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PubMed2004

HIV-1 induces complement factor C3 synthesis in astrocytes and neurons by modulation of promoter activity.

Virus-induced complement expression and activation in the brain is hypothesized to contribute to the process of neurodegeneration in AIDS-associated neurological disorders. Previous experiments have shown that the human immunodeficiency virus (HIV) upregulates the low basal production of complement factor C3 in astrocytes and neurons. Since inhibition of complement synthesis and activation in the brain may represent a putative therapeutic goal to prevent virus-induced damage, we analysed the mechanism of the HIV-induced modulation of C3 expression. Detailed studies using different C3 promoter constructs revealed that HIV activates the synthesis of C3 by stimulation of the promoter. This HIV-induced promoter activation could be measured both in different astrocytic cell lines and in neurons. Deletion constructs of the C3 promoter defined the IL-6/IL-1beta responsive element within the promoter region as a central element for the responsiveness of the C3 promoter towards the influence of HIV. A binding site for the transcription factor C/EBPdelta was identified as important regulatory domain within the IL-6/IL-1beta responsive element, since a point mutation which eliminates the binding capacity of C/EBPdelta to this site also abolishes the induction by HIV-1. Similarly, the viral proteins Nef and gp41 which had also been shown to stimulate the synthesis of C3, exert their effect via the IL-6/IL-1beta responsive element with binding of the transcription factor C/EBPdelta representing the critical step. Our experiments clearly define the mechanism for the induction of complement factors in the HIV-infected brain and reveal a decisive role of the regulator protein C/EBPdelta for the HIV-induced increase in C3 expression.

Astrocytes↗
PubMed1993

Characterization of kinetics and target proteins for binding of human complement component C3 to the surface-exposed outer membrane of Chlamydia trachomatis serovar L2.

In order to characterize the interaction of human complement with Chlamydia trachomatis, flow cytometry was used to quantitate binding of complement component C3 to elementary bodies of C. trachomatis serovar L2 preincubated in fresh serum in the presence or absence of human polyclonal chlamydial antibody. Isolation of each of the complement activation pathways revealed that C3 was activated most effectively by the alternative pathway. The degree of binding by the classical pathway was proportional to the concentration of antibody, but dual-pathway-mediated binding was not greater than antibody-independent alternative pathway binding. Electrophoresis and immunoblotting of detergent-extracted outer membrane protein-C3b complexes indicated that the chlamydial major outer membrane protein was the primary cell surface moiety binding C3b in both the presence and absence of specific antibody. Hydroxylamine cleavage of outer membrane protein-C3b complexes provided evidence that the majority of C3b is bound to the major outer membrane protein by hydroxyl ester bonds. This result was also unchanged by the presence of specific antibody. An unexpected finding was the apparent binding of anti-C3 antibody to a 40-kDa protein of the chlamydial outer membrane complex, perhaps indicating C3 mimicry on the part of the chlamydial major outer membrane protein.

Amino Acid Sequence↗
PubMed1995

Complement component C3: molecular basis of the C3*S025 variant and evidence for molecular heterogeneity of other variants.

Complement component 3 (C3) is the central molecule of the complement system. It displays a number of polymorphic variants with, as yet, unclear functional consequences. We have investigated a number of rare C3 variants by PCR-SSCP (polymerase chain reaction-single strand conformation polymorphism) analysis and could identify the molecular basis of a C3*S025 variant. The decreased electrophoretic mobility of this protein is caused by the exchange of a neutral serine residue to an arginine residue (positively charged). This exchange is unlikely to have functional consequences as it maps to the C-terminus of the alpha-chain. C3 variants appear to have originated from various independent mutations as we could not detect this mutation in different allotypes.

Base Sequence↗
PubMed1992

Conformational differences between surface-bound and fluid-phase complement-component-C3 fragments. Epitope mapping by cDNA expression.

In previous studies a subset of complement-component-C3 (C3) epitopes, C3(D), expressed in denatured and surface-bound C3 and C3 fragments, has been described. These epitopes were detected by antibodies raised against denatured C3. In the present study we used a cDNA expression strategy to localize epitopes recognized by monoclonal and polyclonal anti-C3(D) antibodies. First, DNAse I digestion of C3 cDNA was used to generate 200-300 bp fragments. These cDNA fragments were expressed as beta-galactosidase-C3 fusion proteins using the lambda gt11 vector. The fusion proteins were tested by Western-blot analysis for reactivity with monoclonal and polyclonal anti-C3 antibodies, and the location of the epitopes were determined by sequencing the cDNA fragments. Affinity-purified polyclonal anti-C3(D) antibodies specific for denatured C3 reacted strongly with the C3 fusion fragments corresponding to segments of the 40 kDa subunit of C3c (residues 1477-1510) and the C3d fragment (residues 1117-1155 and 1234-1294) of C3. Adsorption of the polyclonal antibodies with a mixture of EAC3b and EAC3bi (degradation fragments of C3 bound to sheep erythrocytes) abolished binding to fusion proteins spanning the C3d region, but not the 40 kDa fragment of C3c. No effect was seen with the corresponding soluble C3 fragments. The monoclonal anti-C3(D) antibodies (mAbs) 7D326.1 and 7D331.1, specific for EAC3b and EAC3bi, bound to a fusion protein corresponding to amino acid residues 1312-1404, whereas mAb 7D9.2, specific for EAC3d, reacted with a fusion protein spanning amino acid residues 1082-1118. mAbs 4SD11.1 and 4SD18.1, which did not bind to any physiological C3 fragment, detected a fusion protein covering residues 1477-1510. In summary, the segments of C3 represented by amino acid residues 1082-1118, 1117-1155, 1234-1294 and 1312-1404 accommodate C3(D) epitopes that are expressed by erythrocyte-bound C3 fragments, but not by the corresponding fluid-phase fragment, whereas the segments spanning residues 973-1026 and 1477-1510 contain C3(D) epitopes that are exposed exclusively in denatured C3 and therefore hidden in physiological fragments of the protein.

