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Results for “complement C3 inhibitor”

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PubMed1997

Effect of body weight and caloric restriction on serum complement proteins, including Factor D/adipsin: studies in anorexia nervosa and obesity.

Complement plays important roles in host immune defences, and recent studies suggest that adipose tissue is an important site of production for some complement proteins. Starvation has been associated with low complement levels, but studied populations have usually had concomitant opportunistic infections or other conditions which might affect complement levels. To determine the impact of body weight and changes in body weight on serum complement, we investigated levels of complement proteins in otherwise healthy patients with a wide range of body weights, including patients with anorexia nervosa before and after treatment, obese dieters before and after weight loss, and normal weight controls. We found that complement proteins of the alternative pathway (C3, B, and D), alternative pathway haemolytic activity (AP50) and the inhibitors H and I were low in starving anorectics and normalized with weight gain. C3a levels were comparable in anorectics at low weight and after weight gain, indicating that low serum complement levels were attributable to hypoproduction and not complement cascade activation with consumption. Further, levels of C3, B, AP50, H and I, but not D, were higher than controls in obese patients and decreased toward normal after weight loss. Overall, percentage of ideal body weight, changes in body weight, and serum transferrin were each highly correlated with serum levels of complement proteins. We conclude that levels of alternative pathway complement components are determined in part by factors that influence body weight and by weight changes, possibly due to changes in production in adipose tissue or at other sites.

Adult↗

PubMed2006

Anisakis simplex: the activity of larval products on the complement system.

The effects of the larval products (crude extract and excretory-secretory) of Anisakis simplex on the classical and alternative pathways of human complement system were investigated. This could constitute a mechanism to evade host defences, similarly than in other parasitic diseases. The larval products showed a stronger effect on the classical pathway than on the alternative pathway. The most pronounced modulating effects were found for the excretory-secretory products. Chelation of bivalent cations (Ca(2+) or Mg(2+)) by these larval products may be responsible for their mode of action on the alternative pathway, whereas the chelation is not likely to be particularly involved in the anticomplementary activity found on the classical pathway. Detailed studies revealed that the larval products of A. simplex act at the level of the C3 and other complement components. Heating the crude parasite extract led to a notable loss of haemolysis inhibition activity, and the addition of PMSF (a serine protease inhibitor) also cause variation in the activity of the crude extract.

Animals↗

PubMed1976

Separation of six bovine complement components and one inactivator (1, 2).

Six components (C1, C5, C6, C7, C8 and C9) of bovine complement and one inactivator (C3 in) could be separated from bovine serum. Bovine C1 was separated by precipitation at low molarity (0.03 M of relative salt concentration) other components by DEAE-cellulose chromatography using 0.005 M sodium phosphate buffer, pH 7.5, as a base for solvents having the relative salt concentration adjusted by addition of NaCl from 0.03 to 0.3 M. The separated bovine complement components could be tested using intermediates formed from sheep erythrocytes, rabbit hemolysin, guinea pig C1 and remaining human complement components. C2, C3 and C4 of bovine origin remained undetected either because of incompatibility with the intermediates used or interference of inhibitors or inactivators.

Animals↗

PubMed1984

Lack of effect of tranexamic acid on rheumatoid arthritis.

In a double-blind controlled study on 45 rheumatoid arthritis patients, no effect of tranexamic acid (Cyklocapron, 4.5 g per day for 6 weeks) was found in terms of subjective or objective parameters of disease activity. Tranexamic acid did not reduce complement activation, measured by plasma concentrations of the complement C3 split product C3d. Immune complex concentrations in serum were also unaffected. We conclude that plasmin inhibitors do not reduce immune complex mediated complement activation, and they should not be used for treatment of rheumatoid arthritis.

Adult↗

PubMed1991

Gene expression (collagenase, tissue inhibitor of metalloproteinases, complement, and HLA-DR) in rheumatoid arthritis and osteoarthritis synovium. Quantitative analysis and effect of intraarticular corticosteroids.

