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Results for “complement C3 inhibitor”

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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↗

PubMedDate not supplied

Complement determinations in the synovial fluid and serum of a patient with Erythema nodosum leprosum.

Simultaneous serum and synovial fluid CH50, C1, C4, C2, C1 esterase inhibitor and C3 protein were determined in a patient with acute erythema nodosum leprosum. The pattern of synovial fluid complement activity coupled with the demonstration of multiple lepra bacilli free and within histiocytes is more consistent with an infectious than an immune complex induced synovitis.

Arthritis, Infectious↗

PubMed2003

Complement: structure, functions, evolution, and viral molecular mimicry.

The complement (C') system has long been recognized as an important mediator of innate immune defense and inflammation. In recent years there is increasing evidence suggesting that complement components may also participate in non-inflammatory and developmental processes. Here we review our current work on the structural-functional aspects of C3-ligand interactions and the rational design of small-sized complement inhibitors. We present a novel, proteomics-based, approach to studying protein-protein interactions within the C' system and discuss our progress in the study of viral immune evasion strategies. Furthermore we discuss the involvement of complement proteins in organ regeneration and hematopoietic development.

Animals↗

PubMed1984

Relation of clinical activity of rheumatoid arthritis to immune complexes, complement components and anti-immunoglobulins.

Circulating immune complexes by fluid phase Clq binding assay, complement components and anti-immunoglobulin levels were studied in sera of 35 patients with rheumatoid arthritis (RA). In 23 of the 35 sera (65.7%), circulating immune complexes were positive, and the mean +/- SD of Clq binding activity (ClqBA), 44.5 +/- 19.4%, was significantly high compared to that of healthy persons, 17.4 +/- 8.2%. Antigenic determination of complement components revealed that Clq, C3, C5, C9, factor B and Cl esterase inhibitor (ClINH) were significantly high in sera of RA, but C4 and properdin were not. The disease activity correlated with ClqBA, IgG- and IgM-anti-immunoglobulins, C9 and serum IgG. On the other hand, ClqBA correlated with both IgG- and IgM-anti-immunoglobulin levels but not with complement components.

Adolescent↗

PubMed1997

Downregulation of Waf1, C2, C3, and major histocompatibility complex class I loci within an 18-cM region of chromosome 17 in adenovirus-transformed mouse cells.

In this study, the expression of the p53 tumor suppressor gene and the p53-regulated Mdm2 and Waf1 genes was evaluated in adenovirus (Ad)-transformed mouse cells. The expected levels of p53 mRNA and protein and Mdm2 mRNA were detected in all transformed cells. However, the level of Waf1 mRNA was markedly reduced in Ad12-transformed cells and in some Ad5-transformed cells. Waf1 expression was not reduced in untransformed mouse cells infected with Ad12 or Ad5. Expression of the class I major histocompatibility complex (MHC) locus was downregulated in 13 Ad-transformed cell lines (derived from four different strains of mice) that exhibited reduced expression of Waf1. Waf1 is located on mouse chromosome 17 proximal to the MHC class I locus. To determine whether other chromosome 17 genes were downregulated, the cells were examined for expression of other genetic loci. Of those tested, only the C2 and C3 complement loci were expressed in mouse fibroblasts. Expression of C2 (which is within the MHC) and expression of C3 (which is 15 cM distal to the MHC) were downregulated in those transformed cells in which Waf1 and MHC class I were downregulated. The Ad12- and Ad5-transformed cells that expressed low levels of Waf1, MHC class I, C2, and C3 formed tumors in syngeneic adult mice. These data suggest that the downregulation of multiple genes within the 32 Mb of mouse chromosome 17 that includes the Waf1 locus to the C3 locus occurs in Ad mouse-cell transformation and may contribute to the tumorigenicity of transformed cells.

Adenoviridae↗

PubMed2005

Skin venous thromboembolism by combined oral contraceptive in a woman with acquired angioedema and Factor V Leiden mutation.

OBJECTIVE: The purpose of this study is to report a case of acquired angioedema and Factor V Leiden mutation in a woman who had started taking an oral contraceptive (OC), and to review the literature. RESULTS: A 44-year-old nonobese and nonsmoking woman was admitted to our hospital because of pain and progressive erythematous lesion on her left groin. The patient had had a 6-week history of combined OC use. There was no family history of angioedema. With a diagnosis of necrotizing fasciitis, surgical debridement of all necrotic tissue was considered with fasciocutaneous flap. Histopathological analysis showed diffusely fresh bleeding areas with diffused subcutaneous necrosis. The culture of the necrotic tissue was negative. Postoperatively, she restarted combined OC, and then the painful petechial and rapidly disseminated ecchymotic lesions were seen. Oral contraceptive was stopped immediately. A venous Doppler ultrasonography of the lower extremities showed subacute thrombosis in the left popliteal vein. Complement C3 level was normal, but amounts of C4, C1 esterase inhibitor level and activity were low. Factor V Leiden was positive for the heterozygous presence of Factor V gene. CONCLUSIONS: Women with angioedema and Factor V Leiden should be counseled against using hormonal contraceptives containing estrogen, and because they may interact in a synergistic manner in the pathogenesis of cutaneous lesions and/or venous thrombosis, appropriate individualized therapy should be defined. Further studies are needed.

