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PubMed1980

Familial partial deficiency of the third component of complement (C3) and the hypocomplementemic cutaneous vasculitis syndrome.

Familial hypocomplementemia of the third component of complement (C3) was found in four members of a family. The prospositus had cutaneous vasculitis, hypocomplementemia, arthralgia, proteinuria and thrombocytopenia. The combination of clinical, laboratory and pathologic findings resembled the "hypocomplementemic cutaneous vasculitis syndrome" (HCVS) or the "SLE-like syndrome" but serum C3 concentration was 35 to 57 per cent of normal in the propositus and in three relatives. Results of Clq precipitins, cryoglobulins and serologic tests for systemic lupus erythematosus were negative. Proteinuria (815 mg/day) but no hematuria was present. Analysis of the C3 phenotypes in this family showed that three hypocomplementemic members were apparent homozygous C3 slow but one was heterozygous C3 fast-slow. Metabolic studies with 125-Iodinated C3 in the clinically normal mother showed a 50 per cent reduction in C3 synthesis which was consistent with hypocomplementemia documented by serum protein assay. The occurrence of an immune complex-like disease (with characteristics of the HCVS) in a patient with a familial deficiency of C3 suggests that the preexisting C3 deficiency may predispose such persons to certain diseases.

Adolescent↗

PubMed1989

Estimation of postmortem interval using kinetic analysis of the third component of complement (C3) cleavage.

To estimate postmortem interval (PMI), spontaneous cleavage of the third component of complement (C3) was studied in aged blood and cadaveric blood by crossed immunoelectrophoresis. Using the kinetics of C3 cleavage in vitro described as dC/dt = -kC, where C is the concentration of native C3 at time t and k is a first-order rate constant, Arrhenius' equation, and another equation which assumes a linear drop of body temperature after death, the percentages of C3 cleavage were calculated. There was a significant positive correlation between the calculated percentages and the measured percentages of up to 10% in cadaveric blood. We found that the comparison between the calculated percentage of C3 cleavage for each optional postmortem interval and the measured percentage of up to 10% in cadaveric blood leads to the estimation of PMI. This approach is one step towards the development of an accurate method for determining PMI based on C3 cleavage, that is, on a first-order reaction.

Blood Protein Electrophoresis↗

PubMed1995

Expression and tissue localization of donor-specific complement C3 synthesized in human renal allografts.

Recent evidence suggests that the third component of complement, C3, is synthesized in renal tissue, and that increased C3 synthesis occurs in allograft rejection and immune complex-mediated nephritis. However, it is unclear whether intrinsic renal cells or migratory cells in the inflammatory infiltrate, possibly of recipient bone marrow origin, are the source of the C3 detected. This was investigated by determining the C3 allotypes of mRNA and protein produced by transplanted human kidney. Twenty donor-recipient pairs were examined, of which nine pairs had C3 allotypes that were informatively mismatched at the C3 F/S locus. Reverse transcriptase polymerase chain reaction (RT-PCR) followed by amplification refractory mutation system analysis showed intracellular donor-specific mRNA expression in six of these nine cases, at up to 61 days post-transplantation. Nested PCR reactions and the size of PCR products excluded contamination by genomic DNA. Allotype-specific staining of frozen sections of renal cortex demonstrated donor-derived C3 protein in both glomeruli and tubules of all biopsies examined, in a predominantly tubular distribution. These results imply that at least some of the pro-inflammatory effects of complement arise from intrinsic tissue synthesis of donor C3, and that this may represent a previously unrecognized source of tissue injury. The occurrence of local synthesis of C3 of donor allotype may have functional implications related to C3 allotype, and may also be relevant to strategies to inhibit intrarenal complement-mediated injury.

Alleles↗

PubMed1997

Characterization of complement C3, C4, and factor B molecules in human bile.

