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PubMed1992

Complement (C3) levels and activation in rabbits experimentally infected with Trypanosoma evansi.

Rocket immunoelectrophoresis was used to monitor the levels of the third complement component (C3) in the blood of rabbits experimentally infected with Trypanosoma evansi. Although a reduction in the circulating levels of C3 was associated with C3 activation in rabbits with high levels of parasitaemia, there was no evidence for C3 activation in uninfected rabbits, rabbits with early-stage, light infections or rabbits cleared of infection by drug treatment. Host-tolerance to current infection and to re-exposure to the parasite are probably affected by such changes in C3.

Animals↗
PubMed1993

Differential cytokine regulation of complement C3, C4, and factor B synthesis in human intestinal epithelial cell line, Caco-2.

In the intestinal tract, the local synthesis of C3 and components of both the classical (C4) and alternative (factor B) C activation pathway has previously been demonstrated in vivo. However, the cellular source of this local C synthesis has not been identified. In this study, we demonstrated the syntheses of C3, C4, and factor B in the human colonic adenocarcinoma cell line Caco-2, which is regarded as a good experimental model of normal human intestinal epithelial cells. The results of metabolic labeling experiments indicated that the intra- and extracellular molecular sizes and subunit structures of Caco-2-derived C3, C4, and factor B were compatible with previously reported values for these components in other cells. The functional activities of C3 and C4 in the supernatants were also demonstrated by hemolytic titration assay. Furthermore, C syntheses in this line were independently upregulated by several human cytokines: C3 synthesis was dose-dependently enhanced by the addition of IL-1 beta or TNF-alpha; C4 synthesis was enhanced by the addition of IL-6 or IFN-gamma in the same manner; and the addition of IL-1 beta or IL-6 also induced a dose-dependent increase in factor B synthesis. These enhancing effects were confirmed to be specific for individual cytokines by experiments using anti-human cytokine antibodies. It is likely that intestinal epithelial cells are local production sites of C3, C4, and factor B, and that local C syntheses in the intestine are independently regulated by several cytokines, derived from monocytes/macrophages and T cells resident in the mucosal microenvironment.

Adenocarcinoma↗
PubMed1986

Regulation of human cytotoxic responses by complement: C3, C3b and C3d preparations enhance human allogeneic cytotoxic responses.

Complement components and complement breakdown products have been found to participate in the regulation of the immune response. In the present study we investigated the effect of C3 and its fragments, C3b, C3c and C3d on human allogeneic cell mediated lympholysis (CML). C3 and C3b at a concentration of 275 M X 10(-9) and C3d at a concentration of 330 M X 10(-9) enhanced human allogeneic CML by at least two fold. In contrast C3c did not affect CML responses. Both C3b and C3d had to be present at the initiation of the cultures in order to exert their effect. Similar doses of C3b and C3d did not affect the mixed lymphocyte responses (3H-thymidine uptake) while higher doses were clearly inhibitory. None of the preparations induced proliferative or cytotoxic responses in the absence of allogeneic stimulating cells. C3b and C3d added to the mixed lymphocyte cultures caused increased production of interleukin 2. We conclude that C3b and C3d facilitate allogeneic cytotoxic responses through increased production of interleukin 2.

Complement C3↗
PubMed2005

Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia.

OBJECTIVE: Antiphospholipid antibodies (aPL) have been shown to induce thrombosis, activate endothelial cells, and induce fetal loss. The pathogenesis of aPL-induced thrombosis, although not completely understood, may involve platelet and endothelial cell activation as well as procoagulant effects of aPL directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation leads to fetal death in aPL-treated mice. In this study, we tested the hypothesis that aPL are responsible for activation of complement, thus generating split products that induce thrombosis. METHODS: To study thrombus dynamics and adhesion of leukocytes we used in vivo murine models of thrombosis and microcirculation, in which injections of aPL were used. RESULTS: Mice deficient in complement components C3 and C5 were resistant to the enhanced thrombosis and endothelial cell activation that was induced by aPL. Furthermore, inhibition of C5 activation using anti-C5 monoclonal antibodies prevented thrombophilia induced by aPL. CONCLUSION: These data show that complement activation mediates 2 important effectors of aPL, induction of thrombosis and activation of endothelial cells.

