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PubMed1983

Interaction of fibronectin with complement component C3.

The activation of the complement component C3 generates C3a and C3b fragments, and the physiological cleavage of C3b further yields C3c and C3d fragments. We studied here by enzyme immunoassay the ability of human plasma fibronectin to interact with native C3 of human sera and with isolated C3c and C3d fragments of C3. C3 from sera of all six individuals tested bound to solid-phase fibronectin. Soluble fibronectin bound to solid-phase C3c and C3d, and fluid-phase C3c and C3d also bound to solid-phase fibronectin. The binding of fibronectin to solid-phase C3c and C3d could be inhibited by fluid-phase C3c and C3d. The results suggest the possibility that soluble fibronectin may attach to C3-coated particles or that C3-coated particles may adhere to fibronectin-containing structures.

Complement Activation↗

PubMed1986

Relationship between secretory IgA, IgA-containing (C3-fixing) circulating immune complexes, and complement components (C3, C4) in patients with obstructive jaundice.

Serum secretory IgA, IgA-containing circulating immune complexes (IgA-CIC), complement components, and major immunoglobulins were measured in patients with biliary tract stones and/or tumors of the biliary tract or pancreas. The levels of secretory IgA and total IgA were increased in patients with and without obstructive jaundice. The levels of both C3 and C4 were significantly higher in patients with or without obstructive jaundice than in healthy controls. In patients with obstructive jaundice the increased levels of secretory IgA, total IgA, and IgA-CIC were correlated with the increase of C3 but not with that of C4.

Adult↗

PubMed1996

Human nasal epithelium adsorbs complement C3-related fragments and expresses cell membrane complement regulatory proteins.

Recent evidence suggests that complement is activated in human nasal airways in inflammatory states. Activated complement protects the nasal mucosa against microorganisms, but also has the potential to lyse the host's normal cells. Complement-mediated cell lysis depends on adsorption of complement to the cell membrane and on uninterrupted activation of the complement cascade upon the same cell membrane. In the present study, the authors investigated first whether key complement components, C3-related fragments, are adsorbed to nasal epithelial cell membrane. Second, we investigated whether nasal epithelium expresses cell membrane complement regulatory proteins that are known as interruptors of complement activation. Studies were done using fresh nasal mucosa obtained at turbinectomies from allergic rhinitis and vasomotor rhinitis patients. In addition, in order to establish an in vitro model, studies were also done using primary cell cultures of nasal epithelium. We have found that complement C3-related fragments are present on cell membranes of fresh nasal epithelium and that C3-related fragments are adsorbed to the epithelial cell membrane in nasal mucosa tissue segments and in cell cultures that were incubated with autologous serum. Adsorption of C3-related fragments to the cell membrane of cultured nasal epithelial cells was found by flow cytometry analysis to be concentration-dependent. In addition, we found that nasal epithelium in fresh tissue and in cell culture express three cell membrane complement regulatory proteins: membrane cofactor protein (MCP, CD46), decay-accelerating factor (DAF, CD55), and CD59. Our findings in fresh nasal epithelium suggest that complement activation may occur upon the nasal epithelial cell membrane during inflammation in vivo and that nasal epithelium might regulate this complement activation. Our in vitro cell culture model will allow further investigations of complement activation and regulation upon the human nasal epithelial cell membrane.

Adolescent↗

PubMed2005

Complement components (C3, C4) in childhood asthma.