We performed molecular analysis of complement components (C3, C4, and factor B) in human bile by sodium dodecyl sulfate-polyarylamide gel electrophoresis (SDS-PAGE) and immunoblotting. Complement C3 was detected as a molecule composed of a 115-kDa alpha-chain linked to a 70-kDa beta-chain by disulfide bonds, and C3 levels ranged from 45 to 650 micrograms/ml (n = 15). C4 was detected as a triple chain (98-kDa alpha-chain, 73-kDa beta-chain, and 33-kDa gamma-chain) molecule linked by disulfide bonds, and C4 levels ranged from 2.5 to 60 micrograms/ml. Factor B, a component of the alternative pathway, was also detected, as an intact form. Factor B levels ranged from 0.3 to 8.0 micrograms/ml. The sizes and subunit structures of complement components in human bile were compatible with those reported in human serum. The results of a hemolytic assay indicated that complement molecules in human bile were functionally active. These molecules may participate in local immune and inflammatory responses in the biliary tract.

Bile↗

PubMed1997

Serum C-reactive protein and C3 complement protein levels in severely malnourished Nigerian children with and without bacterial infections.

Bacterial infections are the major determinants of fatality in severe protein-energy malnutrition (PEM). Unfortunately, these infections are difficult to diagnose clinically. C-reactive protein (CRP) levels were determined in 17 infected and 10 non-infected Nigerian children with severe PEM and compared with age/sex-matched apparently healthy controls. The aim was to study the response of this acute phase protein to bacterial infections as well as to assess its value in the diagnosis of infections in severe PEM. C3 complement protein levels were also determined in the same group of subjects. The major organisms isolated in samples from these subjects were S. aureus and the coliforms. Mean CRP level in the non-infected children with severe PEM was 13.8 +/- 6.21 mg/l and rose to 159.83 +/- 124.07 mg/l in the presence of infection. The mean value in healthy non-infected controls was 2.01 +/- 0.96 mg/l. The difference in the mean CRP levels between the infected and non-infected PEM children was statistically significant at p < 0.01. The mean difference between the non-infected and the control subjects was not significant. Using a diagnostic level of 20.00 mg/l of CRP gave a sensitivity of 85.0% and a specificity of 80.0%. This CRP level is a useful index of bacterial infections in severe PEM. C3 complement protein was low in the non-infected malnourished group, but rose significantly in the presence of infection to values similar to that of the healthy controls. C3 protein thus behaves as an acute phase reactant in the presence of infection in severe PEM, and does not appear to be consumed, probably due to a deficiency in the early components of the complement cascade. This suggests a role for C3 measurement in the monitoring of bacterial infections in severe PEM.

Bacterial Infections↗

PubMed1979

A simple electrophoretic technique for the estimation of complement C3 conversion: specific application to the investigation of anaphylactoid response to I.V. agents.

A simple electrophoretic technique employing commercially available agarose films is described for the routine estimation of plasma complement C3 conversion. This technique has particular value in the investigation of anaphylactoid responses in patients following the administration of intravenous hypnotic drugs, plasma substitutes or radio-contrast media.

Alfaxalone Alfadolone Mixture↗

PubMed1993

Synthesis of the third component of complement (C3) by human gastric cancer-derived cell lines.

This is a study of complement components secreted by gastric cancer-derived cell lines (MKN28, MKN45, MKN74 and KATO-III), each of which has a different histological origin. Haemolytic activity of complement component was detected only in the culture supernatant of KATO-III (C2 activity) and in that of MKN45 (C5 activity). However, the third component of complement, C3, was detected by an ELISA assay in the supernatants of all cell lines. In our studies focusing on C3 production by these cell lines, we have found that: (i) tumour necrosis factor (TNF) induced an increase in the amount of secreted C3 in a dose- and time-dependent fashion; (ii) TNF (10 U/ml) stimulated C3 secretion by these cell lines to levels of 25.4-62.9 ng C3/10(6) cells per 24 hours; (iii) C3 haemolytic activity was detected in supernatants of TNF-stimulated cell lines. The mean specific activities of C3 by TNF (10 U/ml)-stimulated cell lines were 1.2-5.6 x 10(5) effective molecules/ng (e.m./ng), when that of C3 in normal human serum (NHS) was 1.7 x 10(6) e.m./ng; (iv) de novo synthesis of C3 by these cell lines was demonstrated by the effect of cycloheximide and by the incorporation of 35S-methionine into secreted C3; (v) immunoblot analysis of culture supernatants indicated that secreted C3 was mainly composed of C3 alpha and C3 beta chains, but pro-C3 was also present. These results, which show the de novo synthesis and secretion of C3 by all the tested gastric cancer-derived cell lines in response to TNF, suggest the possibility that C3 may be secreted in the gastric wall as part of its normal physiology, or as a result of tumour pathology, and thereby participate in local immune or inflammatory responses.

