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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↗
PubMed1986

Diabetes and autonomic neuropathy: an immunological association?

Lymphocytic infiltration of autonomic ganglia found at autopsy and a strong clinical association with iritis suggests that diabetic autonomic neuropathy might have an immunological basis. We measured levels of circulating immune complexes, complement (C3, C4), complement breakdown products (C3d), and insulin antibodies in diabetics with autonomic neuropathy and a history of iritis (n = 17), compared to diabetics of similar age and duration with autonomic neuropathy but no history of iritis (n = 20), and with uncomplicated insulin-dependent diabetics (n = 23), together with normal controls (n = 26). We found higher levels of circulating immune complexes in patients with autonomic neuropathy (irrespective of iritis) compared to normal controls, and differences in C3d levels suggesting complement activation. C4 levels were unexpectedly normal in the diabetics with autonomic neuropathy, in contrast to the uncomplicated insulin-dependent diabetic controls. Insulin antibody levels showed no difference between the three groups of diabetics. These findings suggest that immunological mechanisms may be implicated in the aetiology of diabetic autonomic neuropathy and that further studies are indicated.

Adult↗
PubMed1998

Rapid activation of the complement system by cuprophane depends on complement component C4.

Hemodialysis with cuprophane dialyzer membranes promotes rapid activation of the complement system, which is thought to be mediated by the alternative pathway. Complete hereditary deficiency of complement C4, a classical pathway component, in two hemodialysis patients provided the opportunity to investigate a possible role of the classical pathway. In two hemodialysis patients with both C4 isotypes, C4A and C4B, and in one patient with C4B deficiency complement activation occurred immediately after the onset of hemodialysis, with peak levels of C3a and terminal complement complex (TCC) after ten to fifteen minutes. In patients with complete C4 deficiency, C3a and TCC remained unchanged for fifteen minutes and increased thereafter, reaching the highest level after thirty minutes. The leukocyte nadir was also delayed from fifteen to thirty minutes. In vitro incubation of normal, C4A- or C4B-deficient serum with cuprophane caused complement activation after fifteen minutes. In contrast, no activation was observed in sera of four C4-deficient patients. The addition of normal serum or purified human C4 restored the capacity for rapid complement activation. In one patient with severe immunoglobulin deficiency, C3a and TCC levels increased only moderately after 25 minutes of cuprophane dialysis. This patient's serum also exhibited delayed complement activation in vitro, which was normalized after pretreatment of cuprophane with immunoglobulins. Preincubation of normal serum with MgEGTA, a blocker of the classical pathway, inhibited rapid complement activation through cuprophane. As basal levels of C4a are markedly increased in hemodialysis patients (3450 +/- 850 ng/ml) compared to healthy controls (224 +/- 81 ng/ml), no further elevation of C4a was detectable during cuprophane hemodialysis. Incubation of normal serum with cuprophane, however, caused a slight increase in C4a after five minutes. These results indicate that the initial deposition of complement C3b on the cuprophane membrane, necessary for activation of the amplification loop of the alternative pathway, is mediated by the classical pathway C3-convertase C4b2a. We propose an extended concept of complement activation through cuprophane, which is based on four steps: (a) binding of anti-polysaccharide antibodies, (b) classical pathway activation, (c) alternative pathway activation and (d) terminal pathway activation.

Adolescent↗
PubMed1988

Differential effect of inflammatory stimuli on murine plasma C4 and factor B concentrations.

The in vivo effects of a variety of inflammatory stimuli on complement C4 and factor B plasma levels have been examined. MRL/++ (H-2k) mice were given intraperitoneal injections of lipopolysaccharide, turpentine, Corynebacterium parvum pyridine extract residue or high doses of indomethacin. All of these treatments induced an increase in plasma factor B concentrations, which in the case of C. parvum was dose dependent and persisted for at least 7 days. Lipopolysaccharide, turpentine and indomethacin produced decreases in plasma complement C4. C. parvum, however, produced an increase in plasma complement C4 to approximately 240% of controls which was independent of gender. It was also independent of major histocompatibility complex haplotype, since the same effect was seen in C57B1/6J-bg/bg and C57B1/6J-bg/+ mice. The gross increment in complement C4 was, however, related to the major histocompatibility complex. H-2K mice ("low complement C4") had smaller increments than H-2b ("high complement C4"). Mycobacterium bovis (BCG) also produced a transient increase in C4 in the H-2b mice as well as a prolonged increase in factor B levels. These data (i) suggest that different inflammatory stimuli induce different mediators which may have differential effects on factor B and complement C4 synthesis, and (ii) emphasize the independent regulation of complement C4 and factor B. Qualitative variations in the mediators elaborated during chronic inflammatory diseases may help determine complement C4 fluctuations in systemic lupus erythematosus and the wide range of complement C4 concentrations seen in MRL/1 pr mice with active immune complex disease.

Animals↗
PubMed1988

Low serum haemolytic function of the fourth complement component (C4) in insulin dependent diabetes.