In situ hybridization was used to localize and quantify gene expression in rheumatoid arthritis (RA) and osteoarthritis (OA) synovial tissue. Collagenase, tissue inhibitor of metalloproteinases (TIMP), HLA-DR, and complement (C2 and C3) gene expression was studied in synovial tissue from 23 patients with RA, OA, or other inflammatory arthropathies. Gene expression was highly compartmentalized: Collagenase, TIMP, and C2 messenger RNA (mRNA) were localized primarily to the synovial lining layer; HLA-DR mRNA was prominent in the lining and in some sublining lymphoid aggregates; the C3 probe hybridized only to sublining lymphoid aggregates. Relative mRNA levels were quantified using computer-assisted image analysis. There was significantly more collagenase, C2, C3, and HLA-DR mRNA in RA compared with OA patients. However, TIMP mRNA levels were similar in RA and OA. Expression of collagenase, TIMP, C2, C3, and HLA-DR genes correlated with the degree of synovial inflammation. The effect of intraarticular corticosteroid injection on synovial tissue gene expression was studied using serial percutaneous synovial biopsy samples from the knees of 3 RA patients. Joints were biopsied, injected with triamcinolone, and rebiopsied 1-2 weeks later. Histologic inflammation scores were lower in posttreatment synovia. Collagenase and TIMP mRNA, although abundant in presteroid samples, were nearly undetectable in post-steroid tissues. HLA-DR mRNA levels also were significantly decreased. C2 and C3 hybridization significantly decreased in 2 of 3 patients and 1 of 3 patients, respectively. Hence, clinical response to intraarticular steroid therapy was accompanied by histologic improvement and decreased expression of genes that play a role in articular destruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

PubMed2003

Complement activation is critical to airway hyperresponsiveness after acute ozone exposure.

Ozone (O3) can induce airway hyperresponsiveness (AHR) and neutrophilic inflammation. We evaluated the role of complement in development of AHR and inflammation after acute O3 exposure in mice. Mice were exposed to O3 at 2 ppm for 3 hours, and airway responsiveness to methacholine was measured 8 hours after O3 exposure. Complement was depleted or inhibited by intraperitoneal injection of cobra venom factor (CVF) or complement receptor-related gene y (Crry)-Ig, a potent C3 convertase inhibitor; neutrophils were depleted using an antineutrophil monoclonal antibody. CVF attenuated the development of AHR by O3. Administration of Crry-Ig also prevented the development of AHR. Bronchoalveolar lavage (BAL) fluid neutrophilia after O3 exposure was significantly decreased by administration of either CVF or Crry-Ig. Increased BAL fluid total protein after O3 exposure was lowered by depletion or inhibition of complement. In contrast to the effects of complement inhibition or depletion, depletion of BAL neutrophil counts by more than 90% with the monoclonal antibody did not affect the development of AHR after O3 exposure. These data indicated that activation of the complement system follows acute O3 exposure and is important to the development of AHR and airway neutrophilia. However, this neutrophil response does not appear necessary for the development of AHR.

Animals↗

PubMed2001

[Complement activity among individuals at a ground self-defense force base].

OBJECTIVE: This study aims to examine the distribution of hemolytic complement activity, the prevalence of hypocomplementemia and the disorders causing hypocomplementemia among individuals taking part in a mass screening program. METHODS: The subjects consisted of 1340 male Japanese participating in a mass screening program at a Ground Self-Defense Force base in Asaka. We measured the hemolytic complement activity (CH50) after overnight fasting. The CH50 levels for hypercomplementemia and hypocomplementemia were defined as those outside the range of mean +/- 2 SD, respectively. We next measured the concentration of complement components: CIq, C4, B, C3, C5, C9, and C1-inhibitor for men with hypocomplementemia. Rheumatoid factor, ANA, HBsAg, HbsAb, and HCVAb were also measured. RESULTS: The mean +/- SD of age was 43.7 +/- 5.7. The CH50 levels ranged from 7.2 to 66.4 U/ml (mean +/- SD = 37.1 +/- 4.0 U/ml). Twenty-one and 37 men were classified as having hypocomplementemia (CH50 < 29.1 U/ml) and hypercomplementemia (CH50 > 45.1 U/ml), respectively. The age of the individuals with hypocomplementemia was 43.9 +/- 5.6 (Mean +/- SD) years. Three men with C9 deficiencies, 2 men with C5 deficiencies and 7 men with cold activation were identified among the 21 hypocomplementemic men. Three hepatitis C and 2 hepatitis B patients were also found among the 21 hypocomplementemic men. Other disorders found among the hypocomplementemic men were 3 glomerulonephritides and 1 possible SLE. CONCLUSION: We examined the distribution of CH50 levels in 1340 adult male Japanese. We identified 21 men with hypocomplementemia, and also found 5 cases of complement component deficiencies among 21 hypocomplementemic men. In addition the measurement of the complement activity may have also helped detect the presence of hepatitis, hypocomplementemic glomerulonephritis and collagen disease at an early stage.

Adult↗

PubMed2006

CRIT peptide interacts with factor B and interferes with alternative pathway activation.