Complement C3↗

PubMed1988

Complement (C3) metabolism in rheumatoid arthritis in relation to the disease course.

Metabolic turnover studies of the third component of complement, C3, were performed in 23 patients with rheumatoid arthritis (RA) to get a direct insight in the dynamics of complement synthesis and catabolism. Results of these turnover studies were related to the serum level of the total amount of C3 as well as to that of the activation product C3d. A hypercatabolism of C3 was observed in 12 of the 23 patients studied. Six of these 12 patients showed signs of extra-articular RA; only one patient with extra-articular manifestations had a normal catabolism of C3. Decreased serum levels of C3 were not found in any of the patients with a hypercatabolism of C3, indicating that the accelerated turnover was compensated by an increased synthesis. In RA patients levels of the activation product C3d could not correlate with the turnover of C3. However, in selected RA patients without signs of nodules or extra-articular manifestations, they could. Thus, our results indicate that serum levels of C3 and C3d do not reflect C3 metabolism in RA patients. Furthermore, the existence of extra-articular manifestations is accompanied by a more pronounced activation of the complement system.

Arthritis, Rheumatoid↗

PubMed1977

The significance of serial measurement of serum anti-native DNA antibodies and complement C3 and C4 components in the management of patients with systemic lupus erythematosus.

Serial measurements were made over a period of three years of serum DNA-binding capacity and complement C3 and C4 levels in parallel with documentation of clinical features of disease activity in Glasgow patients with SLE. Raised DNA-binding levels were noted in 27 of the 32 patients over this time period. High levels (over 80%) were found in patients with both renal and non-renal disease. In some patients increases in DNA-binding capacity and decreases in C3 levels were associated with changes in disease activity. This pattern was commonest in patients with renal SLE. In others DNA-binding capacity was elevated without any relationship to SLE disease activity. A fall in serum C3 levels was usually significant while serum C4 levels frequently fell without any change in clinical features of disease activity. Very low serum C4 levels (below 15 mg/dl), however, were usually of clinical relevance. The uses of immunological measurements in the differential diagnosis of a major illness in a patient with SLE are discussed. The finding of such an illness in a patient with normal serum DNA-binding levels made it unlikely that the illness was due to an exacerbation of the SLE and more likely that an alternative cause such as supervening bacteraemia was responsible.

Antibodies↗

PubMed1996

Extrahepatic secreted complement C3 contributes to circulating C3 levels in humans.

The majority of complement protein C3 is synthesized by the liver, but many other cell types produce small amounts of functionally active C3. The overall contribution of such extrahepatic C3 production to the total circulating C3 level is unknown. Bone marrow and extrahepatic C3 productions were quantified in bone marrow transplant (BMT) and liver transplant (LT) recipients, respectively, where a mismatch for the C3 allotypes distinguished by the mAb HAV 4-1 had occurred. In the BMT group, donor-derived C3 was detected by ELISA and immunoblotting techniques. It contributed to 0.1 to 2.6% of the total circulating C3 during the immediate post-BMT period in response to inflammatory stimuli. Cell culture and immunostaining techniques demonstrated that monocytes were the source of the C3. By 6 wk following BMT, donor-derived C3 levels had decreased to below the detection limit of the assays. By contrast in the LT group, total extrahepatic C3 levels were higher (3.1-5.7% of the total circulating C3) and remained stable for up to 1 yr post-LT. This study demonstrates that extrahepatic derived C3 forms a larger proportion of the circulating C3 levels than was considered previously and that in the resting state, most of this extrahepatically derived C3 comes from nonmyeloid sources. In addition, monocytes, which in the resting state contribute negligible amounts of C3, have the potential when stimulated to contribute significantly to the total systemic C3 pool. These findings highlight the importance of locally secreted complement proteins.