Animals↗
PubMed1990

Genes associated with rheumatoid arthritis and mild inflammatory arthritis. II. Association of HLA with complement C3 and immunoglobulin Gm allotypes.

Associations were sought between major histocompatibility complex (MHC) genes on chromosome 6 and the complement component C3 and immunoglobulin genes located on other chromosomes which might contribute to susceptibility to mild inflammatory arthritis (IA) or definite rheumatoid arthritis (RA). Frequencies of the complement C3F allele were raised in patients with IA but were normal in patients with RA and controls. When associations between C3F and MHC genes were sought frequencies of some MHC genes were greater in patients with C3F than in those without--for example, HLA-B8 and DR3 in patients with RA and DR2 in patients with IA. Conversely, DR4 frequency was lower in patients with IA with C3F than in those without. Thus the C3F allele may act independently or exert an epistatic effect on MHC genes to increase susceptibility or protect against disease. The frequency of the immunoglobulin heavy chain allotype Glm(2) on chromosome 14 was increased in patients with RA but only in those with the phenotype Gm1,2,3,17;21,5; no significant associations were found between MHC genes and Gm phenotypes. Further, no associations of MHC, C3F, and immunoglobulin genes were shared by patients with RA and those with IA, indicating a different genetic basis for the two clinical entities.

Arthritis↗
PubMed2000

Insulin action and insulinemia are closely related to the fasting complement C3, but not acylation stimulating protein concentration.

OBJECTIVE: An elevated C3 concentration has been reported in people with obesity, type 2 diabetes, hypertension, and dyslipidemia, and has been proposed to play a role in the development of atherosclerosis. We hypothesized that an elevated C3 concentration might be linked to insulin resistance and/or hyperinsulinemia, abnormalities commonly observed in association with the above conditions. RESEARCH DESIGN AND METHODS: Fasting concentrations of C3 and acylation stimulating protein (ASP, C3adesarg), a cleavage product of C3 recently found to stimulate glucose uptake in vitro, were measured in 33 healthy nondiabetic Pima Indians (14 women and 19 men; age 27 +/- 1 and body fat 33 +/- 1%, means +/- SEM). Subjects were characterized for body composition dual-energy X-ray absorptiometry, insulin action (insulin-stimulated glucose disposal [M], hyperinsulinemic glucose clamp), and glucose tolerance (75-g oral glucose tolerance test). RESULTS: Fasting C3 and ASP concentrations were positively correlated (r = 0.43, P < 0.05). Fasting C3 concentration was closely related to percent body fat (r = 0.77), M (r = -0.75), and fasting insulin concentration (r = 0.72) (all P < 0.0001). Fasting C3 concentrations remained significantly related to M and fasting insulin after adjusting for percent body fat (partial r = -0.53 and 0.33, both P < 0.05). In subjects with impaired glucose tolerance, fasting C3 concentrations were higher than in those with normal glucose tolerance--a difference that remained after adjustment for percent body fat and M. We found that fasting ASP concentrations were significantly related to percent body fat (r = 0.37, P < 0.05), but not to M or fasting insulin. CONCLUSIONS: In Pima Indians, fasting C3 concentration is closely related to adiposity, insulin action, and fasting insulin levels and may thus be a mediator for the postulated link between obesity, insulin resistance, hyperinsulinemia, and possibly atherosclerosis.

Absorptiometry, Photon↗
PubMed1980

Complement (C3) conversion by rat intestinal glycoprotein and its degradation products.

