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PubMed2003

Complement C3 F and BF S allotypes are risk factors for Chagas disease cardiomyopathy.

The heterogeneity in the clinical expression of Chagas disease gives strong evidences for the involvement of genetic factors on its pathogenesis. Several studies have indicated different markers of genetic susceptibility to Chagas cardiomyopathy. In the present study, we present evidence of association between complement C3 and BF allotypes, and the susceptibility to Chagas disease and the development of cardiomyopathy. C3, BF, C4A, C4B and C2 polymorphism were determined in 100 seropositive Chagasic patients [cardiomyopathic (CARD), n = 57; asymptomatic indetermined (IND), n = 43] and in 100 non-related seronegative healthy controls. Patients and controls were matched according to their ethnic and geographical origin. A significantly increased frequency of C3F was observed in patients with the CARD form (8/57 14.03%), when compared with those presenting the IND form (0/43, 0%; RR 7.0) and with the healthy controls (5/100, 5%; RR 3.1). A negative association of the BF S allotype was observed in the CARD patients (19/57 33.33%) and in the Chagas total (38/100 38.0%), when compared with the controls (55/100, 55.0%; RR 0.4). All other C3, BF, C4A, C4B and C2 alleles showed no significant differences. These results suggest the allele C3F as a susceptible marker for the progression of the CARD form. On the other hand, BF S may represent a protective role against severe CARD disease. These results corroborate the importance of the alternative pathway in Trypanosoma cruzi infection and indicate possible genetic markers of Chagas cardiomyopathy.

Adult↗
PubMed1985

Limited proteolysis of a chemically modified third component of human complement, C3, by cathepsin G of human leukocytes.

We have investigated the limited proteolysis of the third component of complement, C3, by a human leukocyte protease, cathepsin G, by using a chemically modified C3, which was prepared by treatment of C3 with methylamine and a fluorescent thiol reagent, N-(dimethylamino-4-methylcoumarinyl)-maleimide (DACM) and was thus named DACM-C3me. Although native C3 was hardly cleaved by cathepsin G, DACM-C3me was cleaved by cathepsin G into three major fragments, which were termed C3c-G (150,000 daltons, 150 kd), C3d-G (25 kd), and C3a-G (10 kd). C3c-G was composed of four disulfide-linked polypeptide chains of 75 kd, 35 kd, and two 25 kd. C3d-G and C3a-G were single-chain fragments derived from the alpha chain. The N-terminal sequence of C3d-G was determined as Thr-Glu-Asp-Ala-Val-, suggesting that cathepsin G released C3d-G by cleaving a Met-Thr peptide bond which is located at 19 residues toward the N-terminal from the cysteinyl residue forming an internal thiolester linkage in native C3. C3d-G, like C3d-K (a C3d fragment produced by the action of plasma kallikrein), was found to have bioactivities such as leukocytosis-inducing and immunosuppressive activities.

Amino Acid Sequence↗
PubMed1994

[Regulation of the complement C3 gene expression: regulatory elements required for cytokine-induced expression].

I isolated murine and human genomic cosmid clones of complement C3 gene and sequenced 5'-flanking region of their transcriptional initiation sites to determine cis-elements that participate in regulation of 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 only the TATA element at position -30 is essential for expression of murine C3 in hepatocytes. Deletion and transfection analysis indicated that sequences -395 to -111 are essential for constitutive expression of C3 gene and suggested that sequences between -1457 and -800 contain regulatory elements that are involved in suppressing basal expression. Mutation analyses showed that sequences between -88 and -83 are essential for IL-6 responsiveness and both sequences between -88 and -83 and -77 to -72 are necessary for enhancer activity and responsiveness to IL-1. These sequences are highly homologous to binding sites of DNA binding proteins, C/EBP and NF-kappa B, respectively. Collectively, these results localize cis-acting elements involved in constitutive and IL-1/IL-6-regulated murine C3 gene expression, and provide implication for specific trans-acting factors.