Animals↗
PubMed2002

Haemolytic complement activity, C3 and Factor B consumption in serum from chickens divergently selected for antibody responses to sheep red blood cells.

Antibody responses, serum complement haemolytic activity, and complement component C3 and Factor B consumption were studied in chickens divergently selected for high and low antibody responses to sheep red blood cells, and in a randombred control line. Significantly higher total and IgG antibody responses to SRBC were found after intramuscular immunisation in the high antibody responder (H) line versus the low antibody responder (L) line and the control (C) line. Also significantly higher antibody titres were found in the C line as compared to the L line. Ca-dependent (classical) and Ca-independent (alternative) complement haemolytic activity was significantly higher in the H line than in the L line. Also initial complement haemolytic activity and C3 levels prior to immunisation with SRBC were significantly higher in the H than in the L line. The L line, on the other hand, showed numerically higher Factor B levels. Immunisation with SRBC was followed by a different consumption of C3 in serum of the H line than the L line. The results indicated that divergent selection of chickens for specific antibody responses to SRBC affected complement levels and C3 consumption in these chickens. This suggests a genetic linkage between these two immune traits.

Animals↗
PubMed1984

Protection of the classical and alternative complement pathway C3 convertases, stabilized by nephritic factors, from decay by the human C3b receptor.

Formation and function of the classical (C4b,2a) and alternative (C3b,Bb) complement pathway C3 convertases are regulated by the intrinsic lability of the enzymes, extrinsic decay by C4bp and H, cleavage of C4b and C3b by I, and by the inhibitory action of the C3b receptor molecule (CR1). Binding of C4 nephritic factor (C4Nef) to C4b and of C3 nephritic factor (C3Nef) to C3b stabilizes the C3 convertases and bypasses inactivation by C4bp, H and/or I. In the present study, binding of C4Nef to the classical C3 convertase was found to prevent decay of C4b,2a by inputs of CR1 that were at least 15 times the amount of CR1 which inactivated 50% unstabilized classical pathway C3 convertase sites in 2.5 min. CR1 could however inhibit lysis of C4b,2a(C4Nef)-bearing cells in a dose-dependent manner. The latter inhibitory effect was directed at the interaction of C5 with the C5 convertase, most likely at C5 binding to cell-bound C3b. In an analogous manner to C4Nef in the classical pathway, stabilization of alternative pathway C3b,Bb convertase sites by C3Nef resulted in a relative protection of C3 convertase sites from decay by CR1. Thus, C4Nef and C3Nef can bypass all mechanisms susceptible to regulate function of the classical and alternative pathway C3 convertases. Because CR1 is essential for degradation of C3b bound to immune complexes in whole blood, stabilization of C4b,2a and C3b,Bb by C4Nef and C3Nef may alter in vivo processing of immune complexes in patients with nephritic factors.

Complement Activating Enzymes↗
PubMed1997

Diagnostic value of ferritin, haptoglobin, alpha 1-antitrypsin, lactate dehydrogenase and complement factors C3 and C4 in pleural effusion differentiation.

Searching to define diagnostic criteria for malignant and non-malignant pleural effusions, the differential diagnostic value of ferritin (FRT), haptoglobin (Hp), alpha 1-antitrypsin (alpha 1-AT), lactate dehydrogenase (LDH) and complement factors C3 and C4 were investigated prospectively in 100 consecutive patients with pleural effusions of various aetiologies. Pleural effusion FRT, C3 and C4 concentrations were found to be useful in differentiating exudates from transudates, so that transudates practically could be excluded in pleural effusion: serum FRT ratio lower than 0.5 and/or in pleural effusion values for C3 and C4 higher than 300 mg dl-1 and 70 mg dl-1, respectively. A pleural effusion: serum C3 ratio greater than 2 is seen only in malignant effusions. No discriminative pleural: serum ratio could be found in FRT and C4 values capable of differentiating malignant from non-malignant effusions. Pleural effusion alpha 1-AT and LDH values were elevated in exudates, as compared with transudates, and had an excellent sensitivity and predictive value, but low specificity, in differentiating malignant from non-malignant effusions. Finally, the sensitivity, specificity and positive predictive value of pleural effusion Hp concentrations were lower than those of FRT and complement factors C3 and C4, respectively.

