a link between a rare immunogenetic pattern and the absence of OCB in MS.

Adult↗
PubMed1992

Quantitation of the human component C4: definition of C4 Q0 alleles and C4A duplications.

We determined the C4 plasma concentrations of 48 genotypically CA4- and C4B-defined unrelated individuals from 34 families with a total of 196 members by an enzyme-linked immunosorbent assay using Rg:1,2 (C4A) and Ch:1 (C4B) specific monoclonal antibodies. The results obtained allowed the establishment of rules for the detection of C4 Q0 alleles in the heterozygous form and of C4A gene duplications. In the present study seven homoduplications of the C4A 3 allotype were defined which had not been detected by allotyping. This procedure allows the simple, reliable, and quick determination of Rg:1,2 and Ch:1 plasma levels which are not influenced by daily rhythms of C4 production.

Alleles↗
PubMed1987

Heterogeneity of human C4 gene size. A large intron (6.5 kb) is present in all C4A genes and some C4B genes.

In this article we present a study showing that the human C4 genes differ in length because of the presence or absence of a 6.5 kb intron near the 5' end of the gene. DNA from individuals of known HLA, factor B, and C4 haplotypes was analyzed for restriction fragment length polymorphism (RFLP) by Southern blot analysis with C4-specific cDNA probes. The RFLP patterns obtained showed that the C4 genes are either 22.5 kb or 16 kb in length. They are referred to as long and short C4 genes, respectively. A population study was carried out to examine the distribution of the gene size according to C4 allotypes and haplotypes. Long C4 genes included all C4A genes studied and also some C4B allotypes, e.g., B1 on most C4 A3B1 haplotypes. Similarly, C4B null genes were found to be of the long form. Other C4B allotypes tested were found to be coded for by short C4 genes, including B2, B1 in C4 A6B1 and C4 AQOB1 (with a single C4B gene haplotype).

Complement C4↗
PubMed1993

Genetic, immunologic and biotransformation studies of patients on procainamide.

This report represents follow-up observations of a unique long-term study of patients on procainamide (PA) for various cardiac arrhythmias. Serologic and clinical evaluations associated with drug-related autoimmunity were assessed and patients were characterized for factors postulated to influence susceptibility to autoimmunity, including acetylator phenotype, oxidative metabolism of PA, HLA class profile, and production of interleukin-1 (IL-1) and tumor necrosis factor (TNF). Fifty-two percent had IgM and 70% IgG antibodies to total histones; 67% had IgG antibodies to histone H2A/H2B. Patients were equally divided between fast and slow acetylators. N-oxidative metabolism of PA was indicated by the presence of urinary nitroprocainamide, which correlated with elevated titers of antihistone antibodies. There was a significant incidence of the DQw7 split of DQw3 in PA patients when compared to controls, and the frequency of antibodies to total histones and H2A/H2B was significantly increased in the DQw7 patients. C4A*QO and C4B*QO alleles were more frequent in the PA patients than in controls. IL-1 and TNF production was not different in patients compared to controls. These data suggest that certain genetic factors may serve as markers for PA-related autoimmunity.

Aged↗
PubMed1988

Cardiolipin antibodies and null alleles of C4 in black Americans with systemic lupus erythematosus.

Twelve of 44 black American patients with systemic lupus erythematosus (SLE) (27%) studied during periods of disease activity had increased levels of IgG antibodies against cardiolipin (IgG aCL). IgG aCL occurred almost exclusively in patients who had a partial genetic deficiency of C4A or C4B. Eleven of 29 patients (38%) with a C4A or C4B deficiency allele had IgG aCL, compared with 1/15 patients (7%) who did not have C4A or C4B deficiency allele (p = 0.04). During periods when SLE was less active clinically, IgG aCL levels returned to normal in 10/12 patients. Active SLE, rather than null alleles, appeared to be associated with low C4 levels in patients with IgG aCL.

Adult↗
PubMed1984

Human C4 polymorphism: pedigree analysis of qualitative, quantitative, and functional parameters as a basis for phenotype interpretations.

