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Complement component C3 prepared by the method of Tack & Prahl [(1976) Biochemistry 15, 4513-4521] was found to contain the following trace contaminants: C3b, haemolytically inactive C3 with intact alpha- and beta-chains (C3u) and degraded C3 (apparent mol.wt. 140000) with an intact beta-chain but with a fragmented alpha-chain. The proportion of C3u in the C3 is increased on standing and by freezing and thawing. These contaminants could be separated from each other and from native C3 by chromatography on sulphated Sepharose. They have been characterized by their susceptibility to C3b inactivator in the presence of beta 1H, their ability to be cleaved by C3 convertase and their ability to form alternative-pathway C3 convertase in solution. Incubation of C3b or C3u with beta 1H and C3b inactivator resulted in cleavage of the C3 species; the alpha'-chain of C3b was cleaved to fragments of apparent mol.wts. 67000 and 43000, the alpha-chain of C3u was cleaved to fragments of apparent mol.wt. 75000 and 43000. Native C3 and degraded C3 were unaffected by incubation with beta 1H and C3b inactivator. C3u, unlike C3, was not cleaved to C3b by the classical- or alternative-pathway C3 convertase in solution. When C3b or C3 was incubated with factors B and D, forming C3 convertase, the initial rate of factor-B cleavage was several order of magnitude lower in the presence of C3 than in the presence of C3b. The slow rate observed for C3 could be decreased by preincubation with beta 1H and C3b inactivator or by rechromatography of the C3. The degraded C3 did not support factor-B cleavage by factor D.
In the present study, we examined (i) whether C3 (complement C3) was an independent marker of prevalent CHD (coronary heart disease), and (ii) which preferential associations existed between C3 and some cardiovascular risk factors when jointly analysed with CRP (C-reactive protein) and fibrinogen. In a cohort of 756 unselected adults, 39% of whom had the metabolic syndrome, C3 and other risk variables were evaluated in a cross-sectional manner. In a logistic regression model for the likelihood of CHD, a significant OR (odds ratio) of 3.5 [95% CI (confidence intervals), 1.27 and 9.62)] for C3 was obtained after adjustment for smoking status, TC (total cholesterol) and usage of statins. A similar model, also comprising systolic blood pressure, with a cut-off point of >or=1.6 g/l C3 exhibited a 1.9-fold risk (95% CI, 1.01 and 3.58) compared with individuals below the cut-off point. Both analyses displayed an adjusted OR of 1.37 for each S.D. increment in C3. The significant relationship of C3 with a likelihood of CHD also proved to be independent of CRP. In multiple linear regression models, associations were tested for each acute-phase protein with measures of obesity, fasting insulin, triacylglycerols (triglycerides), TC, HDL (high-density lipoprotein)-cholesterol, physical activity, smoking status, diagnosis of metabolic syndrome and family income. When both genders were combined, C3 was independently associated with serum triacylglycerols, waist circumference, BMI (body mass index) and TC. CRP was independently associated with waist circumference, TC, family income (inversely) and physical activity, and fibrinogen with BMI, TC, smoking status and metabolic syndrome. In summary, elevated levels of complement C3 are associated with an increased likelihood of CHD independent of standard risk factors and regardless of the presence of acute coronary events, suggesting that C3 might be actively involved in coronary atherothrombosis. Unlike CRP and fibrinogen, C3 was preferentially associated with waist girth and serum triacylglycerols.
The clinical differential of chronic prostatitis and psycho-vegetative urogenital syndrome with objective laboratory tests is very difficult. 265 ejaculates with possible chronic prostatitis were bacteriologically examined (including the search for STD agents). To verify an inflammatory process in the prostate and adnexae, we tested the C3 complement, coeruloplasmin and PMN-elastase levels in ejaculate. In addition, semiquantitative leucocyte counts in stained smears of the ejaculate were carried out. 185 of 265 patients had C3 complement below detection levels or in the normal range excluding inflammation of prostate or adnexae. 16.8% of the C3-negative ejaculates showed an elevated PMN-elastase level associated with urethritis anterior and/or posterior caused by STD agents. 80 patients showed elevated C3 levels; 38.8% with elevated coeruloplasmin and PMN-elastase levels. The semiquantitative leucocyte count in the stained smear proved the least sensitive method for verifying an inflammation. Enterococci (55.3%), Mycoplasma (18.8%) and Escherichia coli (16.5) were the dominant pathogens of chronic prostatitis present in number of 10(2) cfu/ml or greater than 10(5) cfu/ml. A correlation to the intensity of the inflammation was not found. These results show how important it is to realise a complete bacteriological examination as well as to determine the C3 complement, coeruloplasmin and PMN elastase.
A cloned gene-specific probe for human complement (C3) was hybridized to DNA samples digested with various restriction endonucleases. The C3 probe detects one restriction fragment length polymorphism (RFLP) that occurs frequently in the French population when DNAs are digested with Sac I. The corresponding DNA alleles can be readily used in linkage analysis of loci on chromosome 19, and such a polymorphism can be followed through myotonic dystrophy families.