Adult↗
PubMed1995

Phosphorylation of complement component C3 and C3 fragments by a human platelet protein kinase. Inhibition of factor I-mediated cleavage of C3b.

Phosphorylation of C3 in vitro has been shown previously to lead to significantly altered function of the protein. Platelets are known to contain and release considerable amounts of protein kinases and ATP, which are prerequisites for protein phosphorylation. The aim of the present study was to investigate whether C3 is phosphorylated extracellularly by human platelets. Platelet-rich plasma was stimulated by human aggregated gamma-globulin or ADP. The remaining cells were removed by centrifugation, and the plasma was incubated with [gamma-32P]ATP. After precipitation with Sepharose-bound Abs to C3c followed by SDS-PAGE, it was shown that C3 was phosphorylated in the alpha-chain by a protein kinase dependent on Mn2+, Ca2+, or Mg2+ ions. The supernatant from washed, activated platelets was incubated with purified C3 or soluble or activated thiol Sepharose-bound C3b, together with [gamma-32P]ATP. Phosphorylation was seen in the alpha-chain of C3, and to the same extent in the alpha'-chain of both C3b preparations. The analysis of acid hydrolysate demonstrated that C3 contained 32P-labeled Thr and 32P-labeled Ser. After extensive proteolysis with trypsin, the major phosphorylation site was located to a peptide of 3 to 4 kDa that was bound to the activated thiol Sepharose via the free sulphydryl group in the C3d fragment. Incubation of phosphorylated C3b with factors I and H showed that phosphorylation inhibited the cleavage of the alpha'-chain of C3b. The results in this study suggest that phosphorylation is a regulator of C3 during platelet activation induced, for example, by immune complexes.

Binding Sites↗
PubMed1988

C3 and C4 complement components and acute phase proteins in late pregnancy and parturition.

To determine whether changes in complement or acute phase proteins can predict onset of labour, complement components C3 and C4, alpha-1-antitrypsin, and alpha-1-acid glycoprotein were measured serially in the third trimester of pregnancy and throughout labour in 11 women. C-reactive protein (CRP) concentration, C3 conversion products, and factor B activation was studied in five pregnancies one week before delivery, during labour, and six weeks after delivery. C3, C4, and CRP concentrations were unchanged and there was no evidence of complement conversion, either immediately before or during labour, by the classical or alternative pathways. A wide variation among subjects but a small variation within subjects for all proteins assayed was noted. It is important to use serial rather than cross sectional biochemical data when determining normal physiological patterns in pregnancy. The proteins measured have no predictive value in the timing of the onset of normal labour.

Adult↗
PubMed2004

Lack of complement factor C3, but not factor B, increases hyperlipidemia and atherosclerosis in apolipoprotein E-/- low-density lipoprotein receptor-/- mice.

OBJECTIVE: To investigate the effect of complement deficiency on atherogenesis and lipidemia, we used mice deficient in the third complement component (C3-/-) or factor B (FB-/-). METHODS AND RESULTS: Complement-deficient mice were crossed with mice deficient in both apolipoprotein E and the low-density lipoprotein receptor (Apoe-/- LDLR-/-). The percent lesion area in the aorta at 16 weeks, determined by en face analysis, was 84% higher in C3-/- mice than in controls (11.8%+/-0.4% versus 6.4%+/-0.8%, mean+/-SEM, P<0.00005). The C3-/- mice also had 58% higher serum triglyceride levels (P<0.05) and a more proatherogenic lipoprotein profile, with significantly more low-density lipoprotein cholesterol and very-low-density lipoprotein triglycerides than control mice. The C3-/- mice weighed 13% less (P<0.01) and had a lower body fat content (3.5%+/-1.0% versus 13.1%+/-3.0%, P<0.01). There were no differences between FB-/- mice and controls. CONCLUSIONS: Complement activation by the classical or lectin pathway exerts atheroprotective effects, possibly through the regulation of lipid metabolism.

Animals↗
PubMed2004

Reference distributions for complement proteins C3 and C4: a comparison of a large cohort to the world's literature.

The lack of credible reference materials and satisfactory methods for quantifying serum levels has limited the bedside use of complement protein (C3 and C4) measurements. However, great technological strides have been made in the last few years. The remaining barrier to a more relevant and cost-effective use of serum protein data for diagnosis and prognosis is the availability of reliable reference intervals from birth to old age for both males and females. Fifty-one publications reporting reference intervals were identified that meet the criteria used in our prior four studies, and these were analyzed statistically. Previous small studies with constrained age ranges agree, on average, with our larger series of life-long reference ranges. This meta-analysis provides support for our reference ranges and places them in the context of previous publications.

Chemistry, Clinical↗