Adult↗

PubMed1979

Effect of a streptococcal preparation on the complement system.

Streptococcal preparation OK-432 (Picibanil), clinically being used as an immunopotentiator, has been shown to activate the complement system either through the classical or the alternative pathway in vitro [15]. In this experiment, OK-432 was found to increase serum complement level in guinea pigs, and in human without malignancy, when investigated by hemolytic assay using sensitized sheep erythrocytes (EA) for the classical pathway activity and unsensitized rabbit erythrocytes (RaE) for the alternative pathway activity. Assay of complement components revealed a significant increase in C3, but decrease in Clq, while no specific tendency was observed in C4, C5, C9, properdin, C3 activator and Cl-inhibitor. These evidences suggested that OK-432 might potentiate immune response of the host by elevating serum complement level, in addition to activate the complement system.

Aged↗

PubMed1988

Biochemical characterization of a factor produced by trypomastigotes of Trypanosoma cruzi that accelerates the decay of complement C3 convertases.

Infective- and vertebrate-stage trypomastigotes of Trypanosoma cruzi resist serum killing by the alternative complement pathway, whereas noninfective vector-stage epimastigotes, from which trypomastigotes derive, are serum-sensitive. This form of developmental preadaption is commonly observed in protozoan parasites, but its mechanisms are poorly understood. We have demonstrated previously that trypomastigotes spontaneously shed molecules which interfere with formation and accelerate the intrinsic decay of complement C3 convertases, a finding which may explain the evasion of complement lysis by trypomastigotes. We now describe the partial purification and characterization of the T. cruzi C3 convertase inhibitor from the supernatant of culture metacyclic and tissue culture trypomastigotes. Decay-accelerating activity for both classical and alternative pathway C3 convertases copurifies on anion-exchange fast protein liquid chromatography and chromatofocusing with 35S-labeled molecules of 87-93 kDa, pI 5.6-5.8. The labeled components are destroyed by papain and retained on concanavalin A-Sepharose, procedures which remove functional decay-accelerating activity from the supernatant. The 87-93-kDa components are immunoprecipitated by sera from patients chronically infected with T. cruzi, but not by antisera to any known regulatory proteins of the human complement cascade. Lytic activity for tissue culture trypomastigotes in chagasic sera is associated with antibody reactivity against the 87-93-kDa 35S-labeled components and with inhibition of decay-accelerating activity. The T. cruzi factor is the first developmentally regulated microbial complement inhibitor to be biochemically characterized.

Animals↗

PubMed1994

Large-scale preparation of highly purified human C1-inhibitor for therapeutic use.

A two-step chromatographic procedure has been developed to purify human C1-inhibitor from cryoprecipitate-poor plasma after removal of vitamin K-dependent proteins and antithrombin III. The procedure, which is fully compatible with modern plasma fractionation schemes, includes anion-exchange chromatography on DMAE-Fractogel EMD, viral inactivation by solvent-detergent treatment, adsorption on SO3-Fractogel EMD and viral removal by nanofiltration on 35- and 15-nm pore size membranes. Overall yields were about 45% and 58% for antigen and activity, respectively, providing 60-70 mg of highly purified inhibitor per litre of plasma. The purified inhibitor had a specific activity of 6.5 +/- 0.5 units/mg protein, representing a more than 400-fold increase in purity compared with plasma. C1-inhibitor purity with respect to total protein was greater than 80%. The main contaminant was complement component C3 which accounted for 4-10% of the total protein. Minor contaminants included low amounts of IgM, IgG, IgA, fibrinogen and albumin. Complement component C4 was undetectable. The purified inhibitor was stable throughout the purification process and for more than 24 h at room temperature after reconstitution of the freeze-dried material. Animal tests in rats and mice demonstrated that the C1-inhibitor concentrate was well tolerated at relatively high doses.

Animals↗

PubMed1998

The phylogeny and evolution of the thioester bond-containing proteins C3, C4 and alpha 2-macroglobulin.

