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PubMed1988

Purification and characterisation of ovine C4: evidence for two molecular forms in ovine plasma.

A relatively rapid procedure is described for the isolation of the fourth component of complement (C4) from ovine plasma. The method, which recovers approximately 30% C4, is based upon DEAE Sephacel anion exchange chromatography of PEG precipitated plasminogen depleted plasma followed by cation exchange chromatography on CM Sepharose and finally gel filtration. SDS-PAGE of purified ovine C4 under reducing conditions revealed a complex pattern of bands which was interpreted on the basis of a three polypeptide chain structure for each of two distinct species, or isotypes, of C4 molecule herein termed C4A and C4B. Each isotype differs in the mol. wt of the alpha chain--108 and 95 K respectively. Nucleophilic substitution of immunoprecipitated ovine C4 with radiolabelled methylamine revealed that both C4 species contained a reactive thiol ester site and that each could be cleaved into an activated form (presumably C4b) characterised by a truncated alpha' chain some 8 K lower in mol. wt. A comparison of the isotype composition of purified C4 with that of immunoprecipitated C4 from the same animal indicated that the purification procedure favoured isolation of the C4B isotype. The mol. wts of both the alpha and beta chains were lowered following digestion of ovine C4 with neuraminidase.

Animals↗

PubMed1984

Genetics of human C4 polymorphism: detection and segregation of rare and duplicated haplotypes.

Applying a combined technology for the detection of allotypic variation of the fourth component of human complement (C4), including immunofixation with anti-C4 and C4-dependent lysis after agarose electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis of C4 to separate the C4A and B alpha-chains, and the determination of Rodgers (Rg) and Chido (Ch) determinants of C4 in serum and at the blotted C4 alpha-chains, we detected rare human C4 allotypes and studied the genetic linkage. Partial inhibitors (p.i.) of anti-Rg and anti-Ch sera were found; the C4A51 allotype characterized as Rg p.i. and the C4A1 and C4B51 allotypes as Ch p.i. were genetically inherited. The C4A1 allotype has a unique Rg- Ch+ C4A alpha-chain. Duplicated C4A loci, A*3, A*2, and A*5, A*2 were both associated with a C4BQO and the HLA haplotype A3-Cw4-Bw35-DR1. These additions to the already known extensive C4 polymorphism may help to sort out their significance for the biological functions of human C4.

Complement C4↗

PubMed1993

[Effect of mistletoe lectin therapy on serum level of defined serum proteins (acute phase proteins) in tumor patients].

The influence of galactoside-specific mistletoe lectin (ML-1) administration on defined acute phase reactants in the serum of cancer patients (mammary carcinoma, n = 4; larynx carcinoma, n = 11; TNM-stages II to IV; after appropriate surgery, chemotherapy, radiation) was studied. Regular subcutaneous injections of the optimal doses of ML-1 (1 mg/kg body weight, twice a week) yielded statistically significant increases of certain acute phase reactants (C-reactive protein, haptoglobin, coeruloplasmin, C3-complement, albumin, immunoglobulin IgM) after four weeks of treatment. However, serum concentrations of transferrin, C4-complement and the immunoglobulins IgG and IgA were found within the biological range (means +/- 2 s). The increase of acute phase reactants after administration of ML-1 correlates positively with the activity of lymphatic cells (e.g. expression of IL-2 and HLA-DR receptors) in FACS (fluorescence-activated cell sorter) staining experiments and indicates the immunoreactive potency of this substance which may be speculated to be cytokine-induced.

Acute-Phase Proteins↗

PubMed1982

Structural and functional characterization of an incompletely processed form of murine C4 and Slp.

The properties of a 128,000-dalton polypeptide, corresponding to the uncleaved alpha- and gamma- chains of the fourth component of murine complement (C4), were studied. A fragment of similar size (137,000 daltons) from the structurally related sex-limited protein (Slp) was also found. These polypeptides have methylamine and iodoacetamide binding sites. suggesting that they, like the alpha-chains of C4 and Slp, possess an internal thiolester. In tryptic peptide map analysis, extensive homology is seen between the 128,000-dalton fragment and native C4 alpha- and gamma-chains. N-terminal sequences for this fragment and C4 alpha are identical, as are those for the 137,000-dalton Slp fragment and Slp alpha. Although the alpha-gamma fragment, like C4 alpha, undergoes denaturation-dependent autolytic cleavage, unlike C4 alpha, it cannot be cleaved by C1 This indicate that some of the properties of C4 do not require the native three-chain structure, whereas others do require it. These findings suggest that the alpha-gamma fragments represent an intermediate step in the processing of the C4 and Slp precursor polypeptides.

