Sporozoites of Plasmodium yoelii infect mice with targeted deletions in ICAM-1 and ICAM-2 or complement components C3 and C4.
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Amino Acid Sequence↗
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Results for “Complement C3”
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Metabolites of procainamide and practolol inhibit complement components C3 and C4.
Drug-induced systemic lupus erythematosus arises from toxic side-effects of administration of hydralazine, isoniazid, procainamide and practolol. Hydralazine and isoniazid are nucleophilic drugs and inhibit the covalent binding reaction of complement components, C3 and C4, an effect likely to lead to deposition of immune complexes (a feature of systemic lupus erythematosus). Procainamide and practolol do not themselves inhibit C3 and C4. A range of metabolites and putative metabolites of procainamide and practolol were synthesized, and tested for their ability to inhibit the covalent binding reactions of C3 and C4. The highly nucleophilic hydroxylamine metabolite of procainamide was strongly inhibitory in both tests, as was a putative hydroxylamine metabolite of practolol. These studies indicate a potential role for the hydroxylamine metabolites in mediating the toxic side-effects of procainamide and practolol, and emphasize the need for adequate measurements of hydroxylamine metabolites in human tissue.
Acecainide↗
Participation of the transcription factor C/EBP delta in the acute-phase regulation of the human gene for complement component C3.
C3, the third component of complement, is critical in the host immune response in that it is involved in both the classical and alternative pathways of complement activation. We have previously shown that a region (bp -127 to -70) within the C3 promoter is indispensable for conferring interleukin 1 (IL-1) responsiveness to this gene. A sequence comparison reveals two CCAAT/enhancer binding protein (C/EBP) consensus sequences, basic DNA binding region and leucine zippers 1 and 2 (bZIP1 and bZIP2), within this region. Site-directed mutagenesis of the more 3' C/EBP site (bZIP1) in the C3 promoter significantly reduced the basal level of expression and the IL-1 responsiveness of the reporter gene, whereas mutation in the second, more 5', C/EBP consensus sequence (bZIP2) had a minimal effect on basal expression and IL-1 inducibility. Electrophoretic-mobility-shift assays, with and without antibodies to the different C/EBP proteins that "supershift" protein-DNA complexes, demonstrated that proteins binding at the 3' C/EBP site formed several complexes. Antibodies to C/EBP alpha supershifted the majority of complexes formed with extracts from control cells. Antibodies directed against C/EBP delta supershifted the major IL-1-inducible complexes. Western immunoblot analyses showed that the level of C/EBP delta protein was increased dramatically in the nuclei of Hep 3B2 cells after 4 h of IL-1 treatment. When Hep 3B2 cells were cotransfected with a C/EBP delta expression vector and a construct with a C3 promoter and a reporter gene, C/EBP delta was able to trans-activate the C3 promoter in an IL-1-responsive manner. The data strongly suggest that C/EBP delta is the major protein responsible for regulating the acute-phase expression of the human C3 gene.
Base Sequence↗
[Study of the complement fractions C3 and C4 by use of immunodiffusion method for evaluation of the course of some infantile glomerular nephropathies].
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Adolescent↗
Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3.
The human end-stage kidney and its experimental analogue, the remnant kidney in the rat, exhibit widespread tubulo-interstitial disease. We investigated whether the pathogenesis of such tubulo-interstitial injury is dependent upon adaptive changes in tubular function and, in particular, in ammonia production when renal mass is reduced. Dietary acid load was reduced in 1 3/4-nephrectomized rats by dietary supplementation with sodium bicarbonate (NaHCO3), while control rats, paired for serum creatinine after 1 3/4 nephrectomy, were supplemented with equimolar sodium chloride. After 4-6 wk, NaHCO3-supplemented rats demonstrated less impairment of tubular function as measured by urinary excretory rates for total protein and low molecular weight protein and higher transport maximum for para-aminohippurate per unit glomerular filtration rate, less histologic evidence of tubulo-interstitial damage, less deposition of complement components C3 and C5b-9, and a lower renal vein total ammonia concentration. Such differences in tubular function could not be accounted for simply on the basis of systemic alkalinization, and differences in tubular injury could not be ascribed to differences in glomerular function. Because nitrogen nucleophiles such as ammonia react with C3 to form a convertase for the alternative complement pathway, and because increased tissue levels of ammonia are associated with increased tubulo-interstitial injury, we propose that augmented intrarenal levels of ammonia are injurious because of activation of the alternative complement pathway. Chemotactic and cytolytic complement components are thereby generated, leading to tubulo-interstitial inflammation. Thus, alkali supplementation reduces chronic tubulo-interstitial disease in the remnant kidney of the rat, and we propose that this results, at least in part, from reduction in cortical ammonia and its interaction with the alternative complement pathway.