OBJECTIVE: To assess the involvement of complements (C3, C4) in the pathophysiology of bronchial asthma. METHODS: Selection of patients (n = 64) were made according to the recommended international criteria for diagnosis and classification of asthma. Serum levels of complement components (C3, C4) were measured by radial immunodiffusion technique in 64 Libyan children (age: 1-12 years, sex: 39 males, 25 females) with mild to moderately severe asthma (Group A). Among these patients, 35 had active disease (AA) and 29 had inactive disease (NA). According to age range, 20, 21 and 23 patients were between 1-3 years (A1), > 3-5 years (A2) and > 5-12 years (A3) respectively. A1 had 9 and 11 patients with active (AA1) and inactive (NA1) disease; A2 had 10 and 11 patients with active (AA2) and inactive (NA2) disease; A3 had 16 and 7 patients with active (AA3) and inactive (NA3) disease respectively. Age matched comparisons were made with 57 healthy children (age: 1-12 years; sex: 30 males, 27 females) (Group B). Among the controls, 15, 19 and 23 children were between 1-3 years (B1), > 3-5 years (B2) and > 5-12 years (B3) respectively. RESULTS: Mean C3 level was significantly elevated in patients, while C4 level was normal (A vs B --> C3: P < 0.2, C4: P > 0.2). Serum C3 level was significantly higher in patients with active disease only, while it was normal in patients with inactive disease (AA, NA, B --> P = 0.045); AA vs NA --> P < 0.05, AA vs B --> P < 0.02, NA vs B --> P > 0.05) and C4 levels were normal in both the groups (AA, NA, B --> P = 0.354). Further, C3 levels were significantly elevated in all the age groups, but in patients with active disease only (AA1, NA1, B1 --> P = 0.0024; AA2, NA2, B2 --> P = 0.0411; AA3, NA3, B3 --> P = 0.0102). CONCLUSION: The elevated C3 level was possibly due to induction by pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1). The probable mechanisms of C3 involvement in the pathophysiology of bronchial asthma were discussed.

Age Factors↗

PubMed1981

Studies on the possible involvement of complement component C3 in the initiation of acid hydrolase secretion by macrophages. I. Correlation between enzyme-releasing and complement-activating capacities of several secretagogues.

A possible relationship between activation of the alternative pathway of complement and acid hydrolase secretion by macrophages has been investigated in vitro by examining the dose--response characteristics of several immunological and non-immunological stimuli of these two processes. Zymosan particles, insoluble immune complexes, methylamine and several other primary aliphatic monoamines were all found to elicit the selective release of lysosomal enzymes from macrophages by a process that correlated well with the ability of these agents to bring about consumption of haemolytically-active components of the alternative complement pathway. By contrast, substances which failed to activate the alternative complement pathway, i.e. soluble aggregated immunoglobulin and several primary aliphatic diamines, were found to be likewise incapable of inducing the selective release of lysosomal glycosidases from macrophages. These observations are interpreted as further evidence for imputing a role for complement C3 in the initiation of lysosomal enzyme release from macrophages.

Animals↗

PubMed1981

Level of complement activity and components C1, C4, C2, and C3 in complement response to bacterial challenge in malnourished rats.

In experimentally induced malnutrition in rats, there was no significant difference between the measured level of complement activity of the classical pathway (50% hemolytic complement [CH50]) and that of the alternative pathway (ACH50), although the levels of complement components C1, C4, C2, and C3 were depressed significantly. The complement activity showed a temporary elevation with a peak at 2 or 3 days after bacterial challenge with Staphylococcus aureus in rats, and we call this the complement response. After 3 days, CH50 and C3 in the malnourished rats and ACH50, CH50, and C3 in the well-nourished rats showed a significant increase, and C1, C4, and C2 in both groups tended to elevate. On the basis of these observations, the significance of the elevation of C3 in the complement response to bacterial infection showed a strong influence by enhancing the activation of both the classical and the alternative pathways, since C3 is known to be the junction of both complement pathways. In this way, C3 responded to an earlier stage than did the other components and may contribute to maintaining the body defense system against infection.

Animals↗

PubMed2006

Complement component C3 transcription in Atlantic halibut (Hippoglossus hippoglossus L.) larvae.

The complement systems of fish are well developed and play an important role in the innate immune response. Complement C3 is the central protein of all three activation pathways and is the major opsonin of the complement system and essential for the generation of the membrane attack complex. A 1548 bp part of complement component C3 was isolated from a halibut liver cDNA library by immunoscreening. The deduced amino acid sequence showed that this part of halibut C3 contained key amino acids for factor H, I and properdin binding as well as two N-glycosylation sites. Digoxigenine labelled mRNA probes were synthesised and the transcription of C3 was monitored in three larval stages at 206, 430 and 1000 degrees d (30, 50 and 99 days post hatching), by in situ hybridisation. C3 mRNA was detected in muscle, liver, brain, chondrocytes, spinal cord, eye, intestines, oesophagus and kidney. These findings are in accordance with a former immunohistochemical study on halibut C3 protein ontogeny, indicating that C3 is indeed locally expressed in many organs from the youngest stages on. Complement may thus be linked to the formation and generation of different organs during development and play an important role in the early immune response of halibut larvae.

