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PubMed2002

Transmission of antibody-induced arthritis is independent of complement component 4 (C4) and the complement receptors 1 and 2 (CD21/35).

The K/BxN murine model of rheumatoid arthritis (RA) is dependent on the specificity of the KRN alpha beta-TCR, to recognize glucose-6-phosphate-isomerase (GPI) on the NOD MHC class II A(g7) allele and production of GPI-specific autoantibodies. Transfer of K/BxN serum into MHC-unrelated and lymphocyte-deficient mice induces RA. To investigate whether K/BxN serum-induced RA involves complement activation and/or the complement receptors (CR) 1 and 2, we analyzed the role of complement C4 and of CR1 and CR2. For this purpose we used C4(-/-) mice impaired in the classical and the lectin complement pathways; Cr2(-/-) mice lacking CR1 and CR2 and, as control strains, BALB/c, C57BL/6, KRN and NOD. RA was assessed by caliper measurement of ankle thickness, clinical index and joint histology. We found that all mouse strains except NOD developed RA. The lack of protection in C4(-/-) mice suggests that antibody-mediated RA is independent of the classical as well as the lectin complement pathways and the split complement product C4b. The lack of protection in Cr2(-/-) mice suggests that absence of CR1 had no significant affect, considering its role in immune complex clearance, inhibition of C3 and C5 convertase and as receptor for C3b/C4b. Also, CR2 lacks a role in disease as analyzed here, in its possible functions as receptor for C3dg, germinal center reaction and activation of alternative pathway on binding iC3. Hence we conclude that the transmission of K/BxN serum-induced RA is independent of the classical and the lectin complement pathways and CR1 and CR2. The crucial role of complement C5, while neither classical nor lectin pathway is necessary, indicates that the alternative complement pathway may have a role in the K/BxN serum-induced RA model.

Animals↗
PubMed1985

Complement factor C4 in schizophrenia.

The complement factor C4 was studied in 165 schizophrenic patients and in 330 controls. A highly significant increase in the frequency of C4B deficiency (BQO) was found among the schizophrenic patients compared with controls (p less than 0.0005).

Complement C4↗
PubMed1989

Sequence of the gene for murine complement component C4.

The gene for murine complement component C4 lies in the S region of the murine major histocompatibility (H-2) complex; in this paper, we report the nucleotide sequence of this gene. The present sequence extends from a SmaI restriction enzyme cleavage site near the 5' end of the gene to a KpnI restriction enzyme cleavage site 569 nucleotides 3' of the polyadenylation site. The sequence spans 15,956 base pairs and together with previously reported data provides a complete sequence extending from the site of transcriptional initiation to the polyadenylation site. The sequence reveals that the C4 gene has 40 introns which range from 75 to 1089 base pairs in length and which include three murine B1 middle repetitive elements, a MT repeat element, and an apparently novel repeat sequence that is also found in noncoding regions of the murine beta-glucuronidase, lymphotoxin (TNF-beta), and rat alpha-crystallin genes. An intron splits the protein coding sequence precisely at the site of proteolytic activation of C4 by complement protease C1s; however, except for this one case, the intron positions show no striking relationship to the structural features of the C4 protein. The length of the murine C4 gene relative to the isotypic C4A and C4B genes in man suggests the independent loss of a 6-kilobase intron from both murine and human C4 genes.

Animals↗
PubMed1985

The origin of the very variable haemolytic activities of the common human complement component C4 allotypes including C4-A6.