Animals↗
PubMed1979

Immunoelectron-microscopical localization of in vivo-bound complement C3 in bullous pemphigoid with the use of the peroxidase-antiperoxidase multistep technique.

In vivo-bound complement C3 in bullous pemphigoid was precisely localized by means of the peroxidase-antiperoxidase multistep technique. In the nonbullous lesions peroxidase deposits filled the lamina lucida completely, i.e., the space between lamina densa and the cell membranes of the basal cells. In developed bullae, the reaction product was located both on the lamina densa and on the surface of separated keratinocytes. These findings may indicate that antigen components in bullous pemphigoid are localized almost exclusively within the ground substance which fills the lamina lucida and covers the surface of the basal cells.

Aged↗
PubMed1984

Acute local inflammation alters synthesis, distribution, and catabolism of third component of complement (C3) in rabbits.

In order to evaluate the basis for changes in plasma concentrations of the third component of complement (C3) during inflammation, we injected purified radiolabeled C3 into normal New Zealand White rabbits and into rabbits with turpentine-induced pleurisy. In the normal animals, C3 was distributed between the intravascular compartment (75%) and the extravascular space (25%), with an exchange rate of 1.8 +/- 0.1% of the plasma pool per hour. The fractional catabolic rate (FCR) was 2.7 +/- 0.3% of the C3 plasma pool per hour, the synthesis rate was 1.0 +/- 0.2 mg C3/kg per h, and the plasma concentration was 1.23 +/- 0.3 mg C3/ml. Rabbits with turpentine-induced inflammation showed a shift of the volume of C3 distribution in favor of the extravascular compartment. In addition, the rate by which 125I-C3 was cleared from the circulation increased by 29% and was related to the appearance of 20% of the C3-bound circulating radioactivity in the affected pleural cavity at the zenith of inflammation. The FCR, calculated by measuring urinary excretion of radiolabel, increased by only 9% and was probably related to the C3 degradation that was observed in the pleural fluid during the early stages of inflammation. The plasma C3 concentration reached a peak at 230% of the baseline concentration, owing to an increase in the rate of synthesis by as much as 480%. The latter increase could be blocked by cycloheximide, an inhibitor of protein synthesis. We conclude that the increase of plasma C3 in the acute phase is due to stimulated synthesis, which is partially offset by a rise in FCR and by a shift of protein to the site of inflammation.

Acute Disease↗
PubMed1988

Survival of albumin, IgG, IgM, and complement (C3) in human blood after ingestion by Aedes albopictus and Phlebotomus papatasi.

The levels of albumin, IgG, IgM, and complement (C3) were determined by enzyme-linked immunosorbent assay in Aedes albopictus and Phlebotomus papatasi at regular intervals after feeding on human blood. Albumin disappeared most rapidly; by 48 hr, detectable levels of albumin had decreased 100-fold. In contrast, IgG and IgM survived longer and were still detectable at low levels several days after ingestion. C3 was intermediate in its rate of degradation. In general, serum protein disappearance occurred more rapidly in Ae. albopictus than in Ph. papatasi, despite a larger volume of blood ingested by the former.

Aedes↗
PubMed1985

Blood level of C3 complement component as an aid in the management of acute phase glomerulonephritis.

Ninety-five patients with acute glomerulonephritis, based upon clearly defined pathological criteria, were studied and scored. The scoring was correlated to their levels of blood complement components. Patients with low C3 serum levels had a severe course during the acute phase of their disease, as compared with those with normal C3 serum levels. No such correlation was established with regard to C4 serum levels. It is suggested that C3 serum level may serve as an indicator of the expected severity of the inflammatory process and thus as an aid in the management of patients with acute glomerulonephritis in the initial phase of the disease.

Acute Disease↗
PubMed1988

Biochemical characterization of a factor produced by trypomastigotes of Trypanosoma cruzi that accelerates the decay of complement C3 convertases.

