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PubMed1995

Complement analysis in adult patients with a history of bacteremic pneumococcal infections or recurrent pneumonia.

Complement deficiencies are known to be associated with increased susceptibility to bacterial infections. In the present study we investigated 80 patients with either a history of pneumococcal bacteremic infection, or recurrent pneumonia, or both. Hemolytic screening tests for complement deficiency were performed and serum concentrations of C1q, C1s, C2, C3, C4, C4 isotypes, factor B, factor D, and properdin were determined. Complete deficiencies of single complement proteins were not found. 10 patients (12%) had a C4 isotype deficiency, but the frequency of homozygous C4A and C4B deficiency was not significantly increased. Seven patients (9%) had hypocomplementemia with low concentrations of at least 2 complement proteins. One of these patients had profound depletion of classical pathway components and findings suggesting acquired C1 esterase inhibitor deficiency. 16 patients (20%) had minor complement aberrations. A majority of the patients with hypocomplementemia suffered from other conditions associated with pneumococcal infections. However, impaired complement function could be a significant predisposing factor in some patients with invasive pneumococcal infections or recurrent pneumonia.

Acute Disease↗
PubMed1977

[Anticomplementary activity of a polyanion: pentosan-poly-sulfoester, II.--Mode of action and "in vitro " inhibition of human complement hemolytic activity (author's transl)].

The drug, pentosan-poly-sulfoester (PPS), is a potent in vitro inhibitor of the human complement hemolytic activity. This CH 50 inhibition represents a real anticomplementary activity (ACA), because this drug has no effect on sensitized sheep red blood cells (EA). The inhibition curve of human serum CH 50, by PPS is sigmoidal. The 50% inhibition is obtained for a 1: 650 dilution of PPS, which corresponds to a concentration of 0.08 mg/ml in normal human serum. Hemolytic titrations of C1, C4, C2, C3, and C5 showed a complete inhibition of C4, C2 and C3, and a partial inhibition of C1 (C1q, C1r, C1s, Ca++) and C5, by this drug. The mechanism of such functional inactivation of the different complement components is not yet elucidated.

Complement C2↗
PubMed1988

Plasma levels of main granulocyte components during cardiopulmonary bypass.

Plasma levels of granulocyte lactoferrin, myeloperoxidase, and elastase in alpha 1-proteinase inhibitor complex were compared with C3a and C5a levels in 10 patients undergoing cardiopulmonary bypass. At the end of the operation, plasma levels of lactoferrin increased from 97.0 +/- 22.8 to 1257 +/- 139.8 ng/ml, myeloperoxidase increased from 37.1 +/- 4.3 to 170.9 +/- 34.9 ng/ml, and elastase in alpha-proteinase inhibitor complex rose from 89.4 +/- 7.4 to 437.8 +/- 97.3 ng/ml. There was also a significant anaphylatoxin formation. To investigate the relationship between complement and granulocyte activation, patients undergoing cardiopulmonary bypass received the calcium channel blocker nifedipine (orally and intravenously) and the antiplatelet drug dipyridamole. The continuous infusion of nifedipine (5.91 +/- 0.53 micrograms/kg body weight per hour) caused significantly lower levels of elastase in alpha-proteinase inhibitor complex and lactoferrin but not anaphylatoxin. Dipyridamole was without effect on complement and granulocyte activation during cardiopulmonary bypass. Our data demonstrate inhibition of granulocyte activation during cardiopulmonary bypass by continuous infusion of nifedipine, even in the presence of complement activation.

Aged↗
PubMed1999

Consumption of C4b-binding protein (C4BP) during in vivo activation of the classical complement pathway.

