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PubMed2000

Complement C3 cleavage and cytokines interleukin-1beta and tumor necrosis factor-alpha in otitis media with effusion.

OBJECTIVES: To analyze whether complement C3a anaphylatoxin, other C3 fragments, interleukin-1beta (IL-1beta), or tumor necrosis factor-alpha (TNF-alpha) contributes to inflammation in chronic otitis media with effusion (OME). METHODS: The amount of C3a was measured by enzyme-linked immunoassay. Further breakdown of C3 was analyzed by Western blotting. IL-1beta and TNF-alpha concentrations were measured by radioimmunoassay. Bacteria were analyzed by culture and polymerase chain reaction. RESULTS: Highly elevated levels of C3a and other C3 cleavage fragments were found in all middle ear effusion (MEE) samples. The mean values (+/- SEM, n = 26) for C3a, IL-1beta, and TNF-alpha were 5,973 +/- 1,124 ng/mL, 1,043 +/- 490 pg/mL, and 79 +/- 14.3 pg/mL, respectively. Comparison to an average C3 level of 555 (+/-108) microg/mL indicated that at least 40.5% +/- 6% of total C3 had become activated within the MEE. C3a concentrations were higher in the group in which the effusion had been present in the middle ear for a prolonged period (> or =4 mo) (P = .04). Children with multiple tube insertions had higher C3 (P = .006) and TNF-alpha (P = .04) concentrations in their MEE samples than those receiving their first tubes. C3 and C3a concentrations in MEE correlated to each other (correlation coefficient [r] = 0.513, P = .0056), as did concentrations of IL-1beta and TNF-alpha (r = 0.7016, P < .0001). No significant correlation was found between complement C3 or C3a levels and IL-1beta, TNF-alpha, or bacterial growth. CONCLUSIONS: Highly elevated levels of C3a in MEE indicate ongoing complement activation, which is stronger than in almost any other disease demonstrated previously. Elevated C3a levels contribute to chemotactic and inflammatory potential in the MEE and correlate with the chronicity of the disease.

Blotting, Western↗
PubMed1986

Complement (C3) metabolism in systemic lupus erythematosus in relation to the disease course.

Metabolic turnover studies of complement components (C3) provide a direct insight into the dynamics of the complement regulation (synthesis and catabolism). To obtain information about the role of the complement system in relation to the disease course in patients with systemic lupus erythematosus (SLE), a prospective study was performed. The results of the C3 turnover studies were also correlated to the complement levels (C3) and to the presence of C3 conversion products (C3d) in circulation. In nearly all SLE patients (in 21 of the 26 metabolic turnover studies) a C3 hypercatabolism was found, with a quantitative difference depending on the disease phase. In the period preceding an exacerbation an impaired C3 synthesis was observed (in three of the four studies), in contrast to SLE patients in stable disease phase where in one case only a decrease C3 synthesis was calculated (1 out of 15 observations). A linear correlation was found between the serum C3-levels and the ratio of C3d/C3, suggesting that both serologic parameters are quantitatively indicative for C3 hypercatabolism. The study shows that in all SLE patients, irrespective of the disease stage, an increased C3 consumption is found, which supports the concept that a chronic inflammatory process is constantly present.

Adult↗
PubMedDate not supplied

Serum C3 complement concentrations correlate with liver function in patients with liver cirrhosis.

BACKGROUND/AIMS: The aim of this study was to investigate whether C3 and C4 serum complement concentrations have prognostic relevance for patients with liver cirrhosis. METHODOLOGY: Serum complement concentrations of C3 and C4 were measured in 69 patients with liver cirrhosis and correlated with the Child-Pugh score. RESULTS: C3 concentrations were 1.06+/-0.21 g/L in patients with Child-Pugh A liver cirrhosis and significantly lower in Child-Pugh B (0.78+/-0.24 g/L) and even lower Child-Pugh C (0.49+/-0.14 g/L) (p=0.006 B vs. A, p<0.001 C vs. B). Patients with consecutive hepatorenal syndrome (HRS) had the lowest C3 concentrations (0.44+/-0.05 g/L (Child-Pugh C +HRS) vs. 0.54+/-0.06g/dL (Child-Pugh C -HRS); p<0.05). C4 concentrations were 0.21+/-0.08 in Child-Pugh A and significantly lower in Child-Pugh B (0.11+/-0.04) and Child-Pugh C (0.09+/-0.04) patients (p<0.001). There was a negative correlation between C3 (r = -0.81, p<0.001) and C4 (r = -0.51, p<0.05) concentrations and the Child-Pugh score. CONCLUSIONS: Serum complement concentrations of C3 and C4 correlate negatively with the Child-Pugh score in patients with liver cirrhosis. C3 concentrations are lower in those Child-Pugh C cirrhosis patients with consecutive development of HRS.