Amino Acid Sequence↗

PubMed1986

Identification of P-57, a serine proteinase, from human erythrocyte membranes, which cleaves both chains of human third component (C3) of complement.

A proteinase, which cleaves human third component of complement, was solubilized from erythrocyte membranes then purified by gel filtration chromatography, fluid phase electrophoresis, and hydroxylapatite chromatography. Labeling of the purified material by 125I or 3H-DFP and measurement of proteolytic activity subsequently isolated by SDS-polyacrylamide gel electrophoresis allowed to identify a 57 kDa single band, in non reducing conditions. Inhibition of this activity by PMSF supports covalent modification of an active serine residue. This membrane serine proteinase cleaved alpha and beta chains of human third component of complement, suggesting that p-57 is distinct from plasma serine proteinases.

Centrifugation, Density Gradient↗

PubMed2002

Involvement of dipeptidyl peptidase IV in immune complex-mediated glomerulonephritis.

Dipeptidyl peptidase IV (DPPIV) is widely expressed in many tissues; however, its precise biological function is poorly understood. One of its possible physiologic roles is an involvement in the immune system, which plays a pivotal role in the pathogenesis of glomerulonephritis. The present study focused on the involvement of DPPIV in immune complex-mediated glomerulonephritis. Experimental nephritis was induced by anti-Thy-1.1 monoclonal antibody E30 using Wistar or F344 rats. The application of a new monoclonal antibody against DPPIV, F16, completely suppressed E30-induced proteinuria and mesangial proliferation in Wistar rats, whereas these preventive effects of F16 were not observed in F344 rats, which spontaneously lack DPPIV protein. Treatment with F16 inhibited glomerular deposition of complement C3 and complement C4 after the binding of E30 to the mesangial cell surface. Because the preventive effect of F16 was attributable to suppression of the complement cascade, we examined its influences on complement-dependent mesangial cell lysis in vitro. We discovered that the complement cascade was markedly inactivated in F16-treated Wistar rat serum but not in F16-treated F344 rats. These results indicate that DPPIV may play a somewhat crucial role in regulating the complement cascade and that inhibition of DPPIV may serve as a new target for preventing complement-dependent tissue injury.

Animals↗

PubMed2000

Quality assessment of heparin coatings by their binding capacities of coagulation and complement enzymes.

In vitro testing of blood contacting materials before clinical application is generally advisable. Four heparin coatings from different manufacturers were tested for adsorbed proteins and soluble activation markers. The surface with the highest antithrombin, thrombin, high-molecular-weight-kininogen (HMWK) and the lowest fibrinogen binding capacity (Carmeda, Medtronic) showed significantly lower levels of granulocytes and platelet activation (beta-TG, PMN-elastase release). No statistically significant differences in soluble markers of the coagulation system could be detected (F1 + 2, TAT). Interestingly, complement activation (TCC) was significantly reduced within the group of the lowest adsorption of the complement factor C3. Our data demonstrate that there is a relation between the binding affinity of proteins (C1-inhibitor, C3-complement) and the consecutive changes in complement activation (TCC). Therefore, measuring adsorbed proteins on artificial surfaces is a suitable, sensitive and very reproducible method for assessing the thrombogenicity of biomaterials.

Adsorption↗

PubMed1986

Diabetes and autonomic neuropathy: an immunological association?