Acid-Base Equilibrium↗
Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury.
Immunological events occurring in the central nervous system (CNS) as a result of head trauma are largely unexplored. We report here that the levels of the alternative pathway complement proteins C3 and factor B are elevated in the cerebrospinal fluid (CSF) of head-injured patients. C3 and factor B indices suggest that changes in C3 and factor B levels in CSF are most likely due to altered blood-brain barrier integrity and not to intrathecal synthesis. These data demonstrate, for the first time, elevated levels of complement proteins in CSF of patients with severe traumatic brain injury. Elevated complement levels in brain injury may contribute to secondary damage.
Adolescent↗
Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H.
The complement system participates in both innate and acquired immune responses. Deficiencies in any of the protein components of this system are generally uncommon and require specialized services for diagnosis. Consequently, complement deficiencies are clinically underscored and may be more common than is normally estimated. As C3 is the major complement component and participates in all three pathways of activation, it is fundamental to understand all the clinical consequences observed in patients for which this protein is below normal concentration or absent in the serum. C3 deficiencies are generally associated with higher susceptibility to severe infections and in some cases with autoimmune diseases such as systemic lupus erythematosus. Here, we review the main clinical aspects and the molecular basis of primary C3 deficiency as well as the mutations in the regulatory proteins factor I and factor H that result in secondary C3 deficiencies. We also discuss the use of animal models to study these deficiencies.
Afibrinogenemia↗
Recombinant adenovirus vectors activate the alternative complement pathway, leading to the binding of human complement protein C3 independent of anti-ad antibodies.
Recombinant adenoviruses are one of the most common gene transfer vectors utilized in human clinical trials, but it is also clear that systemic administration of this virus will be met by host innate and adaptive antiviral immune responses. One element of innate immunity is the complement system, a group of proteins that has evolved to rapidly recognize foreign microbes and viruses and to clear them from the circulatory system prior to their gaining entry to vulnerable host cells. Excessive complement activation can initiate or propagate a number of deleterious inflammatory responses, by release of potent cytokines and anaphylatoxins and/or by direct cellular toxicity. These reactions can progress rapidly and are factors important in serious complications, including the systemic inflammatory response syndrome and the adult respiratory distress syndrome.
Adenoviridae↗
Synthesis of complement components (C3, C2, B and C1-inhibitor) and lysozyme by human monocytes and macrophages.
The synthesis of C3, C2, factor B (B) C1-inhibitor and lysozyme has been studied in monocytes and macrophages isolated from the synovial fluids of patients with rheumatoid arthritis. Concentrations of all 5 proteins in culture supernatants were measured by the sandwich ELISA technique. Kinetic studies showed that only lysozyme and C3 could be detected in monocyte culture supernatants on the first day of culture, whereas C2, B and C1-inhibitor were not present until the third day. In contrast all 5 proteins could be detected in the supernatants of macrophage cultures on day 1. In both monocyte and macrophage cultures synthesis of lysozyme and C1-inhibitor continued throughout the culture period, whereas synthesis of C2, B and C3 appeared to be reduced after the fifth day in culture. Quantitative studies showed that the secretion rates of lysozyme (4,700 X 10(3) molecules/cell/hr) was similar in monocytes and macrophages. Synthesis rates for all 4 complement components in monocyte cultures were less than 0.2% of that for lysozyme. Although the synthetic rates were higher in macrophages, even then they constituted less than 2% of the rate for lysozyme. Synthetic rates for complement components, but not lysozyme, were increased by BSA-anti-BSA antigen-antibody complexes and reduced by serum-treated complexes. Although the functional activity of monocyte B was similar to that for serum, the activity of monocyte C2 was 5 times that of serum C2. As C42 formed with monocyte C2 had a half-life of 13.5 min at 30 degrees C, compared with 4.5 min for the enzyme formed with serum C2, it is probable that monocyte C2 is oxidized by the oxygen products of these cells.
Antigen-Antibody Complex↗
Influence of proquazone (Biarison) on the levels of complement components (C3 and C4) in synovial fluid and on IgM in serum in patients with active rheumatoid arthritis. A preliminary report.