The complement system is an effector of both the acquired and innate immune systems of the higher vertebrates. It has been traced back at least as far as the echinoderms and so predates the appearance of the antibodies, T-cell receptors and MHC molecules of adaptive immunity. Central to the function of complement is the reaction of the thioester bond located within the structure of complement components C3 and C4. The structural thioester first appeared in a protease inhibitor, alpha 2-macroglobulin, in which it is involved in the immobilisation and entrapment of proteases. An important development in the C3 molecule has been the acquisition of a catalytic His residue which greatly increases the rate of reaction of the thioester with hydroxyl groups and with water.

Amino Acid Sequence↗

PubMed2004

Increased serum C3 levels in Crry transgenic mice partially abrogates its complement inhibitory effects.

Complement receptor 1-related gene/protein y (Crry) is a potent murine complement regulator that inhibits C3 convertases. Transgenic mice that overexpress soluble Crry (sCrry), directed systemically by the metallothionein-I promoter, have been used as an animal model for chronic blockade of complement activation. Recently we have found that alternative pathway (AP) activity in Crry transgenic mice was not inhibited as much as expected. To elucidate the mechanism of this effect, we evaluated the AP activities and levels of sCrry and AP complement components in transgenic and non-transgenic mice. In transgenic mice, expression of sCrry was induced by feeding zinc sulphate solution to 70.1 +/- 42.7 micro g/ml mean serum level. Its corresponding level of purified sCrry inhibited 49% of AP activity of normal mice serum; however, the actual AP activities in transgenic mice were not decreased when compared to non-transgenic mice (130.2 +/- 9.0%versus 113.0 +/- 35.4%). Expressed sCrry was functional, as immunoprecipitation and removal of sCrry from transgenic sera with rabbit anti-Crry polyclonal antibody resulted in enhanced AP activity, consistent with initial levels of sCrry. We then compared the changes to C3, factor B, factor H and factor D serum levels in transgenic and non-transgenic mice after induction of sCrry expression. Of these only C3 was increased after zinc feeding in transgenic mice compared to non-transgenic mice (142.8 +/- 14.1%versus 121.4 +/- 15.1%, P = 0.023). These results suggest that the inhibitory effect of chronic exposure to sCrry is compensated by concomitant alteration in C3 levels. This result also suggests the presence of a complement regulatory protein controls the level of serum C3, which has potential importance in the design and interpretation of studies involving chronic use of complement inhibitors.

Animals↗

PubMedDate not supplied

[Substances contained in the coelomic fluid of Lumbricus terristris having functions in common with those of some human complement components].

In the present work, it was demonstrated for the first time that the coelomic fluid of Lumbricus terrestris contained a substance recognized by human classical convertase. This substance permitted an immune, complement-dependent agglutination response of sheep erythrocytes carrying C3-convertase (EAC142). In addition, substances secreted by coelomic leukocytes possessed an inhibitory activity against human complement: the component C3 was cleaved into a C3b fragment. This result suggests the presence of a system the function of which is C3-convertase-like. We have thus shown that some complement functions, with their natural inhibitors, appear early in evolution. Certain of these functions and structures might be preserved throughout evolution.

Animals↗

PubMed1986

Repressed classical complement pathway activities and clinical correlations in chronic lymphocytic leukaemia.

Haemolytic activities of the classical and alternative complement pathways, and levels of C1, C4, C3, factor B and C1 inhibitor (C1-INH) were measured in 137 serum samples of 69 patients with chronic lymphocytic leukaemia (CLL). In most sera IgG, IgA and IgM concentrations were determined as well. Clinical correlations of these laboratory parameters have been studied. C1 and C4 activities were found to be depressed in almost 50% of the sera tested, and hypogammaglobulinaemia was observed with a similar frequency. Low C1 and C4 levels were found mainly in the early stages of the disease. A strong association between the occurrence of infections and hypogammaglobulinaemia was observed, although low immunoglobulin levels frequently occurred in patients without a history of infections. Low C1 and C4 levels were significantly correlated with the incidence of infections, too, and this correlation was observed mostly in the early stages of the disease. The reason for this is not known. The present results suggest that not only low immunoglobulin levels but low C1 and/or C4 levels may contribute to the increased susceptibility to infections in patients with chronic lymphocytic leukaemia.

Complement Activation↗

PubMedDate not supplied

[A case of acquired angioedema].

We report the case of a 46 year-old woman presenting an acquired angioedema. Angioedema is an C1 inhibitor deficiency. Patients present recurrent non inflammatory swelling of the head and extremities and recurrent attacks of severe abdominal pain. This clinical presentation is non specific : investigation of complement is useful for diagnosis. Laboratory testing show low serum levels of C4 with normal levels of C3. Low C1 esterase inhibitor confirm the diagnosis. If acquired angioedema, a cause must be searched.