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One single high dose of dexamethasone (0.5 mg/kg body weight) was administered to a mother, before tests started into the effects of such approach upon the serum total complement (CH 50) and C-3 levels in the mother's umbilical cord blood. Neither CH 50 nor C-3 complement had declined with significance 48 hours from steroid administration. Significant reduction was observed only in cases in which six hours elapsed between steroid administration and childbirth.
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BACKGROUND: The interrelationship between human airway epithelium and complement proteins may affect airway defence, airway function, and airway epithelial integrity. A study was undertaken to determine (1) whether unstimulated human bronchial epithelium generates complement proteins and expresses cell membrane complement inhibitory proteins (CIP) and (2) whether stimulation by proinflammatory cytokines affects the generation of complement and expression of cell membrane CIP by these cells. METHODS: Human bronchial epithelium cell line BEAS-2B was cultured in a serum-free medium. Cells were incubated with and without proinflammatory cytokines to assess unstimulated and stimulated generation of complement C3, C1q and C5 (by ELISA), and to examine the expression of cell membrane CIP decay accelerating factor (DAF; CD55), membrane cofactor protein (MCP; CD46), and CD59 (protectin) by flow cytometry analysis. RESULTS: Unstimulated human bronchial epithelial cell line BEAS-2B in serum-free medium generates complement C3 (mean 32 ng/10(6) cells/72 h, range 18-52) but not C1q and C5, and expresses cell membrane DAF, MCP, and CD59. Interleukin (IL)-1alpha (100 U/ml/72 h) and tumour necrosis factor (TNF-alpha; 1000 U/ml/72 h) increased generation of C3 up to a mean of 78% and 138%, respectively, above C3 generation by unstimulated cells. DAF was the only cell membrane CIP affected by cytokine stimulation. Interferon (IFN)-gamma (10 U/ml/72 h) and TNF-alpha (1000 U/ml/72 h) increased DAF expression up to a mean of 116% and 45%, respectively, above that in unstimulated cells. MCP and CD59 expression was not consistently affected by IL-1alpha, TNF-alpha, or IFN-gamma. CONCLUSIONS: Local generation of complement C3 and expression of cell membrane CIP by human bronchial epithelium and its modulation by proinflammatory cytokines might be an additional regulatory mechanism of local airway defence and may affect airway function and epithelial integrity in health and disease.
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We report two unusual cases in which mesangiocapillary glomerulonephritis occurred in association with meningococcal infection. C3 nephritic factor, an autoantibody to alternate pathway C3 convertase, was present. Low serum complement C3 and C5 levels were also noted. The depressed complement levels, in conjunction with terminal complement complexes at the upper limit of normal, suggest activation of the early and late complement cascade. We suggest that children presenting with meningococcal infection should have a regular urine examination, as well as full complement measurements performed, in view of the association with hypocomplementaemic mesangiocapillary glomerulonephritis. Similarly, prophylactic penicillin should be prescribed for patients with mesangiocapillary glomerulonephritis and persistently low C5 levels to prevent meningococcal complications.
Complement components have a role in various neurological disorders. Complement C3 can be measured by immunochemical methods, but only radioimmunoassays and electroimmunodiffusion assays (EIDs) are sufficiently sensitive to be applied to biological fluids in which the C3 concentration is low, especially cerebrospinal fluid (CSF). We report a sandwich-type time-resolved immunofluorometric assay (TR-IFMA) for C3 in CSF. The linearity (0.7-3650 micrograms/L) and intra- (CV < 4.8%) and inter-assay (CV < 10.9%) precision were satisfactory and the results agreed with those of EID. The assay is extremely sensitive (< 1 microgram/L) and its analytical range is large and well suited to clinical applications. This simple TR-IFMA is thus a nonisotopic alternative to radioimmunoassay for the quantification of complement C3 in CSF.
OBJECTIVE: To determine the value of amniotic fluid (AF) complement C3 as a marker of intra-amniotic infection and to compare complement C3 with other rapid markers of intra-amniotic infection. METHODS: One hundred four women with singleton gestations, in preterm labor with intact membranes, at 23-35 weeks' gestation underwent transabdominal amniocentesis. Amniotic fluid was analyzed for white blood cell (WBC) count, lactate dehydrogenase (LDH), glucose, Gram stain, and complement C3. Cultures for aerobes, anaerobes, and mycoplasma species also were performed. The median values of complement C3, WBC, LDH, and glucose were compared between the culture-positive and -negative groups. Complement C3 was compared with WBC count, LDH, glucose, and Gram stain for sensitivity, specificity, positive and negative predictive values, and accuracy in the prediction of a positive AF culture. Descriptive statistics, receiver operating characteristic curve, Fisher exact test, and Wilcoxon rank-sum test were used for analysis. RESULTS: The prevalence of positive cultures was 11.5% (12 of 104). The culture-positive group had a significantly higher median C3 (7.0 mg/dL) than the median C3 (3.0 mg/dL) of the culture-negative group (P < .001). Also, the median values of WBC (1120.5 cells/mm3) and LDH (2697 U/L) were significantly higher and the median glucose (6.5 mg/dL) was significantly lower among women with positive AF cultures than among women with negative AF cultures (WBC=1 cell/mm3; LDH=165 U/L; glucose=45 mg/dL; P < .001). Eleven of the 12 culture-positive cases had a C3 of 5 mg/dL or more, whereas four of the 92 culture-negative cases had a C3 of 5 mg/dL (P < .001). Nine of the 12 culture-positive cases but none of the 92 culture-negative cases had a C3 of 6 mg/dL or more (P < .001). The relative risks of a positive AF culture were 65.27 (95% confidence interval [CI] 9.08, 469.27) and 31.67 (95% CI 10.40, 96.43) times greater among women with AF complement C3 levels of 5 and 6 mg/dL or more, respectively. Depending on the cutoff point used, complement C3 had similar or higher sensitivity, specificity, positive predictive value, and negative predictive value for intra-amniotic infection when compared with WBC count, LDH, glucose and Gram stain. CONCLUSION: Amniotic fluid complement C3 has value in the diagnosis of intra-amniotic infection in preterm labor with intact membranes. Complement C3 is available readily and compares favorably with other rapid markers of AF infection. This study supports the general concept of fetal inflammatory response to microbial invasion of AF.