Four patients with erosive rheumatoid arthritis and one with psoriasis arthropathy were treated with 600-900 mg/day proquazone for 4-7 weeks. All patients had acute knee effusions. The complement components C3 and C4, as well as IgG, IgA, IgM and total protein, were measured in both the synovial fluid and serum before and after treatment. In the 4 patients with rheumatoid arthritis, a marked increase in C3 and/or C4 levels in the synovial fluid was found, correlating in 3 cases with a good clinical response. However, no corresponding changes in complement levels were recorded in the serum. The patient with psoriasis arthropathy did not show any reaction. These preliminary results suggest that proquazone may influence the immunological processes in rheumatoid arthritis.
Adult↗
Stress response decreases the interleukin-1beta-induced production of complement component C3 in human intestinal epithelial cells.
Interleukin-1beta (IL-1beta) increases the production of complement component C3 in enterocytes. Heat shock regulates the response to cytokines and other inflammatory mediators in various cell types. We tested the hypothesis that the heat-shock response regulates IL-1beta-induced C3 production in the enterocyte. Cultured Caco-2 cells, a human intestinal epithelial cell line, were treated with sodium arsenite (10-500 microM) for 1 h or subjected to hyperthermia (43 degrees C) for 1-4 h, and allowed to recover for 1 h. The cells were then treated with IL-1beta (0.5 ng/ml) for up to 24 h, whereafter C3 levels were measured by ELISA and C3 mRNA by Northern blot analysis. Heat-shock protein of 72 kDa (hsp72) was determined by Western blot analysis. Treatment of the cells with sodium arsenite or subjecting them to hyperthermia induced the expression of hsp72. The IL-1beta-induced expression of C3 mRNA and C3 production were down-regulated by hyperthermia and sodium arsenite in a dose-dependent fashion. The results suggest that the stress response induced by hyperthermia or sodium arsenite decreases IL-1beta-induced C3 production in human enterocytes.
Arsenites↗
Stimulation of histamine receptors of human monocytoid and hepatoma-derived cell lines and mouse hepatocytes modulates the production of the complement components C3, C4, factor B, and C2.
The influence of histamine (and the related agonists and antagonists) alone or in the presence of recombinant human interleukin 1 alpha (IL-1 alpha) and gamma interferon (IFN-gamma) was studied on the production of complement components C3, C2, factor B, and C4 in vitro with human monocytoid cell line U937, hepatoma-derived cell line HepG2, and mouse hepatocytes. Both U937 and HepG2 cells responded to histamine through H1 and H2 histamine receptors. The effect of histamine on the biosynthesis and gene expression of complement proteins was predominantly enhancing via the H1 histamine receptors and inhibitory through the H2 receptors. The actual predominance of the histamine receptor involved (and the outcome of the ligand interaction) seemed to be greatly affected by the simultaneous activation of the cells by IL-1 or IFN-gamma.
Animals↗
Deficiency of complement component C3 is associated with accelerated removal of soluble 123I-labelled aggregates of IgG from the circulation.
Complement and erythrocyte complement receptors CR1 (CD35) play an important role in the clearance of immune complexes. We studied the elimination of soluble 123I-labelled aggregates of human immunoglobulin G (123I-AIgG), used as a model for immune complexes, in two patients with a congenital and two patients with an acquired deficiency of complement component C3, and compared these with 10 healthy controls. The first disappearance halflife of 123I-AIgG was shorter (3.3 +/- 0.4 versus 7.0 +/- 0.4 min in the controls, P = 0.005) and maximal hepatic uptake of aggregates was increased in the C3 deficient patients (maximal liver/background ratio 3.6 +/- 0.4 versus 2.7 +/- 0.2 in controls, P = 0.04). Apparently, in the absence of C3, removal of circulating immune complexes by the liver is accelerated, probably through Fc receptor-dependent mechanisms.
Adult↗
The estrogen-responsive 110K and 74K rat uterine secretory proteins are structurally related to complement component C3.
Estrogens stimulate the synthesis of specific secretory proteins in the rat uterus. Here we show that two of these, polypeptides of relative molecular weight 110,000 (110K) and 74,000 (74K), are structurally related to C3, the third component of complement, a glycoprotein that plays a central role in regulating complement-mediated inflammatory and immune responses. The similarities were based on the observations that (1) NH2-terminal amino acid sequence of the 74K polypeptide showed sequence homology with the beta chain of mouse C3, (2) comparison of the electrophoretic mobilities of the 110K and 74K polypeptides in the presence and absence of reducing agents revealed that they were disulfide-linked subunits of a protein of Mr approximately 180,000, (3) the native protein was immunoreactive with antibodies specific for rat C3, and (4) both polypeptides were immunoprecipitated with antibodies to rat C3.