Several fragments obtained from alkaline borohydride degradation of a rat intestinal glycoprotein fraction have been tested for anti-complementary activity. Oligosaccharide alditols with a molecular weight of less than about 1 X 10(3) daltons showed no activity, whereas reduced oligosaccharides in the molecular weight range of about 1 X 10(3) to 3 X 10(3) daltons exerted a minor conversion of C3 by the alternative pathway. The low molecular weight fragments tested did not influence C3 conversion induced by the intact intestinal glycoprotein fraction. Of the fragments, a peptide fraction, with an 'average' molecular weight of 2 X 10(3) daltons, and peptide-containing glycoconjugates exerted activation by C3 by both the classical and alternative pathways. Classical pathway activation by the intestinal glycoproteins depended on antibody, whereas alternative pathway activation did not. Alternative pathway activation appeared to require Factor B in that the intestinal glycoproteins induced no C3 conversion in serum heated to 50 degrees C for 20 min. The rat intestinal glycoproteins had no protease activity on casein and no stimulating effect on human lymphocytes in vitro. Branching of oligosaccharide chains was not indicated by the methylation analyses carried out.

Agammaglobulinemia↗
PubMed1979

Serum complement (C3 and C4) levels in the Malaysian adult population.

Serum C3 and C4 values were determined in 236 normal adults of three racial groups, using the single radial immunodiffusion techniques. The C3 levels varied from 47 to 119 mg/dl and C4 levels from 16 to 66 ml/dl (mean +/- 2SD). The values were found to be comparable to the normals reported in some Western series. No significant differences in the levels related to sex and race were found.

Adolescent↗
PubMed1975

The recetor sites for complement (C3) on human diploid fibroblasts.

Sheep red cells, sensitized with 19S fraction of antiserum and subsequently treated with mouse serum as the source of complement (EAC), interact with human diploid fibroblasts (WI-38 cells) and form "Rosettes". Under a scanning electron microscope, EAC have not attached directly to the cell surface of fibroblasts, but to the fine processes or microvilli of the latter, as if there were fine bridges between EAC and the surface of fibroblasts. On the other hand, the attachment of sheep red cells washed in PBS (E) or sensitized with 19S fraction of antiserum (EA) to WI-38 cells was not observed. The pretreatment of WI-38 cells with mouse serum did not inhibit the interaction of WI-38 cells and EAC. No phagocytosis of EAC by WI-38 cells was observed in the 2 hrs incubation of both cells. From these results it is suspected that the interaction of WI-38 cells and EAC is immune adherence, and that WI-38 cells have the receptor site for complement, especially for C3, on the surface of cell membrane.

Animals↗
PubMed1987

Functional analysis and quantification of the complement C3 derived anaphylatoxin C3a with a monoclonal antibody.

The C3 fragment C3a belongs to the anaphylatoxins. It has immune regulatory activity and contributes to the pathogenesis of the adult respiratory distress syndrome (ARDS). The low molecular weight (9 kD) of C3a complicates the production of antibodies to C3a. We obtained a monoclonal antibody (designated H13) to human C3a. It reacts with C3a or C3a-desArg and with native C3 but not with C5 or C5a. In immunoblot analysis it reacts with the alpha- but not with beta-chain of C3 and binds to a protein with a mol. wt of about 10 kD present in zymosan-activated sera which is only marginally detectable in nonactivated serum and absent in plasma. H13 crossreacts with the analogous proteins of rabbit, guinea pig and sheep. H13 has the capacity to bind 125I-radiolabelled C3a efficiently but fails totally to react with 125I-C5a or with other C3 alpha-chain fragments. H13 blocks C3a functional activity. It markedly inhibits C3a-induced 3H-serotonin release from platelets in vitro and similarly inhibits the C3a-induced extravasation of Evans blue into the skin in vivo. H13 does not interfere with the haemolytic activity of C3. An ELISA system was established using H13 which permits quantification of C3a in sera of polytrauma patients. The antibody H13 should facilitate further functional analysis of C3a in experimental systems. It should be useful for quantification of C3a in diagnostic assays and also for application in immunopathology.

Animals↗
PubMed1987

Activation of the third component of complement (C3) detected by a monoclonal anti-C3'g' neoantigen antibody in a one-step enzyme immunoassay.

