[Blood and synovial levels of C 3-activator (beta-2-glycoprotein II) in rheumatoid arthritis].
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Arthritis, Rheumatoid↗
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Results for “complement C3 inhibitor”
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[Disorder of the regulation of the inflammatory process in spontaneous pneumothorax].
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Aminopeptidases↗
Biochemistry and biological activity of the complement system.
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Animals↗
[The role of recently identified proteins in rheumatoid inflammation].
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Arthritis, Rheumatoid↗
Activation of stimulus-specific serine esterases (proteases) in the initiation of platelet secretion. I. Demonstration with organophosphorus inhibitors.
The effect of organophosphorus inhibitors of serine esterases (proteases) on secretion from washed rabbit platelets was examined. Five noncytotoxic stimuli were employed: collagen, thrombin, heterologous anti-platelet antibody (in the absence of complement), rabbit C3 bound to zymosan, and platelet activating factor derived from antigen-stimulated, IgE-sensitized rabbit basophils. Diisoprophyl phosphofluoridate, three series of p-nitrophenyl ethyl phosphonates, and a series of cyclohexyl phenylalkylphosphonofluridates were all found to be inhibitory to the platelet secretion. These are irreversible inhibitors of serine proteases but in this system were only inhibitory if added to the platelets concurrently with the stimuli. Pretreatment of either the platelets or the stimuli with the inhibitors followed by washing, was without effect on the subsequent reaction. This suggested the involvement of stimulus-activatable serine proteases in the secretory process. The concept was supported by finding that nonphosphorylating phosphonates or hydrolyzed phosphonates or phosphonofluoridates were without inhibitory action. The effect of a series of phosphonates or phosphonoflouridates in inhibiting each stimulus exhibited a unique activity-structure profile. The demonstration of such unique profiles with four series of inhibitors for each of the five stimuli was interpreted as demonstrating that a specific activatable serine protease was involved in the platelet secretory response to each stimulus.
Animals↗
Regulation by retinoic acid of acylation-stimulating protein and complement C3 in human adipocytes.
Acylation-stimulating protein (ASP), a product of complement C3, stimulates triacylglycerol synthesis in adipocytes. Previous studies have identified transthyretin, associated with chylomicrons, as a stimulator of C3 and ASP production. Since both transthyretin and chylomicrons transport retinyl ester/retinol, our goal was to investigate whether retinoic acid (RA) could be a potential hormonal mediator of the effect. Inhibitors of protein synthesis and protein secretion eliminated the stimulatory effects of chylomicrons on both C3 and ASP production in human differentiated adipocytes, suggesting that de novo protein synthesis and secretion are both required. Incubation with chylomicrons increased C3 mRNA levels (37+/-1.5%). RA alone or with chylomicrons had a stimulatory effect on C3 production (29-fold at 16.6 nM RA) and ASP production. An RA receptor antagonist blocked stimulation of C3 mRNA and C3 secretion by both RA and chylomicrons. Finally, RA and chylomicrons activated a 1.8 kb C3-promoter-luciferase construct transfected into 3T3-F442 and 3T3-L1 cells (by 41+/-0.2% and 69+/-0.3% respectively), possibly via RA receptor half-sites identified by sequence analysis. This is the first evidence documenting stimulation by RA of the C3 gene. Thus we propose RA as a novel cellular trigger in chylomicrons that subsequently results in increased ASP production by adipocytes after a meal.
3T3 Cells↗
Substrate specificities of recombinant mannan-binding lectin-associated serine proteases-1 and -2.