Amino Acid Sequence↗
Allelic variants for complement factors C3, C4, and B in acute necrotizing ulcerative gingivitis.
Impaired immune defense mechanisms and genetic factors appear to play a role in susceptibility to acute necrotizing ulcerative gingivitis (ANUG). Therefore, possible etiological mechanisms might involve genes at the Major Histocompatibility Complex, which include the complement factor loci. We have tested for a possible association between certain complement factor alleles and ANUG using a case-control study design. Specific alleles at complement factors C3 and C4, and properdin factor B (Bf) loci were determined indirectly by high voltage agarose gel electrophoresis in 58 subjects with a history of ANUG and in 58 age-sex-matched healthy controls. The highest relative risk of ANUG, as obtained by conditional logistic regression, for alleles at the C3 locus was 1.9 (90% confidence limits 0.8 to 4.8; p = 0.229) for C3*F-positive individuals. The highest relative risk for alleles at the C4 locus was 2.6 (0.5 to 14.9; p = 0.358) for C4A*3-positive individuals. There was no evidence for an association between Bf allotype and risk of ANUG, with a relative risk of 1.2 for Bf*F- and relative risk of 1.0 for B*S-positive individuals. None of our estimates was statistically significant. We conclude, therefore, that it is unlikely that there is any association between complement factor gene haplotype and susceptibility to ANUG.
Acute Disease↗
Nucleophilic modification of human complement protein C3: correlation of conformational changes with acquisition of C3b-like functional properties.
Inactivation of C3 by enzymatic cleavage, nucleophilic addition, or slow freezing and thawing resulted in the acquisition of similar end-state conformations as judged by near-UV circular dichroism. Although inactivation by the two nonenzymatic processes involves no peptide bond scission, the inactivated C3 resembled C3b in that it possessed a free sulfhydryl group not present in the native protein and an increased surface hydrophobicity as evidenced by enhanced binding of the fluorophore 8-anilino-1-naphthalensulfonate (ANS). The C3b-like functional properties of modified C3 [Pangburn, M. K., & Müller-Eberhard, H. J. (1980) J. Exp. Med. 152, 1102-1114] may thus be understood in terms of the similarity of its conformation to that of C3b. The rate of the conformational change following proteolytic cleavage was fast and appeared to be limited by the rate of the enzymatic reaction. In contrast, the rate of conformational change following addition of methylamine was slow and rate limited by the conformational rearrangement itself, not by the chemical modification. A kinetic analysis of the changes in circular dichroism and ANS fluorescence enhancement suggested that the nucleophilic addition was spectroscopically undetectable and was followed by a minimally biphasic, spectroscopically demonstrable conformational rearrangement. The appearance of C3b-like functional activity in nucleophile-modified C3 largely parallels the time course of the spectroscopically detectable conformational change but is distinctly slower than the rate at which hemolytic activity is lost. While fully transconformed methylamine-inactivated C3 can bind factor B and is susceptible to cleavage by C3b inactivator and its cofactor beta 1H, this cleavage occurs at a substantially slower rate than the equivalent process in C3b. The implications of these findings in terms of the mechanism through which the alterative pathway of complement is initiated are discussed.
Anilino Naphthalenesulfonates↗
Conversion of the C3 component of complement in mice infected with Trypanosoma cruzi.
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Animals↗
SDS denaturation of complement factor C3 as a model for allosteric modifications occurring during C3b binding: demonstration of a profound conformational change by means of circular dichroism and quantitative immunoprecipitation.
The antigenic expression of bound but not fluid-phase C3b closely resembles that of sodium dodecyl sulphate (SDS) denatured C3. For this reason, denatured C3 has been used in this study as a model to characterize the conformational changes associated with bound C3b. It was shown in circular dichroism in the far UV spectrum that profound changes in the secondary structure occurred in denatured C3. Furthermore, quantitation by immunoprecipitation of the previously observed antigenic changes during denaturation demonstrated that C3 lost 2/3 of the antigens associated with native C3 whereas 1/3 were stable. The lost antigens were completely replaced by antigens that are specific for denatured and bound C3. We postulate that the binding of C3b is accompanied by a profound conformational change distinctive of that observed in fluid-phase C3b.
Allosteric Site↗