Animals↗

PubMed1978

Serum immunoglobulin and complement levels in tropical pulmonary eosinophilia, and their correlation with primary and their relapsing stages of the illness.

Serum concentrations of IgA, IgG, IgM, IgE, C3 and C4 complement components were estimated in 19 patients with tropical pulmonary eosinophilia (TPE). Thirteen of the patients presented during their first episode of TPE and 6 of them during a relapse of the disease. We found a remarkable elevation of serum IgE level in TPE, which is consistent with earlier reports. In contrast, there was a modest increase in IgM levels and unchanged or even lower levels in IgA and IgG immunoglobulin classes. There seemed to be a direct relationship between IgE level and degree of peripheral blood eosinophilia in TPE. The outstanding finding, however, was a nearly threefold higher mean serum IgE level in patients with relapsing disease as compared to that observed in patients during the primary attack. This is the first reported study of circulating complement components in TPE. A significant rise of serum C3 level was found in these patients; there was no similar elevation of serum C4 component.

Adolescent↗

PubMed1981

Level of complement activity and components C1, C4, C2, and C3 in complement response to bacterial challenge in malnourished rats.

In experimentally induced malnutrition in rats, there was no significant difference between the measured level of complement activity of the classical pathway (50% hemolytic complement [CH50]) and that of the alternative pathway (ACH50), although the levels of complement components C1, C4, C2, and C3 were depressed significantly. The complement activity showed a temporary elevation with a peak at 2 or 3 days after bacterial challenge with Staphylococcus aureus in rats, and we call this the complement response. After 3 days, CH50 and C3 in the malnourished rats and ACH50, CH50, and C3 in the well-nourished rats showed a significant increase, and C1, C4, and C2 in both groups tended to elevate. On the basis of these observations, the significance of the elevation of C3 in the complement response to bacterial infection showed a strong influence by enhancing the activation of both the classical and the alternative pathways, since C3 is known to be the junction of both complement pathways. In this way, C3 responded to an earlier stage than did the other components and may contribute to maintaining the body defense system against infection.

Animals↗

PubMed1986

Cosegregation of the polymorphic C4 with the MHC in the frog, Xenopus laevis.

Employing isoeletric focusing combined with enzyme-linked immunoelectrotransfer blot analysis, the fourth component of complement (C4) was analyzed in the two highly histocompatible, major histocompatibility complex homozygous groups (J and K) of Xenopus laevis. Each group had a characteristic C4 isoelectric focusing pattern, i.e., an isoelectric point range of 8.0-8.5 for J (C4jC4j) and 7.6-8.1 for K (C4kC4k). In (J X K)F1 frogs, C4 proteins were expressed in a codominant fashion (C4jC4k). In the backcrossed progeny B1 [J X (J X K)F1], those with C4jC4j rejected (J X K)F1 skins hyperacutely (less than 17 days), were high responders against (J X K)F1 cells, and nonstimulators to J cells in mixed lymphocyte reaction (MLR), but they did not suffer from the graft-versus-host reaction (GVHR), even after the injection of (J X K)F1 cell-stimulated J splenocytes. On the other hand, the B1 frogs with C4jC4k acutely or chronically (greater than 17 days) rejected (J X K)F1 skins, were low or nonresponders against (J X K)F1 cells and high stimulators to J cells in MLR, and they suffered from GVHR after the injection of prestimulated J splenocytes. These results argue for the notion that the genes equivalent to mammalian class III map to the MHC at the phylogenetic level of the anuran amphibian.

Animals↗

PubMed1987

DNase I-hypersensitive sites associated with expression and hormonal regulation of mouse C4 and Slp genes.

There are four major regions of DNase I hypersensitivity in the 5' regions of the genes for the murine fourth component of complement (C4) and its homologous neighbor, Slp (sex-limited protein). Hypersensitivity around the start site of transcription and approximately equal to 0.5 kilobases upstream correlates qualitatively with expression of these genes. Two hypersensitive sites, at -2.3 and -2.0 kilobases, map specifically to the Slp gene and correlate with its hormonal regulation. That is, these sites are more prominent in male liver chromatin and become more apparent in chromatin from females treated with testosterone. Further, these sites are established in males to a greater extent than in females prior to expression of Slp and may reflect gene-commitment events. Comparison of chromatin from mouse strains differing in C4 and Slp alleles indicates that the four regions of hypersensitivity may be necessary but are not sufficient for high levels of expression.

Animals↗

PubMed1980

Interaction between the labile binding sites of the fourth (C4) and fifth (C5) human complement proteins and erythrocyte cell membranes.