Mannan-binding lectin (MBL)-associated serine proteases-1 and 2 (MASP-1 and MASP-2) are homologous modular proteases that each interact with MBL, an oligomeric serum lectin involved in innate immunity. To precisely determine their substrate specificity, human MASP-1 and MASP-2, and fragments from their catalytic regions were expressed using a baculovirus/insect cells system. Recombinant MASP-2 displayed a rather wide, C1s-like esterolytic activity, and specifically cleaved complement proteins C2 and C4, with relative efficiencies 3- and 23-fold higher, respectively, than human C1s. MASP-2 also showed very weak C3 cleaving activity. Recombinant MASP-1 had a lower and more restricted esterolytic activity. It showed marginal activity toward C2 and C3, and no activity on C4. The enzymic activity of both MASP-1 and MASP-2 was specifically titrated by C1 inhibitor, and abolished at a 1:1 C1 inhibitor:protease ratio. Taken together with previous findings, these and other data strongly support the hypothesis that MASP-2 is the protease that, in association with MBL, triggers complement activation via the MBL pathway, through combined self-activation and proteolytic properties devoted to C1r and C1s in the C1 complex. In view of the very low activity of MASP-1 on C3 and C2, our data raise questions about the implication of this protease in complement activation.
Base Sequence↗
Changes in wound healing factors in liver cirrhosis after esophageal transection for esophageal varices.
Quantitative changes in plasma wound healing factors in cirrhotic patients after esophageal transection were evaluated and compared with those of non-cirrhotic esophageal cancer patients (controls) after esophageal resection. Serum total protein, albumin and fibronectin were maintained at the same levels as those in controls when multiple units of fresh frozen plasma and albumin products were employed. Nevertheless, the principle protease inhibitors including alpha-1-antitrypsin and alpha-1-acid-glycoprotein showed little increase by the 3rd postoperative day, while those of controls increased as much as twofold at this time. Levels of complements C3 and C4 showed consistent depression, with little change during the study period. We conclude that the levels of some of the plasma proteins essential in wound healing are depressed in cirrhotic patients during the critical period after surgery.
Blood Proteins↗
Aggregation of human platelets in plasma by porcine blood cells in vitro is probably mediated by thrombin generation.
The infusion of pig progenitor cells into baboons is associated with a thrombotic microangiopathy probably related to the interaction of these cells with the baboon endothelial cells and platelets. We have shown previously that pig peripheral blood mononuclear cells (p-PBMC), are able to activate the human coagulation cascade as they are able to generate thrombin when added to defibrinated plasma. In this work, we have tested the interaction of p-PBMC with human platelets to assess the capacity of p-PBMC to cause platelet aggregation and the possible role of complement activation in this aggregation. Human platelet aggregation assays, using collagen (1 or 2 microg/ml), were performed with platelets in platelet-rich plasma (PRP) or platelets washed by filtration. PRP or washed platelets were also incubated with p-PBMC or human PBMC (h-PBMC) at several concentrations and aggregation was measured. The effect of Dansylarginine N-(3-ethyl-1,5-pentanediyl)amide (DAPA), an inhibitor of thrombin, was studied on platelet aggregation caused by the pig cells. Complement activation was measured by deposition of fragment c derived from C3 splitting (C3c) on pig cells incubated with citrated platelet poor plasma (PPP). When human PRP was incubated with p-PBMC, aggregation was a consistent event quantitatively similar to that induced by collagen. No aggregation of washed platelets was observed when these were incubated with p-PBMC or h-PBMC. Aggregation of human platelets in PRP, induced by p-PBMC, was inhibited when DAPA (100 microm) was added to the incubation mixture (23%), indicating that the thrombin inhibitor blocked the capacity of p-PBMC to aggregate human platelets. No deposition of C3c fragments on p-PBMC was detected when the porcine cells were incubated for up to 20 min with citrated PPP. The fact is that p-PBMC induces human platelet aggregation in plasma being thrombin generation a likely explanation for this observation. Our data suggest that, in the system assayed, complement activation is not a cause of platelet aggregation. These findings are relevant for the clarification of the reported thrombotic microangiopathy complicating the intravenous infusion of pig cells in primates in attempts to induce pig tolerance in baboons.
Animals↗
Activation and inhibition of Hageman factor-dependent pathways and the complement system in uncomplicated bacteremia or bacterial shock.