Complement C2 receptor inhibitor trispanning (CRIT) inhibits the classical pathway (CP) C3 convertase formation by competing with C4b for the binding of C2. The C-terminal 11-amino-acid of the first CRIT-extracellular domain (CRIT-H17) has a strong homology with a sequence in the C4beta chain, which is responsible for the binding of C2. Since the CP and alternative pathway (AP) C3 convertases have many functional and structural similarities, we further investigated the effects of CRIT-H17 on the AP. The factor D-mediated cleavage of factor B (FB) was blocked by CRIT-H17. By ELISA and immunoblot, CRIT-H17 was shown to bind FB. CRIT-H17 had no decay activity on the C3bBb complex as compared to decay-accelerating factor. Binding of CRIT-H17 to FB did not interfere with the assembly of C3bB complex. In a haemolytic assay using C2-deficient serum, CRIT-H17 interfered with AP complement activation.

Amino Acid Sequence↗

PubMed1999

Trypsin-like proteinase and its endogenous inhibitor from Yersinia pseudotuberculosis. Biological activity.

A trypsin-like proteinase (YPTP) and its endogenous inhibitor (ITYP) were isolated from the culture filtrate of the pathogenic bacterium Yersinia pseudotuberculosis, and their biological activities were studied. YPTP was found to be highly toxic for random-bred white mice. Under in vitro conditions the proteolytic enzyme destroyed protective proteins of the immune system of the animals--IgG, IgA, and proteins of the complement system (CIq, C3, and C5)--and, consequently, was a pathogenetic factor in yersinioses. The inhibitor ITYP was shown to manifest antibacterial activity against virulent forms of Yersinia pseudotuberculosis, Escherichia coli, and Salmonella typhimurium. The ITYP preparation was harmless and nontoxic.

Animals↗

PubMed1982

Complement biosynthesis by the human hepatoma-derived cell line HepG2.

The human hepatoma-derived cell line, HepG2, synthesized and secreted functional complement proteins C1r, C1s, C2, C3, C4, C5, factor B, C1 inhibitor, C3b inactivator, a small amount of C6, and trace amounts of C8; but failed to produce detectable C1q, C7, or C9. Immunochemically, C2, C3, C4, C5, and B were isolated from culture medium as proteins with molecular sizes and subunit structures identical to the corresponding components isolated from serum. C2 and factor B from cellular lysates had slightly lower molecular weights than the corresponding proteins in culture medium. C3, C4, and C5 were detected as single chain precursor molecules in cellular lysates. These results demonstrate that human C5, like C3 and C4, is synthesized as a single chain precursor that is converted by limited proteolysis to the native two-chain molecule. It also establishes the precursor-product relationship for human pro-C4 and native C4, pro-C5, and native C5.

Carcinoma, Hepatocellular↗

PubMed1981

Complement receptor is an inhibitor of the complement cascade.

A glycoprotein from the membrane of human erythrocytes has been identified as a receptor for C3b (CR1). It promotes the dissociation of the alternative pathway C3 convertase C3b,Bb and the cleavage of C3b by C3b/C4b inactivator. We find that CR1 also inactivates the C3 and C5 convertases of the classical pathway. CR1 inhibits the consumption of C3 by C3 convertase EAC142 and enhances the decay of C4b,2a sites. On a weight basis, CR1 is approximately 5-10 times more active than C4 binding protein, a serum inhibitor of C4b,2a. The binding of 125I-CR1 to EAC14 cells is inhibited by C2. Therefore, it is likely that CR1 and C2 compete for a site on C4b. CR1 inhibited C5 convertase even more effectively, but had no effect on the assembly of the late complement components. At high concentrations, CR1 alone has no irreversible effects on cell-bound C4b. In the fluid phase, CR1 can function as a cofactor for the cleavage of the alpha' chain of C4b by C3b/C4b inactivator. A well-known function of CR1 is to promote adherence of microbes or immune complexes bearing C3b and C4b to cells. This interaction could result in a microenvironment damaging to the plasma membrane of the responding cell because the extrinsic C3b and C4b fragments can serve as additional sites of assembly of enzymes of the cascade. We therefore wish to propose that CR1 on the surface of cells supplies an increased local concentration of a strong inhibitor of the amplifying enzymes of the complement system and provides cells with a mechanism for circumventing damage when they bind C3b- and C4b-bearing substrates.

Complement C3-C5 Convertases↗

PubMedDate not supplied

[Levels of the individual complement components in the blood serum of volunteers on diets with a various levels of optimal protein composition].