A previously produced and characterized rat monoclonal antibody recognizing a neoantigen in the human C3'g' fragment was used as the capture antibody in an enzyme-linked immunosorbent assay. Detection was made using a polyclonal rabbit anti-human C3d and a peroxidase-linked anti-rabbit Ig antiserum. The activity in normal human EDTA plasma was found to be 3% of that in a zymosan-activated serum pool. Fractionation experiments revealed that most of the activity in normal plasma, in vivo activated plasma and in vitro activated serum eluted in one peak with a molecular weight corresponding to iC3b. A positive correlation (P less than 0.01) was found between the present assay and a previously established two-step C3d ELISA both with respect to normal plasma, individual patient samples and consecutively drawn samples following artificial in vivo activation. Complement activation assays based on specific antibodies to 'activation antigens' should be preferred whenever available since they enable direct, rapid and specific quantification of the actual fragment(s).

Antibodies, Monoclonal↗
PubMed2005

Effects of C-reactive protein and the third and fourth components of complement (C3 and C4) on incidence of atrial fibrillation.

Although C-reactive protein (CRP) is a major cardiovascular risk factor, its association with atrial fibrillation (AF) remains controversial. This study explored whether the CRP-related incidence of AF is modified by serum markers of inflammation in a population-based cohort with follow-up data. Serum CRP and 2 components of the complement system (C3 and C4) were determined in 1,011 healthy patients (25 to 64 years old). The incidence of AF was compared between groups defined by levels of CRP, C3, and C4. The follow-up time was 4 years. A high complement level was defined as either C3 or C4 in the top quartile. High CRP was associated with high complement components. An increased CRP level was associated with an increased incidence of AF. The complement components modified these associations. After risk factor adjustment, those with high CRP and high complement components had a significantly higher risk of AF (relative risk 3.0, 95% confidence interval 2.0 to 4.2) than those with normal CRP and low complement levels. In the absence of a high complement level, a high CRP level was not significantly associated with AF (relative risk 1.1, 95% confidence interval 1.0 to 1.4). In conclusion, high CRP levels are associated with high serum levels of complement components. These proteins increase the CRP-related incidence of AF. In the absence of elevated complement components, no statistically confirmed association was found between a high CRP level and AF.

Adult↗
PubMed1983

Induction of granulocyte histaminase release by particle-bound complement C3 cleavage products (C3b, C3bi) and IgG.

The interaction of opsonized particles with human granulocytes promotes a number of important biologic functions, including phagocytosis, superoxide generation, and release of a variety of enzymes, including histaminase. We have previously determined that histaminase release occurs via a C3-dependent process. Although fluid-phase C3b dimers can mediate release, the relative effects of particle-bound C3b and C3bi and of IgG have not been examined. In this report we demonstrate that particle-bound C3 deposited on activators of the alternative C pathway effected histaminase release in the absence of IgG. Particle-bound C3bi and C3b were both effective as mediators of histaminase release. The extent of release varied as a function of the activating surface on which C3 was deposited (zymosan C3b was considerably more potent than C3b bound to rabbit erythrocytes, which was slightly more potent than C3b bound to neuraminidase-treated sheep erythrocytes). In contrast, C3b or C3bi deposited on nonactivating surfaces (such as sheep erythrocytes) at inputs of up to 2,000,000 molecules per granulocyte failed to induce histaminase release unless IgG was also present. The ability of C3b bound to particles that serve as activators of the alternative pathway to induce histaminase release is apparently not the result of decreased susceptibility of C3b to proteolysis or to an increased binding affinity to the C3b receptor, but may relate to the interaction of other surface structures on activating particles with the PMN membrane.

Amine Oxidase (Copper-Containing)↗
PubMed1983

Complement (C3)-receptor-mediated phagocytosis of agarose beads by mouse macrophages. I. Intracellular degradation of agarose-bound C3bi and C3b by lysosomal enzymes.