Levels of components of the contact activation, coagulation, and complement systems and their main inhibitors were measured in 45 critically ill patients during 61 episodes of uncomplicated bacteremia or bacterial shock. Levels of Hageman factor (factor XII), prekallikrein, high-molecular-weight kininogen, factor XI, factor VII, total hemolytic complement, alternative pathway activity, and C3 were within the normal range during uncomplicated bacteremia (n = 29), but during fatal bacterial shock (n = 13) a significant decrease by 40%-50% was observed in all measurements. During nonfatal bacterial shock (n = 19) a moderate decrease was observed in most of these measurements. The capacity of plasma to inactivate kallikrein was significantly higher during bacteremia than during bacterial shock because of a significant increase in the level of C1 esterase inhibitor. Levels of antithrombin III and alpha 2-macroglobulin were below normal in all groups. Thus increased inhibition of the contact activation and complement systems is beneficial during bacteremia.
Angiotensin III↗
Effects of granulocyte neutral proteases on complement components.
The proteolytic effects of collagenase and elastase from human granulocytes were investigated on the human complement components C3 and C5 in serum and with purified components. The conversion of C3 was analyzed with crossed immunoelectrophoresis as described by Ganrot, and the conversion of C5 was detected with immunoelectrophoresis according to Scheidegger's method. Collagenase converted C3 to C3b but had no detectable effect on C5. Elastase converted C3 to C3b and converted C5 to a C5b-like fragment. The proteolysis by collagenase and elastase in serum was not detectable until the molar ratio for enzyme to the protease inhibitors alpha1-antitrypsin and alpha2-macroglobulin was greater than 1.
Complement C3↗
The inhibitory effect of CD46, CD55, and CD59 on complement activation after immunotherapeutic treatment of cervical carcinoma cells with monoclonal antibodies or bispecific monoclonal antibodies.
The role of membrane-bound complement regulatory proteins (mCRP) in the protection of tumor cells in vivo against elimination by the immune system is still unknown. In this study the effect of expression of these mCRP by cervical cancer cells was investigated. In situ expression of mCRP was observed on cervical carcinomas, normal cervical epithelial cells, and the surrounding stroma. Deposition of C3 and C5b-9 was sporadically found on the tumor cells and the surrounding stroma. A low expression of CD46 was statistically significantly associated with deposition of C3. Comparable expression patterns were shown on primary cervical tumor cell suspensions. A relatively high deposition of C4c was found on these tumor cells, indicating classical pathway activation. Furthermore, it was demonstrated that CD55 and CD59 were the most potent inhibitors of C3 deposition and classical pathway-mediated lysis, respectively, on cervical cancer cell lines. The feasibility of increasing complement activation at the tumor cell membrane surface was demonstrated with an anti-HLA Class I*anti-CD55 bispecific mAb. The potential immunotherapeutic applicability was investigated with both anti-G250*anti-CD55 and anti-Ep-CAM*anti-CD55 bispecific mAbs. An approximate 2-fold increase in C3 deposition, compared with the parental anti-Ep-CAM mAb, was attained with an anti-Ep-CAM*anti-CD55 bispecific mAb when the tumor-associated antigen was expressed in sufficient amounts. These results demonstrate that when tumor-associated antigens are expressed in adequate amounts, bispecific mAbs in vivo may be potent immunotherapeutic agents to enhance an inflammatory reaction at the tumor site.
Antibodies, Bispecific↗
Administration of dexamethasone induces proteinuria of glomerular origin in mice.