Protein fractions of complement (C3, C4, C5 and C9) and the control protein Ct-inhibitor) were studied in blood serum of practically healthy men placed on the diet marked by protein deficiency. It was noted that C3 and C9 were particularly sensitive to protein deficiency in the diet (5 to 8.2 g/day according to nitrogen), with the titers of these fractions being low.

Complement System Proteins↗

PubMed1975

Alternate complement pathway induction of aggregation and release of 5-hydroxytryptamine and adenosine diphosphate by rabbit platelets.

The present studies investigated patterns of rabbit platelet aggregation and release of 5-hydroxytryptamine (5HT) utilizing nine variables: three different types of challenge, soluble antigen and antibody (AG-AB), zymosan (Z), an agent known to activate the alternate complement pathway (ACP), and Z preincubated in lightly heparinized plasma so as to become coated with complement (ZC); three different types of platelet-rich plasma (PRP), lightly heparinized PRP in which both complement pathways are active, ethylene glycol tetraacetic acid-PRP (EGTA-PRP) in which only the ACP is active, and ethylene diamine tetraacetic acid PRP (EDTA-PRP), which inhibits both complement pathways; three different types of inhibitors, cobra venom factor (CoF), which causes activation of C3 proactivator (C3PA) to C3 activator (C3A) and fluid phase decomplementation of C3 and C5 through C9, adenosine monophosphate (AMP), a specific antagonist of ADP, and tosyl arginine methyl ester (TAME), an inhibitor thought to act not only on the first component of complement, but also on a platelet membrane site of mediating complement-induced platelet injury as well as on C3PAse. In heparinized PRP, both AG-AB and Z produced biphasic aggregation and prompt and extensive 5HT release. A brief lag period noted with both AG-AB and Z challenge was not observed with ZC challenge, indicating that this lag period represented time required for generation of the necessary complement-dependent membrane-injuring activity. Prior decomplementation by CoF entirely prevented both aggregation and release by either AG-AB or Z but by ZC, indicating first that fluid-phase ACP activation did not produce platelet injury, and second that ZC had on its surface an activity capable of producing immediate biphasic aggregation and prompt 5HT release without the further participation of later acting complement components. Both AMP and TAME eliminated the second phase of aggregation and diminished or eliminated 5HT release with all three challenges, suggesting that both inhibitors might be operative on similar or identical platelet membrane receptors mediating complement-dependent platelet injury. In EGTA-PRP, AG-AB and Z produced delayed monophasic aggregation and delayed and diminished 5HT release, whereas ZC produced immediate although monophasic aggregation but delayed and diminished 5HT release. This suggested that all three challenges were capable of producing ACP-mediated platelet injury.

Adenosine Diphosphate↗

PubMed2002

Complement receptor type 1 (CD35) mediates inhibitory signals in human B lymphocytes.

The complement system---particularly component C3---has been demonstrated to be a key link between innate and adaptive immunity. The trimolecular complex of complement receptor type 2 (CR2), CD19, and CD81 is known to promote B cell activation when coligated with the B cell Ag receptor. In the present study, we aimed to elucidate the role of human complement receptor type 1 (CR1), the other C3-receptor on B cells. As ligand, aggregated C3 and aggregated C3(H(2)O), i.e., multimeric "C3b-like C3", are used, which bind to CR1, but not to CR2. In experiments studying the functional consequences of CR1-clustering, the multimeric ligand is shown to inhibit the proliferation of tonsil B cells activated with a suboptimal dose of anti-IgM F(ab')(2). Importantly, this inhibitory activity also occurs in the presence of the costimulatory cytokines IL-2 and IL-15. The anti-IgM-induced transient increase in the concentration of intracellular free Ca(2+) and phosphorylation of several cytoplasmic proteins are strongly reduced in the presence of the CR1 ligand. Data presented indicate that CR1 has a negative regulatory role in the B cell Ag receptor mediated activation of human B lymphocytes.

Antibodies, Anti-Idiotypic↗

PubMed2006

[Complement component deficiencies in human disease].

The complement system, composed of several plasma and membrane proteins, is an integral part of the innate immune system and plays a role in inflammatory response, destruction of infectious agents, elimination of immune complexes, and control of the specific (adaptive) immune response. Hereditary deficiencies of complement components are relatively rare and associated with susceptibility to a wide variety of clinical diseases. Complement components may be target of antibodies (anti-C1q, factor H, C3 alternative convertase, or C3NeF autoantibodies or anti-C1 inhibitor antibodies) that lead to acquired deficiencies. Testing the complement system is especially necessary in patients with autoimmune diseases, some kidney diseases, recurrent infections (especially meningococcal), and angioedema. Precise clinical descriptions of the phenotypes associated with these deficiencies and their molecular diagnosis are necessary to improve our understanding of the role that the complement system plays in the physiopathological mechanisms of these diseases and to propose the most specific treatment for them.