Infective- and vertebrate-stage trypomastigotes of Trypanosoma cruzi resist serum killing by the alternative complement pathway, whereas noninfective vector-stage epimastigotes, from which trypomastigotes derive, are serum-sensitive. This form of developmental preadaption is commonly observed in protozoan parasites, but its mechanisms are poorly understood. We have demonstrated previously that trypomastigotes spontaneously shed molecules which interfere with formation and accelerate the intrinsic decay of complement C3 convertases, a finding which may explain the evasion of complement lysis by trypomastigotes. We now describe the partial purification and characterization of the T. cruzi C3 convertase inhibitor from the supernatant of culture metacyclic and tissue culture trypomastigotes. Decay-accelerating activity for both classical and alternative pathway C3 convertases copurifies on anion-exchange fast protein liquid chromatography and chromatofocusing with 35S-labeled molecules of 87-93 kDa, pI 5.6-5.8. The labeled components are destroyed by papain and retained on concanavalin A-Sepharose, procedures which remove functional decay-accelerating activity from the supernatant. The 87-93-kDa components are immunoprecipitated by sera from patients chronically infected with T. cruzi, but not by antisera to any known regulatory proteins of the human complement cascade. Lytic activity for tissue culture trypomastigotes in chagasic sera is associated with antibody reactivity against the 87-93-kDa 35S-labeled components and with inhibition of decay-accelerating activity. The T. cruzi factor is the first developmentally regulated microbial complement inhibitor to be biochemically characterized.

Animals↗
PubMed1989

Effects of serotonin (5HT) and complement C3 on the synthesis of the surface membrane precursors of adult Schistosoma mansoni.

The syncytial surface epithelium of Schistosoma mansoni plays an important role in immune evasion. This syncytium is covered by an unusual double-membrane complex consisting of an apical plasma membrane (APM) and an overlying envelope (En) that have been shown to have different rates of synthesis and turnover. It has been suggested that discoid bodies (DBs) and multilamellar bodies (MLBs), the major syncytial inclusion bodies of schistosomes, may be the precursors of the APM and En, respectively. In this ultrastructural study, we examined the effects of serotonin (5HT) and complement C3, which have been shown to stimulate synthesis and turnover of the APM and En, respectively, on the synthesis of DBs and MLBs in vitro. With short-time incubations (20 or 40 min), 5HT stimulated the synthesis of the DBs by 2-fold, whereas C3 accelerated synthesis of the MLBs by 2-fold. Furthermore, when microtubules within the cytoplasmic connections between the syncytium and the underlying cell bodies (the site of membrane synthesis) were disrupted with colchicine, the DBs and MLBs synthesized in response to 5HT or C3 accumulated in the cell bodies. This suggests that the transport of the organelles to the syncytium is dependent upon the microtubules but not the signaling mechanism in response to 5HT or C3. These observations also support the suggestion that the DBs and MLBs are synthesized in subsyncytial cell bodies and serve as precursors of the APM and En, respectively. The rapid synthetic response to 5HT and C3 is also consistent with rapid synthesis and turnover of the APM/En, as suggested by previous studies.

Animals↗
PubMed1987

Brefeldin A arrests the intracellular transport of a precursor of complement C3 before its conversion site in rat hepatocytes.

The effects of brefeldin A on intracellular transport and posttranslational modification of complement C3 (C3) were studied in primary culture of rat hepatocytes. In the control culture C3 was synthesized as a precursor (pro-C3), which was processed to the mature form with alpha- and beta-subunits before its discharge into the medium. In the presence of brefeldin A the secretion of C3 was strongly blocked, resulting in accumulation of pro-C3. However, after a prolonged interval the mature form of C3 was finally secreted. The results indicate that brefeldin A impedes translocation of pro-C3 to the Golgi complex where pro-C3 is converted to the mature form, but not its proteolytic processing, in contrast to the effects of monensin and weakly basic amines.

Animals↗
PubMed1981

Instability of immunoglobulins and complement (C3) as predictor of renal allograft rejection.