Bacterial Infections↗
PubMedDate not supplied

Complement C3: a molecular mosaic of binding sites.

Many of the biological activities of the complement system are mediated by C3, the third complement component, and its proteolytic fragments. At the same time, several of the molecules which regulate complement activation target their action at the C3 molecule. Accordingly, the C3 molecule is equipped with multiple binding sites for at least 14 other complement or complement-related proteins. As described in this review, major progress has been made recently in the identification of the C3 binding sites and the residues involved. Yet this has exposed only the "tip of the iceberg". A novel technique which may facilitate the elucidation of the active sites in C3 is presented. Finally, based on the current knowledge on the C3 molecule, a hypothetical model of the molecular organization of this molecule and its binding sites is presented.

Animals↗
PubMed1992

Levels of complement receptor type one (CR1, CD35) on erythrocytes, circulating immune complexes and complement C3 split products C3d and C3c are not changed by short-term physical exercise or training.

The effect of heavy short-term physical exercise on the levels of complement receptor type one (CR1, CD35) on erythrocytes, the concentrations of circulating immune complexes (IC), and the complement C3 split products C3c and C3d were examined in young healthy males. Fourteen untrained volunteers underwent a 60-min bicycle exercise test at 75% of maximal oxygen uptake (VO2max). Six of the volunteers were exercised twice with an interval of at least one month. Before the second bicycle test they received oral indomethacin. With an interval of at least 1 week, 6 also went through a 60-min back-muscle exercise at up to 30% of VO2max. Blood samples were collected before and during the last few minutes of exercise as well as 2 h and 24 h afterwards. The same parameters were examined once in 29 highly trained racing cyclists. There were no consistent or significant exercise-induced changes in the levels of erythrocyte CR1, circulating IC, C3c nor C3d as measured by an enzyme-linked immunosorbent assay, polyethylene glycol precipitation complement consumption method, and by intermediate gel rocket immunoelectrophoresis, respectively. Neither did these parameters differ from controls in the highly trained group. The results indicate that CR1 on erythrocytes, circulating immune complexes and complement cleavage products C3c and C3d in healthy subjects remain unaffected by short-term heavy physical activity and training.

Adult↗
PubMed1988

Complement C3 and C5 degradation products during hemodialysis treatment: study of an index of membrane bioincompatibility.

In 10 hemodialyses (HD) with cuprophan (CU) and 10 with polyacrylonitrile (PAN), signs of complement activation were investigated by following arterial and venous levels of C3a, C3d and C5a, in order to propose a marker of bioincompatibility. Despite large individual variabilities, significant increases of these molecules were detected at t 20 min, particularly with CU device in the artery and more marked in the vein except for C3d with PAN. During the later stage of HD, while C3a and C5a levels gradually declined, but remained significantly higher than t 0 in all the patients treated with CU, the C3d concentration reached a plateau suggesting a continuous complement activation throughout HD. HD using PAN membranes were associated with a lower C3a, C3d and C5a generation and fewer dialyses generating these products. In some dialyses the higher arterial level of these molecules suggests an extra-dialyzer complement activation especially with PAN membrane. Although C5a venous levels appeared to be the more significant index of complement activation, for clinical purposes we propose the C3d arterial measurement as a reliable, non-expensive and technically simple indicator of membrane intolerance.

Acrylic Resins↗
PubMed1984

Development and clinical application of electroimmunoassays for the direct quantification of the complement C3 split products C3c and C3d.

The present report describes the development of electroimmunoassays for the direct quantification of C3d and C3c, split products of the third complement factor (C3). Both methods were developed as rocket immunoelectrophoreses, using two antibody preparations with specificities against the C and D epitopes on C3. A stable calibrator preparation for C3c and C3d was produced by autolytic cleavage of C3. Investigations of patients with anaphylactic reactions or chronic immunological disorders showed that quantification of C3c and C3d in plasma by these methods reflected the degree and rate of complement activation. C3d determination was found to be the most sensitive and reliable indicator of C activation, both during acute and chronic activation since C3c is eliminated considerably faster from the circulation than C3d (estimated half lives of 2 h and 4 h, respectively). Treatment of rheumatoid arthritis patients with prednisolone caused a prompt decrease of plasma C3d values, indicating that the clinical effect may be due to inhibition of complement activation.