The human complement component C4 occurs in many different forms which show big differences in their haemolytic activities. This phenomenon seems likely to be of considerable importance both physiologically and pathologically. C4 is coded by duplicated genes between HLA-D and HLA-B loci in the major histocompatibility complex in man. Several fold differences in haemolytic activity between products of the two loci C4-A and C4-B have been correlated with changes of six amino acid residues in this large protein of 1722 residues and with differences of several fold in the covalent binding of C4 to antibody-antigen aggregates. Some allotypes of one locus also differ markedly, notably C4-A6 which has 1/10th the haemolytic activity of other C4-A allotypes. A monoclonal antibody affinity column has been prepared which is able to separate C4-A from C4-B proteins and, using serum from an individual expressing only the C4-A6 allele at the C4-A locus, C4-A6 protein has been prepared. Investigation has shown C4-A6 to have the same reactivity as other C4-A allotypes except in the formation of the complex protease, C5 convertase. This protease is formed from C4, C2 and C3 and if C4-A6 is used it has approximately 1/5th the catalytic activity compared with other C4-A allotype. Allelic differences in sequence identified in C4 proteins so far are few and it is probable that the big difference in catalytic activity of C5 convertase is caused by very small changes in structure.

Alleles↗
PubMed1990

The complement component C4 of mammals.

Human complement component C4 is coded by tandem genes located in the HLA class III region. The products of the two genes, C4A and C4B, are different in their activity. This difference is due to a degree of 'substrate' specificity in the covalent binding reactions of the two isotypes. Mouse also has a duplicated locus, but only one gene produces active C4, while the other codes for the closely related sex-limited protein (Slp). In order to gain some insight into the evolutionary history of the duplicated C4 locus, we have purified C4 from a number of other mammalian species, and tested their binding specificities. Like man, chimpanzee and rhesus monkey appear to produce two C4 types with reactivities similar to C4A and C4B. Rat, guinea pig, whale, rabbit, dog and pig each expresses C4 with a single binding specificity, which is C4B-like. Sheep and cattle express two C4 types, one C4B-like, the other C4A-like, in their binding properties. These results suggest that more than one locus may be present in these species. If this is so, then the duplication of the C4 locus is either very ancient, having occurred before the divergence of the modern mammals, or there have been three separate duplication events in the lines leading to the primates, rodents and ungulates.

Animals↗
PubMed1998

Reference typing report for complement component C4.

During the 7th Complement Genetics Workshop, Mainz, Germany, May 1998, a complement component C4 typing exercise took place with the aim of applying present technologies to the definition of reference C4 alleles/phenotypes and the recognition of nonexpressed (Q0) C4 alleles within expressed haplotypes. Eleven samples were submitted from 3 laboratories and tested by 14 participating laboratories with basic protein-typing technologies; in addition, each laboratory contributed data from local expertise. The samples were introduced to the reference typing for one or more characteristic allotype or for partial or total nonexpression of one isotype. The blinded samples were centrally evaluated and the results discussed among the participants at a plenum meeting. From the results, the samples could be classified into a group of common, easy to diagnose pheno-/allotypes, less common but still unanimously recognised variants, and a third group with difficult pheno-/allotypes. Within the latter group, the allotypes were either new (C4A '92'; C4B '93') and/or showed partial or total reversed antigenicity and unusual Rodgers/Chido (Rg/Ch) PCR subtypes (C4A '92'; C4A 12; C4B '35'; C4B '13'). Semiquantitative C4-alpha-chain estimates of relative isotype levels correlated well with the number of alleles seen at each locus by agarose gel electrophoresis, and were superior to other isotype quantitation methods. From the evaluation of the reference typing it was concluded that the recognition of rare, aberrant or hybrid C4 alleles with partial or total reversed Rg/Ch antigenicity or monoclonal reactivity is still difficult in most instances; besides isotype-dependent lysis, relative migration values, immunoblots with Rg- and Ch-specific monoclonal antibodies, Rg/Ch PCR typing, side-by-side comparison with already described allotypes will ultimately be required. The recognition of nonexpressed alleles within C4A and C4B expressed phenotypes remains the major obstacle in C4 genetic typing. Finally, a conclusive interpretation of DNA typing results will be achieved only in the context of complete allotyping results at the protein level, and at present cannot replace conventional protein allotyping.

Alleles↗
PubMed1981

Amino acid sequence around the thiol and reactive acyl groups of human complement component C4.