Lymphocytic infiltration of autonomic ganglia found at autopsy and a strong clinical association with iritis suggests that diabetic autonomic neuropathy might have an immunological basis. We measured levels of circulating immune complexes, complement (C3, C4), complement breakdown products (C3d), and insulin antibodies in diabetics with autonomic neuropathy and a history of iritis (n = 17), compared to diabetics of similar age and duration with autonomic neuropathy but no history of iritis (n = 20), and with uncomplicated insulin-dependent diabetics (n = 23), together with normal controls (n = 26). We found higher levels of circulating immune complexes in patients with autonomic neuropathy (irrespective of iritis) compared to normal controls, and differences in C3d levels suggesting complement activation. C4 levels were unexpectedly normal in the diabetics with autonomic neuropathy, in contrast to the uncomplicated insulin-dependent diabetic controls. Insulin antibody levels showed no difference between the three groups of diabetics. These findings suggest that immunological mechanisms may be implicated in the aetiology of diabetic autonomic neuropathy and that further studies are indicated.

Adult↗

PubMed1988

Secretor state and complement levels (C3 and C4) in insulin dependent diabetes mellitus.

Lower levels of C3 and C4 components of the complement system have been reported for patients with insulin dependent diabetes mellitus (IDDM) but not among those with non-insulin dependent diabetes (NIDDM). We have found a significantly higher proportion of patients who are non-secretors of the ABO blood group antigens among patients with IDDM but not among those with NIDDM. As the gene that controls secretion of these antigens is in the same linkage group as that for the C3 complement component, we compared the levels of C3 and C4 of patients with IDDM by secretor state. The mean level of C3c for 45 non-secretors (75.2 IU/ml) was significantly lower than that found for 59 secretors (86.4 IU/ml) (p less than 0.025). The level of C4 among non-secretors (77.1 IU/ml) was also significantly lower than that of secretors (96.3 IU/ml) (p less than 0.025). The significance of these observations is discussed.

ABO Blood-Group System↗

PubMed1981

Elevated IgG and decreased complement component C3 and factor B in B-thalassaemia major.

Serum immunoglobulins, complements C3 and C4 and factor B were assayed in the sera of children with B-thalassaemia major, siblings and matched controls in an attempt to resolve the controversy surrounding the conflicting results reported in the literature. Significantly elevated IgG and decreased C3 and factor B levels were observed in thalassaemic patients who also had a high incidence of HBS hepatitis and other infections. The controversial results probably reflect differences in the incidence of infection, and the presence of circulating immune complexes due to blood transfusions, in the various communities. The alterations in immunoglobulin and complement levels represent a secondary rather than a primary immune disorder.

Complement C3↗

PubMed1986

Conditions for the immunohistochemical demonstration of complement factor C3 in formaldehyde-fixed and paraffin-embedded renal tissues.

Paraffin sections of formaldehyde-fixed renal biopsies were labeled for complement C3 by a polyclonal rabbit antibody to human complement C3, by the peroxidase-antiperoxidase complex (PAP) and the avidin-biotin peroxidase complex (ABC) techniques, respectively. All tissues had C3 deposits according to direct immunofluorescence on fresh frozen sections. Staining for muramidase was introduced as an intrinsic control for the degree of tissue proteolysis after the necessary trypsin digestion prior to the immunoenzyme labeling. The results indicated that even minute deposits of C3 could be detected in paraffin sections by the ABC method, which was more sensitive than the PAP technique; the ABC method allowed a maximal dilution of 1:2,400 of the primary antibody as compared to 1:800 for the PAP technique.

Animals↗

PubMed2003

Compstatin, a peptide inhibitor of complement, exhibits species-specific binding to complement component C3.

Although activation of complement protein C3 is essential for the generation of normal inflammatory responses against pathogens, its unregulated activation during various pathological conditions leads to host cell damage. Previously we have identified a 13-residue cyclic peptide, Compstatin, that inhibits C3 activation. In this study, we have examined the species-specificity of Compstatin. Bimolecular interaction analysis using a real-time surface plasmon resonance-based assay showed that Compstatin exhibits exclusive specificity for primate C3s and does not bind either to C3s from lower mammalian species or to two structural homologs of C3, human C4 and C5. Furthermore, it showed that although the kinetics of binding of Compstatin to non-human primate C3s were distinctly different from those to human C3, like human C3 its mechanism of binding to non-human primate C3 was biphasic and did not follow a simple 1:1 interaction, suggesting that this binding mechanism could be important for its inhibitory activity. Analysis of Ala substitution analogs of Compstatin for their inhibitory activities against mouse and rat complement suggested that the lack of binding of Compstatin to mouse and rat C3s was not a result of sterically hindered access to the binding pocket due to individual bulky side chains or the presence of charge on the Compstatin molecule. These results suggest that Compstatin's exclusive specificity for primate C3s could be exploited for the development of species-specific complement inhibitors.