Ten families with 82 members were investigated for C4A- and B polymorphism in a blind trial. Phenotyping was done on neuraminidase treated sera by immunofixation and simultaneously by hemolytic overlay electrophoresis. In addition Rg, Ch, BF, C2, HLA-A, B, C, DR, and GLO were determined. After decoding the samples the reliability of blind typing was found to be 84.4% according to segregation patterns. Inconsistencies occurred mostly when A4, A2, or A92 were present. The detection of silent A*Q0 and B*Q0 alleles was more critical than that of "difficult" allotypes. The quantitation of the C4A/B ratio by densitometry of stained gels or by conventional immunochemical measurements of serum C4 level could not substantially improve the identification of A*Q0 or B*Q0. C4 dependent activity in radial diffusion hemolysis showed satisfactory correspondence with the number of expressed C4B alleles. At least three haplotypes with two C4A genes (duplicated A genes) were observed as ascertained from offspring analysis in accordance with the MHC segregation pattern. Individuals with the duplicated C4A gene (C4A*3, A*2, in the absence of any other expressed A allele or together with C4A*92) showed only partial inhibition of Rodgers antisera. Partial inhibition of Chido antisera was seen in individuals with C4B 2 (in the absence of other B allotypes). The findings support the hypothesis of at least two structural C4 loci. They also demonstrate the inconsistency of quantitative data in the recognition of silent alleles.

Alleles↗
PubMed1995

C4 null alleles in a Swedish population.

The distribution of C4 null alleles (C4Q0) was studied in a Swedish population comprising 410 male individuals from Stockholm County and Uppsala City. The prevalances of homozygous C4A*Q0 and C4B*Q0 determined by analysing the gene products in serum were 5.0 and 5.6%, respectively, in the Stockholm population and 4.0% each in the Uppsala population. These values are higher than those previously reported from other Caucasian populations. The finding reflects a different genetic composition of the Swedish population and may have relevance to the disease spectrum in this population as compared to other Caucasian populations.

Adult↗
PubMed1984

C4 polymorphism: use of a monoclonal antibody to distinguish C4A and C4B locus products.

A monoclonal antibody reactive against C4B locus products was used in a passive immunoblotting technique to distinguish C4B from C4A electrophoretic variants. The technique is simple and has the advantage of being able to distinguish clearly those C4B variants which may be either difficult to define by conventional hemolytic assay alone or which would normally be designated as C4B products on account of their lack of hemolytic function. Patterns detected by immunoblotting can be compared directly with patterns obtained by immunofixation with anti-C4 from the same gel.

Alleles↗
PubMed1995

Covalently-bound human C4b dimers consisting of C4B isotype show higher hemolytic activity than those of C4A in the C3-bypass complement pathway.

The ability to form a covalent dimer of human C4b was investigated with purified isotypes C4A and C4B, and antibody-sensitized liposomes supplemented with C1. In this system, no C4A or C4B formed a complex with the antibody or C1. Whereas both C4A and C4B isotypes formed dimers to a similar extent, C4B formed an ester-linked dimer and C4A an amide-linked dimer. Both of these dimers served as a subunit for the C3-bypass pathway C5 convertase, since liposomes bearing Ab, C1 and a dimer of C4A or C4B, allowed the formation of C5 convertase by the addition of C2. The degree of complement-mediated liposome lysis however, was observed to be 2-3 times higher in the C4B-bearing particles than in those bearing C4A. These results indicate that the second C4b-binding site on the first C4b is different between C4A and C4B, and that in the C3-bypass pathway, C4B has a higher degree of hemolytic activity than C4A, as in the conventional classical complement pathway.

Biopolymers↗
PubMed1991

The genomic structure of two ancestral haplotypes carrying C4A duplications.

Two major histocompatibility complex (MHC) ancestral haplotypes (AH) HLA A24, Bw52, C2C, BfS, C4A3+2, C4BQO, DRw15, DQw6 (52.1) and HLA A24, Cw7, B7, C2C, BfS, C4A3+3, C4B1, DR1, DQw5 (7.2), which occur with the haplotype frequencies of approximately 10% and 4% respectively in the Japanese population, carry duplicated C4A alleles by C4 allotyping. Southern blot analysis with Taq I indicated that the 52.1 AH has two C4 genes defined by 7.0 kilobase (kb) and 6.0 kb C4 hybridizing fragments but both encode C4A allotypes, being C4A3 and C4A2 respectively. The 7.2 AH carries two C4A3 and one C4B1 alleles and restriction length polymorphism (RFLP) analysis with Taq I showed that 6.0 kb and 7.0 kb fragments are in the proportion of 2:1. By pulsed field gel electrophoresis (PFGE) analysis, the lengths of the Pvul fragments carrying C4 and Cyp21 genes were approximately 390 kb for 52.1 and 440 kb to 7.2. The results indicate that the RFLP markers do not correlate with C4 isotype (A or B) or allotype and that the C4 gene copy number is a function of the number of genomic blocks containing C4 and Cyp21.