Ten renal allograft recipients were studied for a period of three months with weekly measurements of serum complement C3 including a baseline value before transplantation. Immunoglobulins (IgG, IgM, IgA) were studied in nine of these patients. Fifteen rejection episodes occurred, three patients losing their graft because of irreversible rejections. The patients were followed for 2.5 years. The degree of of change in serial C3 and immunoglobulin levels from baseline was determined by variability index s. Fourteen out of 15 rejections were preceded by si (C3) greater than .1, one to several weeks in advance. The si (Ig) was useful in week 1 and predicted the rejection missed by si (C3). We conclude that instability of immunoglobulins and complement as measured by s is not only associated with rejections but appears to be a precursor to rejection events. We suggest the following prognostic two-step procedure: (1) Week 1: If either si (C3) or si (Ig) greater than .1, predict rejection. (2) Cases that pass step 1 are monitored by C3 at weekly intervals. As soon as si (C3) greater than .1, predict rejection.

Complement C3↗
PubMed1998

Targeted disruption of the murine gene coding for the third complement component (C3).

Complement is a system of more than 30 proteins found both in plasma and on cell membranes. The complement system has several important functions in the immune response including initiation of inflammation, neutralization and elimination of pathogens, regulation of antibody responses, clearance of immune complexes and disruption of cell membranes. Under certain conditions complement may, however, act as a mediator of deleterious inflammatory reactions and complement activation has been implicated in the pathogenesis of autoimmune disorders, atherosclerosis, neurodegenerative diseases, bioincompatibility reactions and decompression sickness. Using gene targeting, we have generated mice deficient for the third complement component (C3). These mice represent an animal model in which complement activation by any pathway is prevented at an early stage. The C3-deficient mice should be valuable for the study of the roles of the complement system in vivo in a variety of physiological and pathological situations.

Animals↗
PubMed1993

Synthetic Alzheimer amyloid beta/A4 peptides enhance production of complement C3 component by cultured microglial cells.

Primary microglial cultures prepared from newborn mice showed the production and release of the third component of complement (C3). Newly synthesized [35S]methionine-labelled C3 was purified by immunoprecipitation using anti-C3-antibody. C3 was detected by SDS-PAGE and fluoroaraphy of the immunoprecipitated protein from cell lysates as a 195 kDa band, and from the supernatants of cultures as two major bands corresponding to the C3 alpha-chain (125 kDa) and beta-chain (75 kDa), consistent with known C3 characteristics. Increased biosynthesis of C3 was elicited by endotoxin lipopolysaccharide (LPS). Further, the synthesis of C3 was increased 5-10-fold in response to various synthetic peptides corresponding to the amyloid beta/A4 protein, which is the main constituent of extracellular amyloid deposits in Alzheimer's disease (AD). The increased synthesis of C3 was shown to be dose dependent at concentrations of beta/A4 peptide ranging from 10 micrograms/ml to 50 micrograms/ml. These results suggest that complement components found previously in amyloid deposits may be partly derived from reactive microglia preferentially associated with senile plaques in AD brain.

Amyloid beta-Peptides↗
PubMedDate not supplied

Interactions of the third component of human complement (C3) with tumour cells: evidence for presence of C3b acceptor sites and direct activation of C3 by tumour cells.

The interaction of C3 with different tumour cell lines was investigated. Our results indicated that nearly all the cell lines had C3b acceptors on their membranes. The binding of C3b was visualized by the detection of this protein on the cell surface with fluoresceinated anti-C3c serum. The involvement of proteases in the activation of C3 was demonstrated: complement-membrane fluorescence occurred in the presence of EDTA but was completely abolished with epsilon-aminocaproic acid. Experiments performed with purified C3 led to the conclusion that the protease activity might be the initial event for the activation of the alternative pathway by tumour cells.

Burkitt Lymphoma↗
PubMed1984

Polymorphism of complement C3 in chronic inflammatory bowel disease. Predominance of the C3F gene in Crohn's disease.