Activation of the complement cascade contributes to brain injury after intracerebral hemorrhage (ICH). However, a recent study found that complement C5 deficient mice had enhanced ICH-induced brain injury. The present study, therefore, investigated the role of complement C3 (which is upstream from C5) in ICH. Male complement C3 deficient and sufficient mice had an intracerebral infusion of 30-muL autologous whole blood. The mice were killed and the brains were sampled for edema, Western blotting, immunohistochemistry and histologic analysis. Behavioral tests including forelimb use asymmetry test and corner turn were also performed before and after ICH. Compared to complement C3 sufficient mice, C3 deficient mice had less brain edema, lower hemeoxygenase-1 levels, less microglia activation and neutrophil infiltration around the clot after ICH. In addition, the C3-deficient mice had less ICH-induced forelimb use asymmetry deficits compared with C3-sufficient mice. These results suggest complement activation may affect heme metabolism and the inflammatory response after ICH suggesting that complement C3 is an important factor causing ICH-induced brain injury.
The third component of complement (C3) is an important mediator of inflammation. Murine and human genomic cosmid clones were isolated, characterized and sequenced 5' to the complement C3 gene transcriptional initiation sites to determine cis elements that participate in constitutive and regulated C3 gene expression. The murine and human 5' flanking regions are 51% identical overall, with positions -36 to -1 and -146 to -68 showing 80% identity. Four TATA boxes were identified upstream of the murine transcriptional initiation site, but deletion and transfection analysis using reporter gene constructs in HepG2 cells indicated that only the TATA element at position -30, together with sequences -395 to -111, are essential for constitutive expression of murine C3 in hepatocytes. Deletion analysis also suggested that sequences between -1457 and -800 contain regulatory elements that are involved in suppressing basal expression. Sequences between -90 to -41 confer both enhancer activity and interleukin-1/-6 (IL-1/IL-6)-responsiveness. Mutation analyses showed that both sequences between -88 and -83 and -77 to -72 are essential for enhancer activity and responsiveness to IL-1, but only sequences between -88 and -83 are necessary for IL-6-responsiveness. A gel-retardation assay showed that several nucleoproteins, perhaps of the C/EBP family, from HepG2 cells bound to sequences between -88 to -83. Collectively, these results localize cis-acting elements involved in constitutive and IL-1/IL-6-regulated murine C3 gene expression and provide evidence for specific transacting factors.
Complement C3 deposition around lesions is an early event in the inflammation of acne vulgaris. The aims of this study were to determine the relationship between the capacity of individual comedones to cleave complement C3 and their microbial flora. The contents of 48 open comedones were expressed from the upper back of acne vulgaris patients and each comedo was homogenized individually and assayed for microbial content and capacity to induce cleavage of complement C3 in an in vitro assay system. An association between Propionibacterium population size and extent of C3 cleavage was found, but Staphylococcus and Pityrosporum population sizes did not appear to have an appreciable influence. A strong association between the weight of expressed material and C3 cleavage was apparent, irrespective of microbial population size. This observation suggests that comedones contain non-microbial material having the capacity to induce complement cleavage and hence initiate inflammation.
The major Epstein-Barr virus (EBV) envelope glycoprotein, gp350, was purified from the B95-8 cell line and analyzed for its ability to mediate virus attachment to the isolated EBV/C3d receptor (CR2) of human B lymphocytes. Purified gp350 and EBV, but not cytomegalovirus, exhibited dose-dependent binding to purified CR2 in dot blot immunoassays. Binding was inhibited by certain monoclonal antibodies to CR2 and to gp350. Liposomes bearing incorporated gp350 bound to CR2-positive B-cell lines but not to CR2-negative lines. Liposome binding was also inhibited by the OKB7 anti-CR2 monoclonal antibody. A computer-generated comparison of the deduced gp350 amino acid sequence with that of the human C3d complement fragment revealed two regions of significant primary sequence homology, a finding which suggests that a common region on these two unrelated proteins may be involved in CR2 binding.
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