Antibodies, Monoclonal↗

PubMed1979

Complement C3 and immunoglobulin in inflammatory acne vulgaris.

In patients with moderate to severe inflammatory acne, complement (C3) was detected by immunofluorescence in sixteen early inflammatory acne lesions but in only one of thirteen biopsies of non-inflamed skin from acne sites. C3 deposition occurred particularly in the walls of small dermal blood vessels and at the dermo-epidermal junction. IgM was identified in vessel walls in four of sixteen early lesions. In eight late inflammatory lesions C3 deposition was much less prominent and was present in vessel walls in only two. None of the late lesions showed vascular deposition of IgM. The observations indicate that complement activation occurs in inflammatory acne and it is suggested that this may play a pathogenic role in the inflammation.

Acne Vulgaris↗

PubMed1988

Estimation of postmortem interval based on the third component of complement (C3) cleavage.

To estimate postmortem interval (PMI), the spontaneous conversion of the native third component of complement (C3) to its derived fragments in whole blood was studied by crossed immunoelectrophoresis. C3 cleavages in vitro at different temperatures showed that the incubation of whole blood at a higher temperature led to a faster conversion of beta 1C (native C3) to beta 1A (C3c). In cadaveric blood, we found a significant positive correlation between percentage of C3 cleavage and PMI. From these results, it is possible to estimate PMI from the ratios of C3 cleavage.

Body Temperature↗

PubMed1996

Inherited complement C3 deficiency: reduced C3 mRNA and protein levels in a Laotian kindred.

To determine the molecular basis of complement C3 deficiency in a Laotian kindred, the homozygous C3-deficient male propositus was studied. By ELISA, this individual's serum was determined to contain approximately 4 microg/ml C3 (0.3% of normal). In accord with this result, anti-C3 immunoprecipitation of [35S]-methionine-labeled fibroblasts from this C3D individual revealed pro-C3 of normal size (180,000 Mr), but in significantly reduced amounts (approximately 1% of normal fibroblasts), that was processed and secreted with normal-size alpha- and beta-chains. In addition, C3-specific mRNA of normal size (5.2 kb) but in reduced quantity (approximately 1% of normal) was detected in this individual's fibroblasts by Northern analysis. The nucleotide sequence of the transcriptional initiation site, the promoter, and the IL-1beta/IL-6 cis-regulatory elements of the C3-deficient gene are normal in this C3-deficient individual, indicating that the low C3 mRNA and protein levels are not caused by reduced C3 transcription that is the result of a cis-mutation. Moreover, cDNA sequencing studies revealed no defect in the C3-deficient mRNA, including the areas mutated in four previously characterized C3-deficient patients. These data indicate that (1) C3 protein deficiency in this Laotian patient results from reduced levels of C3-specific mRNA, (2) the small amount of expressed C3 protein is processed and secreted normally from the deficient cells, and (3) the molecular genetic defect(s), although not yet delineated, is different from those described in other C3-deficient individuals, thereby providing additional evidence for numerous mutations that cause inherited C3 deficiency in humans.

Cells, Cultured↗

PubMed1986

A model system for the study of the assembly and regulation of human complement C3 convertase (classical pathway).

The formation of classical C3 convertase of complement and its regulation by C4b-binding protein (C4bp) were studied using two different approaches: (a) the analysis was first carried out in fluid phase; a soluble stabilized C3 proconvertase could be assembled from C4b (or C4b-like C4) and iodine-treated C2 in the presence of Ni2+ ions. Upon activation of this complex by C1s, a C3 convertase C4b(C4b-like C4)-C2a was generated which was able to cleave purified C3. C4bp dissociated both C3 proconvertase and C3 convertase, but its effect was more important on C3 convertase. (b) A model system of phospholipid vesicles has been developed to study the assembly of the C3 convertase on a membrane. Among different phospholipid mixtures tested, P-glycerol/P-choline vesicles were found most effective for C4b binding. Optimal conditions were determined for C4b fixation on these vesicles; bound C4b participated in the formation of a functional membrane-associated C3 convertase. C4bp was found to bind to phospholipid vesicles with a higher affinity than C4b; it was able to dissociate the vesicle-associated C3 convertase.