Antibody Specificity↗
PubMed2003

Serum alpha1-antitrypsin but not complement C3 and C4 predicts chronic inflammation in hemodialysis patients.

BACKGROUND: We studied whether predialysis serum levels of positive acute phase markers such as alpha1-antitrypsin (AT), and complement components C3 and C4 could identify the presence of chronic inflammation in maintenance hemodialysis (HD) patients. METHODS/RESULTS: In 103 stable HD patients, AT directly correlated with C-reactive protein (CRP) (P < 0.005), alpha1 acid-glycoprotein (P < 0.005), fibrinogen ( P < 0.05), lipoprotein (a) (P < 0.01) and von Willebrand factor antigen (P < 0.05), while C3 and C4 were not related to any of these inflammatory markers. In the patients with elevated CRP and hypoalbuminemia, the mean AT value of 1.74 +/- 0.50 g/L was higher (P = 0.008) than that of 1.38 +/- 0.27g/L in the subjects with normal CRP and albumin. Using the above cut-off levels, the positive and negative predictive values of AT on the presence of severe inflammation were 0.86 and 0.62, respectively, and the sensitivity and specificity were 86% and 73%, respectively. CONCLUSION: Serum AT levels above 1.74 g/L and below 1.38 g/L may select the HD patients with severe inflammation from those without. Measurements of C3 and C4 are not helpful in this situation.

Adolescent↗
PubMed1982

Measurement of the complement C3 breakdown product C3d by rocket immunoelectrophoresis.

A method is described for quantitative measurement of C3d in plasma and synovial fluid by the use of rocket immunoelectrophoresis after fractionation of the samples with 22% polyethylene glycol. This method has the advantage over radial immunodiffusion of being more sensitive (detecting C3d down to 3 mg/l) whilst proving equally reproducible. Investigations indicate that the collection of blood samples in EDTA prevents in vitro activation of C3 even after storage for up to 6 h at room temperature and up to 12 weeks at -70 degrees C. Elevated levels of C3d were found in a proportion of SLE and RA plasma samples and in synovial fluids from patients with inflammatory synovitis. It is suggested that C3 conversion in vivo may be assessed by measurement of C3d by the technique described, and when used in conjunction with measurements of complement components and immune complexes, offers a means of investigating complement catabolism by the classical and alternative pathways.

Animals↗
PubMed2001

Intraglomerular synthesis of complement C3 and its activation products in IgA nephropathy.

BACKGROUND: Complement activation is thought to be pathologically important in IgA nephropathy (IgAN). Although C3 deposition in the mesangium is found in IgAN, the origin of C3 is not clear. We recently demonstrated intraglomerular C3 synthesis in the human kidney; however, the activation and pathological role of locally synthesized C3 remains unclear. Here we performed nonradioactive in situ hybridization for C3 mRNA and immunohistochemistry for C3 and its activation products, such as C3d and membrane attack complex (MAC), to determine whether locally produced C3 in glomeruli was activated in IgA nephropathy. METHODS: Renal samples from 14 patients with IgAN and 5 with minimal change nephrotic syndrome (MCNS) were examined. Uninvolved portions of surgically removed kidneys with tumors served as normal controls. RESULTS: C3 mRNA was not detected in glomeruli in control tissue and MCNS, but was strongly expressed in resident glomerular cells of IgAN, including mesangial cells, glomerular epithelial cells and the cells of Bowman's capsule. Examination of serial sections disclosed that more than 70% of cells positive for C3 mRNA were also stained for C3 protein, C3d, and MAC. Double staining for in situ hybridization and immunohistochemistry also revealed that those C3 mRNA signals were present in intraglomerular cells positive for C3. The expression of C3 mRNA and MAC in glomeruli correlated significantly with the degree of mesangial matrix expansion. CONCLUSIONS: Our results demonstrated that locally synthesized C3 is activated in the glomeruli of IgAN and that its expression correlated with the severity of mesangial matrix expansion. These findings suggest that activation of C3 may be involved in tissue injury in IgAN through the formation of membrane attack complex.

Adolescent↗
PubMedDate not supplied

[Levels of total hemolytic complement, C3, C4 and antibodies against the myocardium in rheumatic fever].