Activation of the fourth component of complement (C4) by C1s results in the generation of a reactive acyl group, able to react with putrescine, and in the release of a free thiol group that cannot be detected in the native haemolytically active molecule. Both the reactive acyl group and the free thiol group have been shown to reside in C4d, a fragment of the alpha'-chain of C4b derived from digestion of the molecule with the control proteins C3b inactivator and C4-binding protein. Peptides derived from CNBr digestion of [1,4-14C]putrescine-labelled and iodo(2-14C]acetic acid-labelled C4d have been obtained and used to establish a continuous sequence of 88 residues from the N-terminus of the molecule. The thiol and reactive acyl groups are contained in an octapeptide that shows near identity with the equivalent sequences reported for alpha 2-macroglobulin and C3. Other adjacent short sections also show homology of sequence between the three proteins, and it is highly likely that they contribute to the overall structure that gives a unique reactivity to the thiol ester bond postulated to exist in the native forms of the three proteins.

Amino Acid Sequence↗
PubMed1985

Distribution of complement protein C4 concentrations in bovine plasma.

Complement component C4 concentrations were measured in 40 pure bred Hereford cattle and 40 cattle from a mixed breed herd. Significant differences were not observed between the two groups studied nor between bulls and cows. However, the distribution of C4 concentrations was relatively disperse and appeared polymodal suggesting the presence of two isotypes of C4. Polyacrylamide gel electrophoresis of immunoprecipitated bovine C4 showed many samples to have two C4 alpha chains differing in relative molecular mass by about 1800. Isoelectric focusing of bovine plasma in agarose gels followed by immunofixation with specific anti-C4 antisera revealed two populations of native C4 differing in pI by about 0.3 pH unit. An association between the type of C4 alpha chain present and the pI of the native C4 molecule was observed. Collectively these findings indicate the presence of two structural C4 genetic loci in cattle.

Animals↗
PubMed1984

Genes for murine fourth complement component (C4) and sex-limited protein (Slp) identified by hybridization to C4- and Slp-specific cDNA.

Murine fourth component of complement (C4) and sex-limited protein (Slp) are two closely related serum proteins whose structural genes lie in the S region of the murine H-2 complex. We have cloned two very similar (95% nucleotide sequence identity) cDNAs; they encode amino acid sequences that are distinct but that correspond equally well with the limited amino acid sequence available for murine and human C4. We have identified one of these as C4 cDNA and the other as Slp cDNA by comparing, in a RNA blot hybridization experiment, the extent of hybridization of the two cDNAs to liver mRNAs from inbred mouse strains expressing varying amounts of C4 and Slp proteins in their plasma. The C4 and Slp cDNAs were used in a Southern blot experiment to identify the C4 and Slp genes in the molecular map of the S region.

Amino Acid Sequence↗
PubMed1982

A molecular basis for the two locus model of human complement component C4.

The major histocompatibility complex(MHC)-linked fourth component of complement (C4) shows a high degree of polymorphism in several animal species. In man C4 polymorphism was detected by distinct charge differences of the variants. O'Neill et al. showed that this C4 polymorphism was controlled by two closely linked genetic loci, F (C4A) and S (C4B) and these results were extended by Awdeh et al. with an improved typing method. Biochemical analysis of human C4 has revealed that it consists of three polypeptide chains, alpha, beta and gamma. In all reports so far on the molecular analysis of human C4, no molecular weight differences between the A and B locus-encoded molecules have been noticed. Here we demonstrate that the C4A and C4B locus-encoded alpha-chains have a molecular weight (MW) of 96,000 and 94,000, respectively, presenting for the first time a molecular basis for the difference between all C4A and C4B variants tested. Even rare variants that are difficult to allocate to the A or B locus on the basis of charge differences could be identified as C4A or C4B variants in this way, thereby providing new insights into the relationships between the C4A and C4B loci.

Complement C4↗
PubMed1979

The purification and characterization of bovine C4, the fourth component of complement.