The phagocytosis by macrophages of C3bi-coated agarose beads reached a plateau after 15 min, compared with 30 min for C3b-coated beads. By using 125I-labelled C3bi or C3b coupled to the agarose beads, we found that 70% and 95% of total radioactivity were removed from the beads after 12 h and 36 h of intracellular digestion, respectively. Intracellular degradation of C3bi linked to agarose beads was also demonstrated by testing binding of monoclonal antibodies against human C3c, C3g and C3d to beads extracted from the cells after phagocytosis. Such extracted beads also showed reduced attachment to new macrophages compared with non-ingested beads. Treatment of the cells with leupeptin, an inhibitor of the lysosomal enzyme cathepsin B, or with dextran sulphate to inhibit phagosome-lysosome fusion greatly reduced the release of labelled protein from the agarose during the first 12 h. These findings show that C3bi and C3b on agarose is destroyed intracellularly by lysosomal enzymes.

Animals↗
PubMed1996

Identification and characterization of complement C3 receptors on human astrocytes.

Astrocytes express C components and have been implicated as a major source of intrathecal C. To ascertain the effects of C activation on these cells, we have evaluated the expression of CR1, CR2, and CR3 (CD35, CD21, and CD11b/CD18) in primary fetal astrocytes and astrocyte cell lines. None of the astrocyte cells tested expressed CR3, whereas primary astrocytes and one of four astrocyte cell lines expressed CR1 (220 kDa), as assessed at the protein and mRNA level. Primary fetal astrocytes and all four astrocyte cell lines expressed CR2 (155 kDa). Expression of CR2 by astrocytes was confirmed at mRNA level by reverse-transcriptase PCR, using different combinations of seven specific CR2 oligonucleotides, and by partial sequencing of the astrocyte CR2 cDNA. Astrocyte CR2 cDNA presented 100% homology with the lymphocyte CR2 cDNA between the position 181 bp to 600 bp and position 1017 bp to 1347 bp. An alternative splicing pattern of exon 11, reported previously in B cells, was observed in astrocyte CR2 cDNA. Astrocyte CR2 was functional, in that it specifically bound C3d and the EBV surface protein gp340, and the binding was blocked specifically with polyclonal anti-CR2. Scatchard analysis of membrane expression of CR2 on astrocytes revealed 2000 functional sites per cell with a Kd (3 x 10(-7) M) identical with that of CR2 on B cell (Raji).

Astrocytes↗
PubMed1999

Deposition of complement C3 and factor H in tissue traumatized by burn injury.

Activation of complement is known to accompany burn injury. To study deposition of complement proteins within tissue traumatized by burn we employed the technique of intravital microscopy using a murine dorsal skinfold chamber model. C3, factor H, factor B, HSA, and transferrin were labeled fluorescently and injected into the tail vein of mice which had been subjected to a small third degree burn within the skin fold. Only C3 and factor H deposited within blood vessels of the traumatized tissue. Binding was specific because it occurred only in and proximal to burn sites, and neither C3 nor factor H was observed to accumulate in blood vessels of healthy tissue. Furthermore, fluorescently labelled HSA, factor B, and transferrin all failed to deposit at or around burn loci. The deposition of C3 and factor H occurred within 10 min of injury and was intravascular occurring in major blood vessels, capillaries, and post-capillary venules, with little evidence of accumulation in the interstitium. Since both C3 fragments and factor H are recognized as adhesion molecules by granulocyte receptors, these deposited proteins could promote leukocyte accumulation, thereby contributing to an initiation of an inflammatory cascade at a site of burn injury.

Animals↗
PubMed1980

Preparation of an R3 reagent (serum depleted of the third component of human complement (C3)) by immunoadsorption. Application to the hemolytic assay of human C3.

We have devised a simple one-step preparation of C3 depleted serum (R3). Fresh normal human serum, with complement activation inhibitors, was depleted of C3 by affinity chromatography on a Sepharose anti-C3c. To prevent non-specific interactions, a high ionic strength buffer containing saccharose was used. Immunochemical analysis and complement activity assays demonstrate that this C3 depleted serum is a suitable R3 reagent. This R3 reagent has been used successfully for titration of hemolytic activity of C3 in normal and abnormal sera. Two simple, specific and sensitive assays are described.

Animals↗