C4BP has a central role in regulating the classical complement (C') pathway, but it is still uncertain whether or not it is consumed during in vivo complement activation. Attempts to demonstrate changes in C4BP plasma levels in systemic lupus erythematosus and essential mixed cryoglobulinaemia have failed, probably due to up-regulation of this protein during the inflammatory reaction. We have studied one patient with severe post-transfusion complement-mediated anaphylaxis (CMA), and 67 patients with hereditary C1 inhibitor deficiency (hereditary angioedema (HAE)). The first of these two conditions is characterized by the absence of systemic inflammatory reaction and the second by acute and chronic activation of the C' classical pathway. C4BP, C4BP-C4b complex, and soluble terminal C' complex (sC5b-9) were measured in the patients' plasmas by ELISA techniques and C3a and C4a by radioimmunoassays. In CMA, 15 min after the transfusion, there was a massive C' activation, with increases in C4a, C3a, sC5b-9, C4BP-C4b complexes and decreases in C4, C3 and C4BP. All parameters reverted to preinfusion values within 24 h. Depletion of C4 was correlated with that of C4BP. In patients with HAE, the median value of C4BP (83% range 54-165) was significantly lower (P < 0.0001) than in normal controls (99% range 70-159), with no difference between patients in remission or during acute attacks. C4BP-C4b complexes could not be detected in HAE patients. The results of this study indicate that C4BP is consumed in vivo during acute, and possibly during chronic activation of the C' classical pathway, and that this protein, after interaction with C4b, not longer circulates in plasma.

Adult↗
PubMed1993

Complement inhibition with soluble complement receptor type 1 in cardiopulmonary bypass.

Although complement activation during cardiopulmonary bypass (CPB) is well documented, its pathogenic role in postperfusion organ injury is unproven. In this study, soluble human complement receptor type 1 (sCR1), a potent inhibitor of complement activation, was used to determine the contribution of complement activation to pulmonary injury in a porcine model of CPB. In vitro experiments demonstrated that sCR1 inhibits both classic and alternative complement pathways in the pig. Seven control piglets and 6 piglets treated with sCR1 (12 mg/kg intravenously) underwent 2 hours of hypothermic (28 degrees C) CPB followed by 2 hours of observation. In control piglets, total hemolytic complement activity and functional activities of C3 and C5 declined to 61.3%, 67.8%, and 61.4% of prebypass values, respectively, after 2 hours of CPB. Plasma from animals treated with sCR1 had virtually no hemolytic activity (total hemolytic complement activity < 5% of baseline), demonstrating effective complement inhibition. Similar degrees of neutropenia developed in the two groups during CPB, and there was no difference in post-CPB lung tissue myeloperoxidase level. Two hours after CPB, pulmonary vascular resistance increased 338% in control piglets but only 147% in piglets pretreated with sCR1 (p < 0.05); the alveolar-arterial gradient was not significantly different between controls (331 +/- 52 mm Hg) and piglets receiving sCR1 (290 +/- 85 mm Hg). Histologic examination revealed similar degrees of pulmonary edema in both groups. These data constitute direct evidence that complement activation plays a pathogenic role in lung injury after CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Slp is an essential component of an EDTA-resistant activation pathway of mouse complement.

Slp (sex-limited protein) is a mouse serum protein encoded by a major histocompatibility complex class III gene. It is considered to be a product of a duplicated complement component C4 gene, but without functional activity. Originally it has been found expressed only in adult males with the S region of the H-2d or H-2s haplotype. In this report we present evidence that Slp is involved in a form of mouse complement activation that occurs after fractionation of serum by polyethylene glycol precipitation. This activation pathway is EDTA-resistant (i.e., independent of classical and alternative pathway activation), is regulated by C1 inhibitor, and leads to the generation of hemolytically active membrane attack complexes. A positive correlation between this EDTA-resistant mouse complement activity and reported Slp levels was found. Direct evidence for a functional role of Slp came from substitution experiments in which purified Slp induced hemolytic activity in polyethylene glycol-fractionated, Slp-deficient mouse serum. Selective depletion of other complement components suggested a role for C1s-, C2, and C5, but not C3, in the Slp-dependent complement activation. A model for this type of mouse complement activation is presented.

Aging↗
PubMed1997

Biocompatibility of heparin-coated circuits in pediatric cardiopulmonary bypass.

In this study, we evaluated the biocompatibility of heparin-coated circuits in pediatric cardiopulmonary bypass (CPB). Eight patients were divided into 2 groups: the control group (Group C) and heparin-coated group (Group H). In Group H, CPB circuits, including the arterial pump, oxygenator, and cannulas were heparin-coated. Before, during, and after CPB, blood samples were obtained to assess the platelet counts (Plat), alpha 2-plasmin plasminogen inhibitor complex (PIC), thrombin-antithrombin III complex (TAT), C3 activation products (C3a), interleukin (IL)-6, IL-8, and polymorphonuclear neutrophil leukocyte (PMN) elastase. There was no significant difference in Plat, PIC, or TAT between groups. Group H showed significantly low levels of C3a (during and after CPB), PMN elastase (during CPB), and IL-6 (after CPB). These data demonstrated that in pediatric CPB, heparin-coated CPB circuits reduced the activation of complements and the production of PMN elastase and IL-6, suggesting the superior biocompatibility of the heparin-coated circuits.