The fourth component of complement, C4, was isolated from bovine plasma in high yield, by using simple purification techniques. The protein, like human component C4, is a beta-globulin with a mol.wt. of about 200 000 and consists of three polypeptide chains, alpha, beta and gamma, with apparent mol. wts. of 98 000, 82 000 and 32 000 respectively. The chains of C4 have been separated by methods previously used for human C4. Their amino acid compositions are very similar to those of the human component, but differences in carbohydrate distribution have been observed. The haemolytic activity of bovine C4 is totally destroyed by incubation with bovine C1s, the activated subcomponent of the first component of complement. Component C4, treated in this way, was shown to be cleaved in the alpha chain, which was decreased in mol.wt. by about 9000, corresponding to the removal of subcomponent C4a.

Amino Acids↗
PubMed2001

Genetics of human complement component C4 and evolution the central MHC.

The two classes of human complement component C4 proteins C4A and C4B manifest differential chemical reactivities and binding affinities towards target surfaces and complement receptor CR1. There are multiple, polymorphic allotypes of C4A and C4B proteins. A complex multiplication pattern of C4A and C4B genes with variations in gene size, gene dosage and flanking genes exists in the population. This is probably driven by the selection pressure to respond to a great variety of parasites efficiently and effectively, which the bony fish achieved through the multiplication and diversification of the related complement C3 proteins. Complement C4, C3 and C5 belong to the alpha2 macroglobulin protein family but acquired specific features that include an anaphylatoxin domain, a netrin (NTR) domain, and stretches of basic residues for proteolytic processings to form multiple chain structures. Complement C3 and C4 are important in the innate immune response as they opsonize parasites for phagocytosis. The emergence of complement C3 predates proteins involved in the adaptive immune response as C3 is present in deuterostome invertebrates such as echinoderms. The human C4 genes are located in the central MHC at chromosome 6p21.3. C3 and C5 are located at chromosome 19 and 9, respectively, with representatives of the other groups of genes paralogous to the MHC at 19p13.1-p13.3, 1q21-25, and 9q33-34. The central MHC also contains genes for complement components C2 and Bf. These genes appear to have similar evolutionary histories to C3/C4/C5 and are used here to illustrate stepwise processes resulting in co-location of diverse domains, chromosomal duplication, local segmental duplication and divergence of sequence and function. This model of evolution is useful in the investigation of innate and acquired immunity and in seeking explanations for diseases associated with MHC ancestral haplotypes.

Amino Acid Sequence↗
PubMed1985

The effect of null C4 alleles on complement function.

C4 is encoded at two polymorphic genetic loci (C4A and B), and "null" or unexpressed alleles are relatively common. An increased frequency of nulls has been reported in a variety of diseases. In the present study, C4 allotypes and C4 hemolytic efficiencies (the ratios of functional to antigenic levels) were determined for a population of 75 normal unrelated individuals. Of these, 28 had three gene products (single null at C4A or B) while three had no expressed C4A products and three had no C4B products (homozygous null). Mean antigenic C4 levels correlated with the number of expressed gene products but there was a wide spread of individual values. Those homozygous null for C4A had greater, and for C4B less, hemolytic efficiency than those with four gene products. However, there was no difference in the in vitro kinetics of C3 convertase formation between homozygous null C4A or C4B individuals. Therefore, the presence of null genes for C4 does not appear to compromise complement function sufficiently to account for the reported disease associations. Some of the associations may result from the fact that null genes for C4, as part of an extended HLA haplotype, may be genetically linked to disease susceptibility.

Adult↗
PubMed1985

Dimerization of human complement proteins C3 and C4 in dilute lauryl sulfate buffer after reaction with methylamine.