The levels of the hemolytic complement (UH 50%), C3, C4 and the antibodies against myocardium and against the antigenic fractions of myocardium precipitated with ammonium sulphate were studied in 8 patients with active rehumatic fever (ARF), 28 with inactive rheumatic fever (IRF) and 26 people without cardiopaties (NI). The UH 50% was low in 2 out of 36 patients with rheumatic fever (RF). C3 was normal and C4 low in 12.5% of the ARF patients. C3 had subnormal values in 25% and C4 in 33% of IRF patients, this last value had a stadistic significant decrease with respect to the values of C4 in normal people. The 36 patients with RF had antibodies against the myocardium and also against the heart antigenic fractions precipitated with 10% ammonium sulphate. 11.5% of the normal group had anti-myocardial antibodies and none had antibodies against the fractions. The levels of anti-streptolysin-O and C-reactive protein were higher in the ARF group than in the patients with IRF or the normal people. The participation of the hemolytic complement, the anti-myocardium antibodies, the anti-streptococcus antibodies and the cytophilic activity in the etiopathogeny of rheumatic fever is discussed.

Autoantibodies↗
PubMed2002

Complement C3 activation is required for antiphospholipid antibody-induced fetal loss.

The antiphospholipid syndrome (APS) is characterized by recurrent fetal loss, vascular thrombosis, and thrombocytopenia occurring in the presence of antiphospholipid (aPL) antibodies. The pathogenesis of fetal loss and tissue injury in APS is incompletely understood, but is thought to involve platelet and endothelial cell activation as well as procoagulant effects of aPL antibodies acting directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation in the placenta leads to fetal death in utero. We hypothesized that aPL antibodies activate complement in the placenta, generating split products that mediate placental injury and lead to fetal loss and growth retardation. To test this hypothesis, we used a murine model of APS in which pregnant mice are injected with human IgG containing aPL antibodies. We found that inhibition of the complement cascade in vivo, using the C3 convertase inhibitor complement receptor 1-related gene/protein y (Crry)-Ig, blocks fetal loss and growth retardation. Furthermore, mice deficient in complement C3 were resistant to fetal injury induced by aPL antibodies. While antigenic epitopes recognized by aPL antibodies are important in the pathogenesis of APS, our data show that in vivo complement activation is required for aPL antibody-induced fetal loss and growth retardation.

Animals↗
PubMed2001

Molecular analysis of hereditary deficiency of the third component of complement (C3) in two sisters.

We report two sisters with hereditary deficiency of the third complement component (C3) and a homozygous mutation at C3303G (Tyr1081Stop) of the gene. They developed systemic lupus erythematosus-like symptoms during adolescence. Their C3 were not detected in serum immunochemically. Their mother and a brother had half of the normal C3 levels and a heterozygous mutation in the same position. Western blot analysis of murine L-cells transfected with the mutant C3 cDNA showed no C3 protein, however mRNA was detectable using reverse-transcriptase polymerase chain reaction. To the best of our knowledge, this is the first report of C3 deficiency due to a stop codon in the gene.

Adolescent↗
PubMed2003

Association of serum complement (C3, C4) and immunoglobulin (IgG, IgM) levels with hormone replacement therapy in healthy post-menopausal women.

BACKGROUND: Recently published data suggest that hormone replacement therapy (HRT) may increase cardiovascular risk during the early months of therapy. Activation of the immune system is known to be involved in several types of cardiovascular disease. In this cross-sectional study, serum C3, C4, IgG and IgM levels were evaluated in healthy post-menopausal women receiving two different short-term HRT regimens, and in untreated women. METHODS: Serum C3, C4, IgM and IgG levels were assessed in 18 women receiving transdermal 17beta-estradiol (50 micro g/day) + continuous oral medroxyprogesterone acetate (MPA; 2.5 mg/day), in 56 women taking oral conjugated equine estrogen (CEE; 0.625 mg/day) + continuous MPA, and in 80 control women not receiving HRT. RESULTS: The mean serum C3 level was significantly higher in women using oral CEE + MPA than in women receiving transdermal 17beta-estradiol + MPA, and those not on HRT (P = 0.02 and P < 0.001 respectively). Furthermore, women taking oral CEE + MPA had significantly higher mean levels of C4 compared with untreated women (P < 0.01). IgG and IgM levels were similar among women either of the two HRT regimens and between women not on HRT. CONCLUSIONS: Oral HRT may be involved in the development of cardiovascular disease through inflammatory mechanisms, as suggested by increased serum levels of C3 and C4.

Adult↗