We have shown that the labile binding site of C3b interacts covalently with receptive surfaces. We report here an analogous study of the interaction between the labile binding sites of the closely related complement proteins, C4 and C5, with sheep erythrocyte membranes. We find that i) C4b binds covalently to cell surface components; ii) the bond between C4b and receptive molecules is hydroxylamine sensitive; iii) the alpha-polypeptide of C4b binds to receptive molecules; and iv) C5b does not interact covalently with cell surfaces.

Autoradiography↗

PubMed2005

Complement components (C3, C4) in childhood asthma.

OBJECTIVE: To assess the involvement of complements (C3, C4) in the pathophysiology of bronchial asthma. METHODS: Selection of patients (n = 64) were made according to the recommended international criteria for diagnosis and classification of asthma. Serum levels of complement components (C3, C4) were measured by radial immunodiffusion technique in 64 Libyan children (age: 1-12 years, sex: 39 males, 25 females) with mild to moderately severe asthma (Group A). Among these patients, 35 had active disease (AA) and 29 had inactive disease (NA). According to age range, 20, 21 and 23 patients were between 1-3 years (A1), > 3-5 years (A2) and > 5-12 years (A3) respectively. A1 had 9 and 11 patients with active (AA1) and inactive (NA1) disease; A2 had 10 and 11 patients with active (AA2) and inactive (NA2) disease; A3 had 16 and 7 patients with active (AA3) and inactive (NA3) disease respectively. Age matched comparisons were made with 57 healthy children (age: 1-12 years; sex: 30 males, 27 females) (Group B). Among the controls, 15, 19 and 23 children were between 1-3 years (B1), > 3-5 years (B2) and > 5-12 years (B3) respectively. RESULTS: Mean C3 level was significantly elevated in patients, while C4 level was normal (A vs B --> C3: P < 0.2, C4: P > 0.2). Serum C3 level was significantly higher in patients with active disease only, while it was normal in patients with inactive disease (AA, NA, B --> P = 0.045); AA vs NA --> P < 0.05, AA vs B --> P < 0.02, NA vs B --> P > 0.05) and C4 levels were normal in both the groups (AA, NA, B --> P = 0.354). Further, C3 levels were significantly elevated in all the age groups, but in patients with active disease only (AA1, NA1, B1 --> P = 0.0024; AA2, NA2, B2 --> P = 0.0411; AA3, NA3, B3 --> P = 0.0102). CONCLUSION: The elevated C3 level was possibly due to induction by pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1). The probable mechanisms of C3 involvement in the pathophysiology of bronchial asthma were discussed.

Age Factors↗

PubMed1999

Neurological manifestations of chronic hepatitis C.

Hepatitis C virus (HCV) infection is often associated with abnormal immunological responses. We describe four patients with vasculitic neurological signs and symptoms following HCV infection. A 56-year-old woman with HCV infection developed peripheral neuropathy characterized by asymmetric distal painful hypesthesia, dysesthesia and moderate motor weakness of the lower limbs. Serological examinations revealed cryoglobulinemia and low levels of complement C4. A biopsy of the sural nerve revealed vasculitic neuropathy. HCV infection associated immunomediated vasculitis was diagnosed. While steroid therapy was ineffective, treatment with interferon-alpha improved the neuropathy considerably without, however, eliminating HCV infection. A 62-year-old man with HCV infection developed peripheral sensory neuropathy. Complement C3 was slightly diminished. Nerve biopsy revealed vasculitic neuropathy. A 71-year-old woman developed chronic symmetric sensomotor polyneuropathy. HCV hepatitis followed blood transfusions. Cryoglobulins tested positive, consistent with type II cryoglobulinemia. Complements C3 and C4 were diminished. Inflammatory infiltrates in the sural nerve biopsy specimen led to the diagnosis of chronic vasculitic disorder. A 55-year-old woman with HCV infection developed vasculitis of the skin, connective tissue, visceral organs, and kidney, leading to hemodialysis. Neurologically she developed severe apathy and drowsiness, myoclonic jerks, exaggerated deep tendon reflexes, and positive pyramidal signs. Magnetic resonance imaging of the brain showed diffuse increased signal abnormalities involving supra- and infratentorial white matter suggesting cerebral vasculitis. Cryoglobulins were positive, complements C3 and C4 slightly diminished (54 mg/dl, 4.3 mg/dl). Supportive therapy resulted in neurological improvement. Treatment with interferon-alpha was discontinued because of agranulocytosis. In patients with peripheral neuropathy or signs of leucencephalopathy, a hepatitis C associated vasculitis should be considered in the differential diagnosis.