Buffers↗

PubMed1981

Changes in conglutinin, immunoconglutinin, complement C3 and fibronectin concentrations in cattle acutely infected with Babesia bovis.

Further pathophysiological studies of the hypotensive shock syndrome associated with acute Babesia bovis infection in cattle have demonstrated changes in the plasma concentrations of conglutinin, complement C3, fibronectin and immunoconglutinin. Decreases in the first three components are presumably due to their contribution towards intravascular sludging of infected erythrocytes within the microvascular system during the acute phase of infection. In contrast, the increase in fibronectin and immunoconglutinin in the recovery phase suggests the involvement of these proteins in the reticulo-endothelial clearance of infected or damaged erythrocytes, immune complexes and cryofibrinogen.

Acute Disease↗

PubMed1998

Acute induction of interleukin-6 and biphasic changes of serum complement C3 by carrageenan in mice.

Carrageenan has been widely used as an irritant to evoke inflammation in animals or to selectively deplete macrophages in vivo. Although precise understanding of carrageenan activity is a prerequisite for the experimental use of this polysaccharide, the effects of this agent on host-biological systems are still poorly understood. We investigated the effect of carrageenan on serum concentrations of complement C3 and interleukin (IL)-6, a potent complement-inducing factor. Intraperitoneal administration of carrageenan (4 mg) in mice resulted in an initial fall in serum C3 (70% of control, P < 0.05) between 3 and 6 h, but was followed by a significant rise (180% of the control, P < 0.05) at 24h. Prior to the rise in complement C3, a sharp peak of serum IL-6 was observed at 6h after carrageenan treatment. These results indicate potential of carrageenan to enhance host complement systems, which may be associated with, at least in part, an acute induction of IL-6.

Animals↗

PubMed1993

Pathways of complement (C3) activation in rabbits infected with Trypanosoma evansi.

Immunoelectrophoresis was used to evaluate the pathways of complement (C3) activation with sera from rabbits infected with Trypanosoma evansi. C3 activation via the classical pathway was of a higher magnitude than via the alternative pathway using both the intact parasite and soluble parasite antigens. This observation indicates that although the two pathways may be activated during infection, the activation of the classical pathway may be dominant in a host's response to a T. evansi infection during both the early and late stages of the disease.

Animals↗

PubMed1993

Immunoglobulin (IgG and IgA) and complement (C3) concentrations in uterine secretion following an intrauterine challenge of Streptococcus zooepidemicus in mares susceptible to versus resistant to chronic uterine infection.

The validity of measuring concentrations of immunoglobulins in undiluted uterine secretions was established. The concentrations of IgG, IgA, and cleavage factor C3 of the complement system in uterine secretions were compared in mares with different resistance to chronic uterine infection (CUI). The uteri of mares susceptible (n = 6) and resistant to CUI (n = 5) were inoculated with 5 x 10(6) Streptococcus zooepidemicus when the mares were in estrus. Uterine secretions were sampled, and sampling was immediately followed by a uterine lavage at 5 and 24 h after bacterial inoculation. During a subsequent estrus, bacterial inoculation of the uterus was repeated, and samples were taken from the mares 12 and 36 h later. The fraction of uterine secretion in each uterine washing was determined by dividing the protein concentration of the undiluted uterine secretion by the protein concentration of the corresponding uterine washing. There was a significant correlation between measured concentrations of immunoglobulins in uterine secretions and calculated concentrations in the uterine washings (p < 0.05). Concentrations of IgG and C3 in uterine secretions declined similarly in both susceptible and resistant mares during the first 24 h after bacterial inoculation (p < 0.04). In contrast to the susceptible group, which showed a continuous decline at 36 h, resistant mares demonstrated an increased concentration of both IgG and C3 at this time. Concentrations of IgA did not differ between susceptible and resistant mares. It was concluded that the described method of sampling uterine secretions was useful for analyzing IgG and IgA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