Autoimmune Diseases↗

PubMed2006

Kaposi's sarcoma-associated herpes virus complement control protein: KCP--complement inhibition and more.

The complement system is an important part of innate immunity providing immediate protection against pathogens without a need for previous exposure, as well as priming the adaptive immune response through opsonisation, leukocyte recruitment and enhancing humoral immune responses. Its importance is not only shown through recurring fulminant infections in individuals with complement component deficiencies, but also through the many complement evasion strategies discovered for a wide range of infectious microbes (including acquisition of endogenous host complement inhibitors and expression of own homologues). Knowledge of these mechanisms at a molecular level may aid development of vaccines and novel therapeutic strategies. Here, we review the structure-function studies of the membrane-bound complement inhibitor KCP that is expressed on the surface of Kaposi's sarcoma-associated herpesvirus (KSHV) virions and infected cells. KCP accelerates the decay of classical C3 convertase and induces the degradation of activated complement factors C4b and C3b by a serine proteinase, factor I. Molecular modeling and site-directed mutagenesis have identified sites on the surface of KCP required for complement inhibition and support the hypothesis that KCP has evolved to mimic the structure and function of endogenous human inhibitors. KCP additionally enhances virion binding to permissive cells through a heparin/heparan sulfate-binding site located at the N-terminus of the protein.

Amino Acids↗

PubMed2000

Production and functional analysis of rat CD59 and chimeric CD59-Crry as active soluble proteins in Pichia pastoris.

Crry (CR1-related gene/protein) is a rodent complement regulator that inhibits C3 convertases. CD59 is a conserved protein inhibitor active towards C8 and C9. We have previously produced rat Crry as a recombinant soluble (rs) protein in Pichia pastoris. In this study we produced functionally active rat rsCD59 and a chimeric rsCD59-Crry protein in P. pastoris. The GPI anchor addition site of rat CD59 (Asn-79) was replaced either by a stop codon to produce rsCD59, or with the sequence of the first five short consensus repeats of Crry to produce rsCD59-Crry. Proteins were generated by fermentation and purified by affinity chromatography on an anti-CD59 column. In a standard classical pathway haemolysis assay, all three rs proteins had inhibitory activity, with 50% inhibition at 0.5 microM (rsCrry and rsCD59-Crry) and 4.4 microM (rsCD59). In an assay examining inhibition of C5b-9, in which C5b-7 was first formed, followed by purified C8 and C9, rsCD59 and rsCD59-Crry were active with 50% inhibition at 0.8 microM (rsCD59-Crry) and 1.3 microM (rsCD59). The degree of inhibition was independent of whether the C8 and C9 were of rat or human origin. Therefore, we have produced rsCD59 and rsCD59-Crry in P. pastoris. The rsCD59 retains its inhibitory activity towards C5b-9, while rsCD59-Crry appears to have the combined activities of Crry and CD59. In a haemolytic assay, the inclusion of CD59 to Crry is of no additional benefit to Crry, which may illustrate the overall importance of the C3 convertase step. Yet, inclusion of Crry to CD59 increases the potency of CD59 towards C5b-9.

Animals↗

PubMed1989

Pancreatic pseudocyst fluid--a mixture of plasma proteins and pancreatic juice possessing a high proteolytic activity.

Pancreatic pseudocyst fluid from eight patients was examined biochemically. The fluid was found to be a mixture of plasma proteins and pancreatic juice, possessing a high proteolytic activity against high- as well as low-molecular-weight proteins. The proteolytic activity was found to be trypsin-, kallikrein- and plasmin-like. Gel filtration studies showed proteolytic activity to be present corresponding to alpha-2-macroglobulin-bound proteases and also to free proteases. Quantitative immunochemical levels were about 30-100% of normal plasma levels for alpha-2-macroglobulin, C1 inhibitor, antithrombin III and alpha-2-antiplasmin. However, there was practically no functional inhibitory capacity left in the pseudocyst fluid, except for alpha-1-protease inhibitor, which retained its inhibitory capacity. Neither native kininogen nor complement factor C3 was found: this was probably a result of the proteolytic activity. It is concluded, that a continuing proteolytic activity within the pseudocyst, although decreasing with aging of the cyst, could explain symptoms and complications caused by the pseudocyst.

Adult↗