The administration of glucocorticoids has been reported to exacerbate proteinuria in a few patients with glomerulonephritis. This effect has not been well recognized, and the pathogenetic mechanism responsible for this phenomenon remains to be clarified. In this study, we observed that a high daily oral dose (0.5 mg/kg body weight) of dexamethasone was capable of inducing overt proteinuria in mice, beginning on day 5 and persisting for a 19-day duration. One fourth of mice also intermittently presented with slight hematuria beginning on day 12. Renal lesions in the dexamethasone-treated mice, which were killed on day 23, were characterized by mild mesangial expansion, segmental or global hyalinosis/sclerosis in deep cortical glomeruli, and focal tubular changes. No glomerular inflammatory cell infiltration or proliferative lesion was noted in any of the mice. Ultrastructural features of glomeruli included mesangial widening characterized by either an increase of mesangial matrix, dilated mesangial channels filled with slightly electron-dense material or mesangial lysis-like appearance showing intracytoplasmic microcysts filled with electron-lucent material, and evidence to support injury of endothelial cells, erythrocytes, and podocytes. An immunofluorescence study revealed enhanced glomerular deposition of IgG, IgA, IgM, and fibrinogen (P < 0.001, compared with normal control mice), but no glomerular C3 deposition was identified in any of the dexamethasone-treated mice. Charge analysis showed no impairment in anionic property of glomerular tufts in the dexamethasone-treated mice. In addition, the dexamethasone-induced proteinuria was greatly attenuated by treatment with a low molecular weight heparin, although it was not reduced by an angiotensin-converting enzyme inhibitor. Data from these experiments suggest that a large dose of glucocorticoids is potentially nephrotoxic. Alteration of a size-dependent permeability may predominantly contribute to the dexamethasone-induced proteinuria. However, the effect of glomerular hyperfiltration may be only partially involved in the pathogenesis of this dexamethasone-induced glomerulopathy in mice.
Angiotensin-Converting Enzyme Inhibitors↗
Structure-function relationships of complement receptor type 1.
Human complement receptor type 1 (CR1) is a large, multifunctional glycoprotein which is a member of the regulators of complement activation family. Like other members of this family, it is composed mainly of tandemly arranged modules, each about 60-70 amino acids long, known as complement control protein repeats (CCPs). Each domain folds independently and contains a hydrophobic core wrapped in beta sheets. These domains mediate interactions with C3/C4-derived fragments. CR1 is the most versatile inhibitor of both classical and alternative pathway C3 and C5 convertases due to its decay-accelerating activity and co-factor activity for C3b/C4b cleavage. Moreover, CR1 plays a major role in immune complex clearance due to its high affinity for C3b and C4b. CR1 is an excellent model to study structure-function relationships because its functions are mediated by two distinct but highly homologous sites, each composed of three CCPs. CR1 derivatives carrying just one active site were used to define critical sequences/amino acids. This was achieved by testing functional profiles of the proteins carrying a mutated active site produced by substituting peptides/amino acids with their counterparts from the other site. These mutated proteins, of which we analyzed over 100, permitted the fine mapping of the functional sites. CR1 on primate erythrocytes varies in size. In most cases it is smaller and has fewer active sites than does human CR1. This variation was used to determine that increased copy number (3,000 to 20,000 versus 300 for human CR1) compensates for a smaller size. Moreover, studies of primate CR1 led to the finding that subtle differences in the critical areas, as compared to human sites, produce active sites with a broader functional repertoire. These alterations ensure that short CR1 forms possess similar biologic activities to the large CR1 forms. There is much interest in producing therapeutic agents to inhibit unwanted complement activation. Based on these structure-function analyses, smaller and more potent complement inhibitors derived from CR1 can be produced.
Amino Acid Sequence↗
Acute anaphylaxis associated with serum complement depletion.
A 45-year-old woman with rheumatoid arthritis developed anaphylaxis 6 min after receiving a subcutaneous injection of lidocaine, followed by an intra-articular injection of lidocaine mixed with methprednisolone acetate. One hour after the onset of anaphylaxis, serum complement component levels were markedly depressed and remained so far 18 hr. Circulating immune complexes and antibodies to lidocaine could not be demonstrated. Neither lidocaine nor methylprednisolone acetate activated the patient's complement system in vitro. Subsequently, total hemolytic activity (CH50) levels were variable, complement component protein concentrations of C1q, C1s, C4, C2, C3, C5, C6, C9, and Factor B were normal, but hemolytic activity of C4 and C2 was diminished. Serum C1 inhibitor concentrations were normal or slightly depressed. The patient has never had any symptoms suggestive of angiodema. It is postulated that the endogenous complement abnormality present in this patient may have contributed to the anaphylactic reaction.