Angioedema↗

PubMed2000

Expression of a complete and functional complement system by human neuronal cells in vitro.

We demonstrate in vitro expression of complement components, i.e. C3, factor H (FH), factor B (FB), C4, C1-inhibitor (C1-inh), C1q, C5, C6, C7 and C9, by four human neuroblastoma cell lines IMR32, SKNSH, SH-SY5Y and KELLY. Activating proteins C4, C9 and C1q, and regulatory proteins FH and C1-inh were produced constitutively by the four cell lines. C3, C6 and FB were mainly produced by SKNSH and SH-SY5Y. Western blot experiments showed that secreted proteins were structurally similar to their serum counterparts. An additional polypeptide of 43 kDa with FH immunoreactivity was detected, which could correspond to the N-terminal truncated form found in plasma. Regulation of complement expression by inflammatory cytokines, lipopolysaccharide and dexamethasone was tested in vitro. These factors had no significant effects on activating synthesis of components C3, FB and C4, but expression of regulating components C1-inh and FH was strongly increased particularly by IFN-gamma and tumor necrosis factor-alpha. The rate of synthesis of complement components was dependent on the differentiation of neuroblastoma cells. This effect of differentiation was also observed on normal rat neurons. Rat cerebellar granule cells constitutively expressed mRNA for C4 and C1q, but expression of C3 mRNA was induced by differentiation. This study shows that neurons could be another local source of complement in the brain, besides astrocytes and microglia. Human neuroblastoma cell lines can constitute an interesting model to analyze complement biosynthesis by human neurons. Local complement expression by neurons in vivo may be implicated in some physio-pathological processes.

Animals↗

PubMed2000

Impaired human ovarian follicular fluid complement function in hereditary angioedema.

We sought and detected functionally active complement in human ovarian follicular fluid obtained during the peri-ovulatory period. All the functional complement activities tested, including total haemolytic complement, classical pathway activity, alternative pathway activity and C1 inhibitor function were present with values within the normal serum range. Active complement in follicular fluid is relevant for the function of the enzymatic multifactorial mechanism of ovulation. The presence in hereditary angioedema patients of both complement (C1 inhibitor deficiency and chronically consumed complement) and ovarian abnormalities (cystic ovaries), led us to study complement function in the follicular fluid of women of reproductive age affected with hereditary angioedema. In contrast to healthy women, hereditary angioedema patients showed dramatically reduced classical pathway activity and undetectable functional and antigenic C1 inhibitor. C4 was very low, while C3 and B were slightly reduced or within the normal serum range. This complement profile was also detected in patients' sera. Since hereditary angioedema patients often show cystic ovaries (polycystic or multifollicular), the presence of multifollicular ovaries in the two patients studied, along with complement dysfunction, may be relevant. These findings, as well as the normalisation of the ovaries found by us in hereditary angioedema patients and in the patients reported here who were undergoing danazol treatment, and the increase in C1 inhibitor and the improvement of clinical symptoms, suggest a further link between complement and ovarian function.

Adult↗

PubMed1988

Influence of plasma protease inhibitors and the secretory leucocyte protease inhibitor on leucocyte elastase-induced consumption of selected plasma proteins in vitro in man.

Cleavage of C3, fibronectin, antithrombin III and alpha 2-antiplasmin in human plasma following the addition of increasing amounts of human leucocyte elastase was studied using an in vitro model. The cleavage was correlated with the degree of saturation of the plasma protease inhibitors alpha 2-macroglobulin and alpha 1-protease inhibitor and also with varying amounts of secretory leucocyte protease inhibitor. When alpha 1-protease inhibitor approached saturation, there was a prompt cleavage of all the four plasma proteins studied. The secretory leucocyte protease inhibitor was needed in a concentration of 6 mumol/l in the present model to block this consumption completely. This concentration also gave some protection of alpha 1-protease inhibitor and alpha 2-macroglobulin.

Antithrombin III↗

PubMed1984

Complement inhibitors in normal cornea and aqueous humor.

C1 inhibitor, beta 1H and C3b inactivator are important inhibitory proteins that regulate the complement system. These inhibitor proteins were detected by gel double diffusion in eluates from normal corneas, but not in normal aqueous humor. Functional tests of C1 inhibitor and C3b inactivator showed low-to-absent levels of these inhibitory proteins in normal aqueous humor. On the other hand, the mean activities of C1 inhibitor and C3 inactivator in corneas were nearly as high as those in sera, and there were no statistically significant differences between the values. The lower molecular weights of complement inhibitors, relative to other complement components, may account for their higher levels in normal cornea and may tip the balance in favor of inhibition of complement activation in the noninflamed cornea.

Adolescent↗