Alleles↗
PubMed2006

Identification of plasma protein biomarkers associated with idiopathic pulmonary arterial hypertension.

We have employed SELDI-TOF MS to screen for differentially expressed proteins in plasma samples from 27 patients with idiopathic pulmonary arterial hypertension (IPAH) and 26 healthy controls. One ion (m/z approximately 8600) that was found to be elevated in IPAH was validated by SELDI-TOF MS analysis of a second and separate set of plasma samples comprising 30 IPAH patients and 19 controls. The m/z 8600 was purified from plasma by sequential ion exchange and reverse-phase chromatographies and SDS-PAGE. It was identified, following trypsin digestion, by MS peptide analysis as the complement component, complement 4a (C4a) des Arg. Plasma levels of C4a des Arg measured by ELISA confirmed that the levels were significantly higher (p < 0.0001) in IPAH patients (2.12 +/- 0.27 microg/mL) compared with normal controls (0.53 +/- 0.05 microg/mL). A cut-off level of 0.6 microg/mL correctly classified 92% of IPAH patients and 80% of controls. Further studies will be needed to determine its performance as a diagnostic biomarker, whether used alone or in combination with other biomarkers. Nevertheless, this study demonstrates that putative biomarkers characteristic of IPAH can be identified using a conjoint SELDI-TOF MS - proteomics approach.

Adult↗
PubMed1992

Polymorphisms of HLA class III genes in allergic contact dermatitis.

HLA class III polymorphisms (BF, C4A, C4B) were studied in 55 patients of different age and sex suffering from allergic contact dermatitis, with sensitization to different substances. In the overall group of patients no significant correlation between the disease and HLA markers was found. BF F allele was present in 34% and BS S in 64% of patients suffering from allergic contact dermatitis to nickel only versus 16.45% (relative risk, RR = 2.61) and 80.76% (RR = 0.42), respectively, of the control population. The BF FB subtype frequency was 23.91% versus 7.57% in the control samples (RR = 3.88). We thus hypothesize that this polymorphic serum protein might be involved in the pathogenesis of allergic contact dermatitis to nickel.

Adolescent↗
PubMed1981

Comparative study on biological activities of various anaphylatoxins (C4a, C3a, C5a). Investigations on their ability to induce platelet secretion.

Several anaphylatoxic substances (human C3a, guinea pig C3a, human C4a, guinea pig C5a, and a synthetic C3a-related hexapeptide) were compared with regard to their ability to induce secretion of [3H] serotonin from guinea pig platelets. Functional identity of the C3a preparations, C4a, and the hexapeptide was demonstrated by the phenomenon of crossed desensitization. Whereas C3a of human and guinea pig origin proved to be qualitatively and quantitatively identical, C4a expressed only 3% of the activity of the C3 fragments on a molar basis. Investigations with goat anti-guinea pig C3a demonstrate that human and guinea pig C3a possess one antigenic determinant in common; however, this determinant is not the C-terminal amino acid sequence. Addition of the anaphylatoxins with low doses of thrombin led to a potentiation of [3H] serotonin release from the platelets. Under these conditions C3a concentrations of 1.5 X 10(-10) mumol/liter (65 pg of C3a) could be detected. Thus the platelet system represents the most sensitive in vitro assay known for evaluation of biological activity of the C3a anaphylatoxins.

Anaphylatoxins↗
PubMed1992

[Fundamental and clinical studies of homologous immunoglobulin-free priming in cardiopulmonary bypass, with special reference to anaphylatoxin production].

In in-vitro study, human immunoglobulin (Ig) denatured by O2 bubbling markedly produced C4a, C3a, and C5a, whereas human albumin treated identically did not. White blood cells (WBC) treated by O2 bubbling significantly increased C3a levels alone, but at a much lesser grade than the Ig. A new priming method, i.e., homologous concentrated red cell (CRC) and human albumin was discerned from the experimental facts in-vitro, and we investigated the clinical effects of that priming method. C4a, C3a and C5a in BOG primed with homologous whole blood (HWB) were slightly higher than those in MOG during CPB. Those in the Ig-free priming group were more mildly increased than those in the HWB priming group, not only during CPB, but also after protamine administration; this tendency was clearer in BOG. It is concluded that (1) human immunoglobulin (Ig) denatured by O2 bubbling produces anaphylatoxins via the classical pathway; (2) WBC treated identically produces C3a at a far milder grade; (3) priming with CRC and human albumin reduces plasma anaphylatoxin levels; and (4) pulmonary function at an early postoperative period was improved in the homologous Ig-free priming group, especially with BOG.

Albumins↗