Low serum concentrations of the fourth component of complement (C4) are found in insulin dependent diabetes, and may be important in the aetiology of the disease. To ascertain whether function of C4 is also impaired both its haemolytic activity and its concentration were measured in 34 insulin dependent diabetics, 15 non-insulin dependent diabetics, 20 healthy subjects, and 12 pairs of monozygotic twins discordant for insulin dependent diabetes. C4 function was measured by a radial immune haemolytic assay, and C4 concentration by laser nephelometry. Both measurements were significantly lower in insulin dependent diabetics (C4 function: median 47%, range 4-100%; C4 concentration: 0.22 g/l, 0.10-0.38 g/l) than in non-insulin dependent diabetics (67%, 33-138%, p less than 0.01; 0.27 g/l, 0.16-0.50 g/l, p less than 0.02) and controls (74%, 33-138%, p less than 0.01; 0.27 g/l, 0.18-0.40 g/l, p less than 0.03). C4 function and concentration were lower in both diabetic (48%, 12-100%; 0.17 g/l, 0.08-0.31 g/l) and non-diabetic twins (47%, 12-100%; 0.17 g/l, 0.07-0.36 g/l) than controls (p less than 0.01; p less than 0.01). Thirteen (38%) of the insulin dependent diabetics had a reduction in either C4 function or concentration, but in only five were both features reduced. Values of function and concentration were strongly correlated in both diabetic and non-diabetic twins (r = 0.95, p less than 0.001; r = 0.92, p less than 0.001). These results show defects in C4 function and concentration in insulin dependent diabetes, which--being present in the non-diabetic co-twin of diabetics--may represent a genetic predisposition to the disease.

Adult↗
PubMed1987

A high frequency of inherited deficiency of complement component C4 in Darwin Aborigines.

A high frequency of serum complement component C4A deficiency may explain the higher prevalence and greater severity of systemic lupus erythematosus reported in Australian Aborigines. Inherited deficiencies of serum complement components C4A, C4B, and C2 were examined in two Australian Aboriginal populations from Darwin and Alice Springs and compared with the prevalence of complement deficiencies in white Australian blood donors. The frequency of C4A deficiency alleles was 29% in Darwin Aborigines compared with 12% in Alice Springs and 17% in Canberra blood donors. Partial C4B deficiency was also higher in Darwin Aborigines than in the other populations. Inherited deficiency of serum complement component C2 was not observed.

Alleles↗
PubMed1999

The complement component C4 in sudden infant death.

UNLABELLED: The aim of the present study was to compare partial deletions of the complement C4 gene in victims of totally unexplained sudden infant death (SID) (n = 89) and borderline SID (n = 15) with and without slight infections prior to death, in cases of infectious death (n = 19), and in living infants with and without infections (n = 84). The SID and borderline SID groups were pooled. In this total SID group slight infections prior to death was associated with deletion of either the C4A or the C4B gene (P = 0.033), and the SID victims with such infections had a higher deletion frequency than the controls (P = 0.039). There were no differences between the living infants with and without upper airway infections. CONCLUSION: The present study confirms that partial deletions of the C4 gene in combination with slight upper airway infections may be a risk factor in sudden infant death.

Child, Preschool↗
PubMed1987

Neutrophil lysosomal enzyme release and complement activation during cardiopulmonary bypass.

Complement activation and neutrophil degranulation were concomitantly studied during uncomplicated cardiopulmonary bypass (CPB). Plasma concentrations of complement factor C4, complement split product C3d, the neutrophil lysosomal enzyme elastase complexed with alpha 1-proteinase inhibitor (PI) and fibronectin were measured in 12 patients, C3d and elastase/PI increased significantly during CPB (volume-corrected results). The C3d rise was almost linear, whereas elastase/PI showed exponential increase. Mean elastase/PI and mean C3d concentrations at different times during CPB covaried closely. The study showed that during CPB neutrophil lysosomal enzyme release is intimately related to complement activation, although activation of the two systems may be caused by a common third activator within the extracorporeal circuit.

Adult↗
PubMed1982

[Immunological parameters in subjects with essential arterial hypertension. II. Serological observations].

M, G, and A immunoglobulins as well as C3 and C4 complement fractions were determined in 20 patients with essential hypertension: all the values were in the normal range. Nearly half of the patients had an abnormally high value of circulating immune complexes as determined with Clq binding assay and/or with CIC test. The rise of circulating immune complexes is not related to the stage of arterial hypertension.

Adult↗
PubMed2001

Some patients with antiphospholipid syndrome express hitherto undescribed antibodies to cardiolipin-binding proteins.

Contrary to infective anticardiolipin (aCL) antibodies, autoimmune aCL antibodies react with phospholipids (PL) mainly via binding to the plasma glycoprotein cofactor beta2-Glycoprotein I (beta2GPI). While there is a well-documented link between the risk of thrombosis and the presence of beta2GPI-dependent anticardiolipin antibodies, the pathological impact of other antiphospholipid antibodies is less clear. By means of cardiolipin affinity-chromatography, we isolated and identified 3 CL-binding proteins, complement component C4, complement factor H and a kallikrein-sensitive glycoprotein, and tested for the presence of autoantibodies against these proteins in patients with antiphospholipid syndrome (APS), systemic lupus erythematosus (SLE) and other autoimmune diseases. High titers of autoantibodies to C4 as compared to age- and sex-matched healthy controls were present in 3 of 26 patients with APS, and weak titers were found in 2 of 26 patients with SLE and in none of 26 patients with other autoimmune diseases. Autoantibodies to complement factor H were found in 4 APS, 3 SLE and none of the other autoimmune patients. Autoantibodies to kallikrein-sensitive glycoprotein were detected in 6 APS patients, 1 SLE patient, and 1 patient with another autoimmune disease. A close relationship between these antibodies was found, suggesting their origin from a common macromolecular complex. However, no relationship with anti-beta2GPI antibodies was found, with the three patients with higher levels of autoantibodies having a low titer of anti-beta2GPI antibodies. In conclusion, some patients with APS harbor circulating antibodies to other CL-binding proteins which might be useful to further characterize these patients.

Adolescent↗