Polymorphism of the third component of complement (C3), occupying a key position in cascade reactions, was investigated in 125 consecutive outpatients, 53 with Crohn's disease and 72 with ulcerative colitis. A sample of 1378 randomly selected healthy volunteers of Danish origin served as controls. Occurrence of the F and FS phenotype of C3 (C3F and C3FS ) was increased in the group of Crohn's disease patients (chi 2 = 2.80, p less than 0.05, one-tailed test) and in a subgroup of Crohn patients with the gastrointestinal disease process confined to ileum (chi 2 = 6.91, p less than 0.01). C3 phenotype distribution was unaffected in ulcerative colitis. Only S and F alleles of C3 ( C3S and C3F) were recognized and C3F frequencies were 0.33 in Crohn patients with small bowel disease, 0.23 in all Crohn patients, 0.18 in ulcerative colitis patients and 0.17 in healthy volunteers. The results are compatible with a positive association of the C3F gene and Crohn's disease located in the small bowel.

Alleles↗
PubMed2004

Complement C3 is required for the progression of cutaneous lesions and neutrophil attraction in Leishmania major infection.

To elucidate the role of complement-mediated uptake in Leishmania major infection in vivo, transgenic BALB/c mice that express the cobra venom factor (CVF) under control of the alpha1-antitrypsin promoter were infected. CVF expression in these mice leads to a continuous activation and subsequent consumption of complement C3 in the serum. In contrast to susceptible non-transgenic BALB/c mice, CVF-transgenic mice are highly resistant to L. major infection and show a significantly reduced parasite dissemination. Transient depletion of C3 in wild-type BALB/c mice delays progression of lesions for some days. Both CVF-transgenic and non-transgenic mice exhibit similar T cell responses upon infection. However, in CVF-transgenic mice, no infiltration of neutrophils, which were the prominent infiltrating cells at the site of infection in normal susceptible mice, could be detected. We conclude that C3 cleavage is required for the attraction of neutrophils that participate in parasite dissemination.

Animals↗
PubMed1993

Endogenous complement C3 synthesis in immune complex nephritis.

Human renal epithelial and mesangial cells have been shown to synthesise complement C3 in culture, but the relevance of this finding to the development of complement-mediated nephritis is uncertain. We investigated C3 gene expression in tissue biopsies that showed three main categories of renal injury. By semiquantitative polymerase chain reaction, biopsies from patients with immune-complex glomerulonephritis and those with cell-mediated interstitial nephritis showed increased C3 expression (p < 0.05), but biopsies from patients with non-immune glomerular injury did not. These findings suggest that local C3 production is enhanced in immune-mediated nephritis and are consistent with the hypothesis that locally synthesised complement components are involved in the pathogenesis of tissue injury.

Complement C3c↗
PubMed2000

Transforming growth factor-beta1 acts as a potent inhibitor of complement C3 biosynthesis in human pancreatic cancer cell lines.

In this study, we attempted to determine how transforming growth factor (TGF)-beta1 affects complement C3 secretion in the pancreatic cancer cell lines PANC-1 and BxPC-3. We also compared the responses in C3 secretion with those in interleukin (IL)-8 secretion. The C3 and IL-8 expression was evaluated at the protein and messenger RNA (mRNA) levels. The activation of nuclear factor-kappaB (NF-kappaB) was assessed by an electrophoretic gel mobility shift assay (EMSA). IL-1beta and tumor necrosis factor (TNF)-alpha both induced a marked increase in C3 and IL-8 secretion. However, TGF-beta1 potently decreased the IL-1beta- and TNF-alpha-induced C3 secretion, whereas the IL-8 secretion was weakly but significantly enhanced. These responses were also observed at the mRNA level. In PANC-1 cells, IL-1beta and TNF-alpha induced a rapid activation of nuclear factor (NF)-kappaB, and TGF-beta1 enhanced this activation slightly. The induction of Fos protein has been reported to be required for the inhibitory action of TGF-beta1, and the translocation of Fos protein into the nucleus was associated with TGF-beta1 stimulation in PANC-1 cells. Our results suggest that TGF-beta1 may act as a potent inhibitor of C3 secretion in pancreatic cancer cell lines under inflammatory conditions. This action of TGF-beta1 did not correlate with NF-kappaB activation, but associated with the translocation of Fos protein into the nucleus.

Antibodies↗