Aged↗

PubMed1982

Characterization of the Mr difference between secreted murine fourth component of complement and the major plasma form: evidence for carboxyl-terminal cleavage of the alpha chain.

The alpha-chain of murine fourth component of complement (C4) secreted by cells in vitro and in vivo has a Mr that is larger by approximately equal to 4,000 than that of the alpha-chain of the principal form of C4 in plasma. By using in vivo labeling of C4 with [35S]methionine, C4 was shown to be first synthesized with the higher Mr ("secreted") alpha-chain, which was then quickly processed (t1/2 approximately equal to 1 hr) extracellularly to the mature ("plasma") C4 possessing the lower Mr alpha-chain. Both forms of C4 were functional as assayed by the ability of their alpha-chains to be cleaved by the protease C1, to bind methylamine, and to undergo denaturation-dependent autolysis. When secreted C4 and plasma C4 were activated to C4b, the Mr difference of 4,000 was maintained in the alpha'-chains. The Mr difference was localized to the carboxyl-terminal autolytic fragment of the alpha-chain and was unaffected by the removal of carbohydrate. C4 from resident peritoneal macrophage cultures could be converted to the plasma form by incubation with heparin/plasma. This conversion could be blocked by EDTA or 1,10-phenanthroline. These data suggest that an enzyme, presumably a neutral proteinase present in mouse plasma, cleaves the carboxyl terminus of newly synthesized C4 alpha-chains, thereby creating the major form of C4 in plasma.

Animals↗

PubMed1990

[Concentration of complement C3 and C4 in sera containing monoclonal IgA or IgG].

The complement C3 and C4 components concentration has been determined in 18 patients with monoclonal protein IgA and in 18 others with monoclonal protein IgG. It has been stated that the concentration of the complement component C3 has moderately been elevated if compared with that in the control group. This elevation has been more significant in the group of patients with monoclonal protein of the lambda type. The concentration of the complement component C4 has statistically significantly been elevated in patients with monoclonal protein IgA and significantly diminished in those with monoclonal protein IgG.

Adult↗

PubMed1986

Serum C4 concentration in the monitoring of systemic lupus erythematosus: requirement for C4 allotyping.

We have examined the influence of genetic and other factors on the serum concentration of the fourth component of complement (C4) in four patients with systemic lupus erythematosus (SLE) studied over 3 to 8 years. Complement allotyping was performed to determine the number of C4 null genes in each patient. Two patients with C4 null genes had relatively low serum C4 concentrations with normal serum anti-DNA binding and no evidence of active disease. By contrast two patients without null alleles appeared to be consuming C4 when the serum C4 concentrations were within the conventional reference range. We therefore propose the use of appropriate reference ranges adjusted for the number of null alleles. Such adjusted reference ranges may improve the utility of serum C4 concentration in monitoring disease activity.

Alleles↗

PubMed2001

Genetic, structural and functional diversities of human complement components C4A and C4B and their mouse homologues, Slp and C4.

The complement protein C4 is a non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. The covalent binding of C4 to immunoglobulins and immune complexes (IC) also enhances the solubilization of immune aggregates, and the clearance of IC through complement receptor one (CR1) on erythrocytes. Human C4 is the most polymorphic protein of the complement system. In this review, we summarize the current concepts on the 1-2-3 loci model of C4A and C4B genes in the population, factors affecting the expression levels of C4 transcripts and proteins, and the structural, functional and serological diversities of the C4A and C4B proteins. The diversities and polymorphisms of the mouse homologues Slp and C4 proteins are described and contrasted with their human homologues. The human C4 genes are located in the MHC class III region on chromosome 6. Each human C4 gene consists of 41 exons coding for a 5.4-kb transcript. The long gene is 20.6 kb and the short gene is 14.2 kb. In the Caucasian population 55% of the MHC haplotypes have the 2-locus, C4A-C4B configurations and 45% have an unequal number of C4A and C4B genes. Moreover, three-quarters of C4 genes harbor the 6.4 kb endogenous retrovirus HERV-K(C4) in the intron 9 of the long genes. Duplication of a C4 gene always concurs with its adjacent genes RP, CYP21 and TNX, which together form a genetic unit termed an RCCX module. Monomodular, bimodular and trimodular RCCX structures with 1, 2 and 3 complement C4 genes have frequencies of 17%, 69% and 14%, respectively. Partial deficiencies of C4A and C4B, primarily due to the presence of monomodular haplotypes and homo-expression of C4A proteins from bimodular structures, have a combined frequency of 31.6%. Multiple structural isoforms of each C4A and C4B allotype exist in the circulation because of the imperfect and incomplete proteolytic processing of the precursor protein to form the beta-alpha-gamma structures. Immunofixation experiments of C4A and C4B demonstrate > 41 allotypes in the two classes of proteins. A compilation of polymorphic sites from limited C4 sequences revealed the presence of 24 polymophic residues, mostly clustered C-terminal to the thioester bond within the C4d region of the alpha-chain. The covalent binding affinities of the thioester carbonyl group of C4A and C4B appear to be modulated by four isotypic residues at positions 1101, 1102, 1105 and 1106. Site directed mutagenesis experiments revealed that D1106 is responsible for the effective binding of C4A to form amide bonds with immune aggregates or protein antigens, and H1106 of C4B catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens. The expression of C4 is inducible or enhanced by gamma-interferon. The liver is the main organ that synthesizes and secretes C4A and C4B to the circulation but there are many extra-hepatic sites producing moderate quantities of C4 for local defense. The plasma protein levels of C4A and C4B are mainly determined by the corresponding gene dosage. However, C4B proteins encoded by monomodular short genes may have relatively higher concentrations than those from long C4A genes. The 5' regulatory sequence of a C4 gene contains a Spl site, three E-boxes but no TATA box. The sequences beyond--1524 nt may be completely different as the C4 genes at RCCX module I have RPI-specific sequences, while those at Modules II, III and IV have TNXA-specific sequences. The remarkable genetic diversity of human C4A and C4B probably promotes the exchange of genetic information to create and maintain the quantitative and qualitative variations of C4A and C4B proteins in the population, as driven by the selection pressure against a great variety of microbes. An undesirable accompanying byproduct of this phenomenon is the inherent deleterious recombinations among the RCCX constituents leading to autoimmune and genetic disorders.