Anaphylaxis↗
Trypsin-activated complex of human factor B with cobra venom factor (CVF), cleaving C3 and C5 and generating a lytic factor for unsensitized guinea pig erythrocytes. II. Physico-chemical characterization of the activated complex.
A complex, CVF-B, between cobra venom factor (CVF) and human factor B(B) showed weak, short-lived enzymatic activity against the third component of human complement (C3). Once activated with trypsin, it showed strong, stable activity against C3 and C5. CVF-B, an activated form of CVF-B complex, was not affected by the trypsin inhibitor, diisopropylfluorophosphate and neuraminidase. Heating at 56 C for 30 min completely destroyed its activity and heating at 50 C for 30 min destroyed approximately half its activity. The activity of DVF-B decrease markedly at pH 6.0 but was stable at pH 6.5 to 8.5. CVF-B lost 90% of its activity on reduction with 1 mM dithiothreitol, and was completely adsorbed on a cellulose acetate membrane. CVF-B was found to be a complex of CVF and glycine-rich gamma-glycoprotein, with a molecular weight of 340,000. The CVF-B molecule consisted of 4-polypeptide chains, 3 of which were derived from CVF and one from GGG. Hemolytically active CVF-B may be formed from 2 molecules with four-polypeptide chains linked by unknown bonds. Human, rat and guinea pig sera could react with CVF-B to generate a lytic factor. Human and sheep erythrocytes were not sensitive to the lytic factor generated by CVF-B, whereas liposomes prepared from their membrane lipids were equally sensitive to the lytic factor.
ABO Blood-Group System↗
[Expression and role of complement regulatory proteins on human gametes and pre-implantation embryos].
Human gametes and pre-implantation embryos express selectively several complement regulatory proteins. Membrane cofactor protein (MCP, CD46) and decay accelerating factor (DAF, CD55) are regulators for C3 convertases and protectin (CD59) is an inhibitor of the membrane attack complex. These three proteins were identified on human sperm and found to be functional. CD55 and CD59 were both expressed by the plasmic membrane of unfertilized oocytes and pre-implantation embryos. CD46 was not present on unfertilized oocytes but appeared at the 6/8 cell-stage embryo when human gene expression first occurs. Complement receptor 1 (CR1, CD35) and MHC class I antigens were not found on oocytes neither on embryos. Such a selective expression of complement regulatory proteins associated with the lack of MHC class I antigens may represent an immune protective mechanism by which human gametes and pre-implantation embryos escape from complement-mediated damage during their travel through the female genital tract. Indeed uterine, tubal and follicular fluids contain all the components of the complement cascade, including classical and alternative pathways. Nevertheless participation of CD46 and CD59 in cell to cell interaction during fertilization and/or implantation cannot be excluded. CD59 is an adhesive molecule involved in the rosette phenomena and CD46 has been described as the human receptor for measles virus, which binds through a fusion protein. Monoclonal antibodies raised against these two proteins (CD46 and CD59) are able to inhibit heterospecific fertilization between zona-free hamster oocytes and human spermatozoa suggesting the role of these proteins during fertilization.
Animals↗
A plasmid-encoded outer membrane protein, TraT, enhances resistance of Escherichia coli to phagocytosis.
The presence of the outer membrane protein TraT, encoded by plasmid R6-5, reduces the sensitivity of Escherichia coli cells to phagocytosis by macrophages. This effect is independent of the bacterial capsule and is more evident in the presence of adsorbed normal human serum. The property of inhibiting phagocytosis is specifically abolished by anti-TraT protein antiserum and anti-TraT immunoglobulin G but not by Fab fragments. These results indicate that the TraT protein is a passive inhibitor of phagocytosis. Inhibition of phagocytosis is produced because the TraT protein antagonizes opsonization by complement, such that C3 deposition is reduced and altered in distribution.
Antibodies, Bacterial↗