In the presence of methylamine and dilute lauryl sulfate (pH 8.0), the human C3 and C4 complement proteins dimerize almost completely. Under these conditions, the related complement protein C5 does not show any tendency to form dimers. This is shown by x-ray and neutron scattering at 9 degrees C and 0.15 M ionic strength. The radii of gyration of the C3 and C4 dimers are very similar, 7.7 and 7.4 nm, and the cross-sectional radii of gyration are the same, 3.4 nm. The scattering curves of the C3 and C4 dimers as well as their Fourier transforms, the p(r)-curves, can be explained by scattering from a model consisting of an elongated elliptic cylinder with semiaxes 6.5 and 2.1 nm and length of 23 nm. This elongated elliptic cylinder model is consistent with the elliptic cylinder model of C4 (Osterberg, R., Eggertsen, G., Lundwall, A., and Sjöquist, J. (1984) Int. J. Biol. Macromol. 6, 195-198) provided that the protein molecules dimerize via their cross-sectional surfaces. Also, the model is consistent with the model of the related protein, alpha 2-macroglobulin, where the four subunits are supposed to form pairwise dimers of an elliptic cylindrical form (Osterberg, R., and Malmensten, B. (1984) Eur. J. Biochem. 143, 541-544).

Buffers↗
PubMed1992

Effects of cell differentiation on the synthesis of the third and fourth component of complement (C3, C4) by the human monocytic cell line U937.

Association of complement synthesis with cell differentiation in U937 cells was investigated using granulocyte-macrophage colony-stimulating factor (GM-CSF), vitamin D3 and interferon-gamma (IFN-gamma) as differentiation-inducing agents. GM-CSF or vitamin D3 enhanced the synthesis of the third component of complement (C3) by U937 cells, but had no stimulatory effect on the synthesis of the fourth component of complement (C4). IFN-gamma increased both C3 and C4 synthesis by U937 cells. Combination of two of these three agents resulted in synergistic enhancement and all three agents caused maximal enhancement of C3 synthesis. Vitamin D3 enhanced IFN-gamma-induced C4 synthesis by U937 cells. These results were confirmed by ELISA and SDS-PAGE after biosynthetic labelling. GM-CSF, vitamin D3 or IFN-gamma increased the expression of complement receptor type 3 (CR3), one of the markers of monocyte/macrophage differentiation. Two of these agents caused a further increase and all three agents maximal increase in CR3 expression. Since C3 was synthesized in parallel with the degree of CR3 expression, the synthesis of C3, but not C4, by U937 cells is thought to be closely related to cell differentiation. It was reconfirmed that the synthesis of C3 and C4 by U937 cells was independently regulated.

Cell Differentiation↗
PubMedDate not supplied

Intrathecal synthesis of complement components C3c and C4 in the central nervous system infections with signs of the acute serous meningitis syndrome.

Two hundred and ten patients with meningismus and the infections of the central nervous system (CNS) with the clinical symptoms and signs of the acute serous meningitis syndrome, were divided in to groups according to etiology (enterovirus meningitis-ENTERO, serous meningitis various etiology-SM and tuberculous meningitis-TBC). Intrathecal synthesis (ITS) of C3c and C4 complement components and IgG were determined by the method of cerebrospinal indexes (I), to examine their role in differential diagnosis of this syndrome. Correlative study between the CSF/serum ratio (Q) for albumin (Alb) and QC3c and QC4 in patients with no proven ITS of this two complement proteins, and the comparative study of the increased value of C3cI and C4I (and IgGI) between the examined groups of the patients was done. Highly significant correlations were found between QAlb and QC3c (r = 0.89, p < 0.001) and QC4 (r = 0.85, p < 0.001). In 22.4% of the examined patients ITS of C3c and C4 were found. There was no difference in frequency of ITS of the two complement proteins between the examined groups, nor inside any particular group. TBC group had significantly lower (p < 0.05) intensity of ITS of C3c and C4 than MNG and ENTERO, and significantly higher intensity of ITS of IgG (p < 0.05) than the other tested groups. CSF index was confirmed as a valid method to detect intrathecal C3c and C4 production. Determination of ITS C3c and C4 could not be of great help in differential diagnosis in the acute serous meningitis syndrome. The intensity of ITS of C3c and C4, related to the intensity of ITS of IgG, could be of help in the determination of the duration of the disease.

Acute Disease↗