Amino Acid Substitution↗

PubMed1987

Immunoproteins in the endometrium: clinical correlates of the presence of complement fractions C3 and C4.

The presence of complement fractions C3 and C4 in endometrial tissue was studied in a consecutive series of patients undergoing diagnostic laparoscopy, to determine their specific association with endometriosis. The incidence of complement in eutopic endometrium of patients grouped according to four diagnoses was: endometriosis, 66% positive (23 of 35); active pelvic inflammatory disease, 85% positive (11 of 13); combined endometriosis with pelvic inflammatory disease, 25% positive (one of four); laparoscopically normal pelvis, 67% positive (10 of 15). These differences were not statistically significant. Complement was equally likely to be found in proliferative, secretory, menstrual, or inflammatory endometrium. Endometrial complement was found less frequently in patients with severe endometriosis as compared with those with the mild form. Among patients with endometriosis and infertility, complement was much more likely to be found in patients with primary infertility than in those with secondary infertility (p less than 0.007). In short-term follow-up of these patients, the absence of complement in the eutopic endometrium appeared to be a good predictor of subsequent pregnancies.

Complement C3↗

PubMed1997

Antigen-antibody complexes enhance the production of complement component C3 by human mesangial cells.

Deposition of immune complexes (ICX), with or without complement, occurs in various forms of glomerulonephritis. It has been reported that upregulation of complement C3 mRNA expression is found in kidneys of patients with ICX glomerulonephritis. In vitro studies have indicated that mesangial cells (MC) synthesize C3. Furthermore, MC express Fc gammaRIII receptors. This study investigates whether ICX alter C3 and factor H production by MC. MC were cultured in medium alone or in medium with insoluble heat-aggregated rat IgG (AIgG) or with insoluble ICX. Basal production of C3 and factor H was 10 +/- 1 ng/10(6) and 605 +/- 15 ng/10(6) cells, respectively. The presence of 400 microg/ml AIgG or ICX resulted in upregulation of C3 production to 999 +/- 15 ng/10(6) and 510 +/- 1 ng/10(6) cells, respectively, whereas no significant change in factor H production was observed. The upregulation of C3 was inhibitable by cycloheximide, suggesting that de novo protein synthesis was required. By reverse transcription PCR and Northern blot analysis, it was demonstrated that C3 and interleukin-6 mRNA expression was upregulated in MC after incubation with AIgG. No detectable change in factor H mRNA expression was seen. In conclusion, it is shown that incubation of MC with AIgG or ICX not only results in upregulated production of inflammatory mediators such as cytokines, but also leads to an upregulation of C3 synthesis. Therefore, it is hypothesized that ICX deposited within the mesangium may enhance the local production of C3 via interaction with Fc receptors on MC.

Actins↗

PubMed2006

Structural transitions of complement component C3 and its activation products.

Complement sensitizes pathogens for phagocytosis and lysis. We use electron microscopy to examine the structural transitions in the activation of the pivotal protein in the complement pathway, C3. In the cleavage product C3b, the position of the thioester domain moves approximately 100 Angstrom, which becomes covalently coupled to antigenic surfaces. In the iC3b fragment, cleavage in an intervening domain creates a long flexible linker between the thioester domain and the macroglobulin domain ring of C3. Studies on two products of nucleophile addition to C3 reveal a structural intermediate in activation, and a final product, in which the anaphylatoxin domain has undergone a remarkable movement through the macroglobulin ring.

Chromatography, Gel↗