Amino Acid Sequence↗

PubMedDate not supplied

IgE and complement in allergic children.

The following measurements were made using radial immunodiffusion with commercial M-Partigen plaques (Behringwerke, Marburg): Global-IgE in the serum of 29 children (17 atopic asthmas, 3 non atopic asthmas and 9 acute urticarias); C3 and C4 complement fractions in 56 patients (27 atopic asthmas, 11 non atopic asthmas and 18 acute urticarias); C3PA complement fraction in 41 patients (18 atopic asthmas, 9 non atopic asthmas and 14 acute urticarias). High IgE serum levels were observed chiefly in the cases of atopic asthma with polysensitization and in urticarias. The anomaly of the complement system most often found in children was an increase of C4 (23,2% of the cases), not related to the clinical form or duration of the disease. An increase of the C3 fraction (14,6% of the cases) was also observed together with an increase of these two fractions in all the cases where an increase of C3PA was observed. Only in 11,1% of atopic asthmas was a decrease of the serum concentration values of C3 observed.

Age Factors↗

PubMed1989

Transcript encoded on the opposite strand of the human steroid 21-hydroxylase/complement component C4 gene locus.

The gene encoding human adrenal steroid 21-hydroxylase (P450c21) and its highly similar pseudogene are duplicated in tandem with the two genes encoding the fourth component of human serum hemolytic complement (C4). This 60-kilobase gene complex, which lies within the major histocompatibility complex on the short arm of human chromosome 6, has been studied in considerable detail because genetic disorders in steroid 21-hydroxylation and in C4 are common. We have cloned a cDNA encoded by a previously unidentified gene in this region. This gene lies on the strand of DNA opposite from the strand containing the P450c21 and C4 genes, and it overlaps the last exon of P450c21. The newly identified gene encodes mRNAs of 3.5 and 1.8 kilobases that are expressed in the adrenal and in a Leydig cell tumor but are not expressed in nonsteroidogenic tissues. The sequence of the longest cDNA (2.7 kilobases) shows no similarity to known sequences available in two computerized data bases. The 5' end of this sequence is characterized by three repeats, each encoding about 100 amino acids flanked by potential sites for proteolytic cleavage. Although numerous studies have shown that gene deletions causing congenital adrenal hyperplasia occur in this region, none of these gene deletions extends into this newly identified gene, suggesting that it encodes an essential function.

Amino Acid Sequence↗

PubMed1992

C4 serum levels in newborns of diabetic mothers: relationship with metabolic assessment during pregnancy.

Serum levels of C4 complement factor are lower in diabetic patients: it is supposed that this finding is related to genetic inheritance factors of diabetes. The purpose is to compare C4 levels in newborns of diabetic mothers with maternal metabolic control during pregnancy. The results suggest that metabolic control could influence the expression of genetic factors of diabetes; in fact C4 serum levels in newborns are significantly higher (p < 0.01) than controls, but not different from those observed in large newborns of non diabetic mothers.

Complement C4↗