Anticoagulants↗
PubMed1981

The intrinsic coagulation-kinin pathway, complement cascades, plasma renin-angiotensin system, and their interrelationships.

Activation of the classical complement pathway is initiated by immune complexes consisting of IgM antibody or IgG subclasses 1, 2, and 3. Binding to Clq leads to activation of C1s and digestion of C4 and C2 to yield a C3 convertase. The alternative complement pathway is initiated by complex polysaccharides as well as immune complexes of the IgA class which interact with Factors B, D, C3, and properdin to yield a stabilized C3 convertase consisting of PC3Bb. Cleavage of C3 and C5 by either pathway yields the C3a and C5a anaphylatoxins which cause histamine release from mast cells and formation of the C5b6789 attack complex causes cell lysis. Both immunologic and nonimmunologic tissue damage can initiate the surface dependent pathways of coagulation, fibrinolysis, and kinin formation. Surface bound Hageman Factor interacts with complexes of prekallikrein and HMW-kininogen as well as Factor XI and HMW-kininogen to form activated Hageman factor, kallikrein, and Factor XIa. Factor XIa continues the coagulation pathway, kallikrein and Factor XIa convert plasminogen to plasmin and kallikrein digests HMW-kininogen to yield bradykinin. The Cl inhibitor, which inactivates Cls is the major plasma inhibitor of activated Hageman factor and kallikrein. In its absence, a potentially fatal form of angioedema is seen. The inactivator of the C3a and C5a anaphylatoxins is identical to carboxypeptidase N, the major plasma inactivator of bradykinin thus demonstrating the common control mechanisms which regulate the complement and kinin-forming pathways.

Blood Coagulation↗
PubMed1995

A monoclonal antibody that blocks the complement regulatory activity of guinea pig erythrocytes and characterization of the antigen involved as guinea pig decay-accelerating factor.

MCA44 is a mAb with the capacity to sensitize neuraminidase-treated guinea pig E for hemolysis by homologous guinea pig C, and the Fab fragments of this mAb could also sensitize guinea pig E interfering with the function of a membrane inhibitor of C on guinea pig E. Using an immunosorbent column to which MCA44 was coupled, the antigenic molecule termed 44Ag was purified from the glycoprotein fraction extracted from E membranes. C intermediate sheep E treated with guinea pig C1 and C4 after sensitization with Ab (EAC14b cells) lost the ability to generate C3 convertase with C2 after incubation with 44Ag. Treatment of guinea pig E and PBL with phosphatidyl-inositol specific phospholipase C (PIPLC) partially removed 44Ag, as determined by flow cytometric analysis after immunofluorescence staining with MCA44. However, 125I-labeled 44Ag adsorbed to human E was efficiently removed by PIPLC treatment with a slight reduction in M(r). The 44Ag purified on an immunosorbent column showed three bands on SDS-PAGE. However, partial N-terminal amino acid sequences of the 55-kDa, 70-kDa, and 88-kDa bands under nonreducing conditions were identical and the sequence was 55% homologous to the N-terminal sequence of human decay accelerating factor (CD55). Intracutaneous administration of MCA44 or its F(ab')2 fragment resulted in increased capillary permeability, even after 3 days, as determined by the appearance of Evans blue spots after i.v. administration of the dye. Because control Abs including anti-class I-MHC did not cause such increased capillary permeability, the increase in permeability caused by MCA44 was likely induced by blocking the function of 44Ag in vivo, indicating a crucial role for these molecules in preventing over-activation of C at the site.

Amino Acid Sequence↗
PubMed1991

Complement activation by artificial blood substitute Fluosol: in vitro and in vivo studies.

A perfluorocarbon blood substitute, Fluosol, is undergoing clinical trials as an adjunct to chemotherapy. The adverse effects associated with its administration have been postulated to result from complement activation. When gel electrophoresis and Western blotting of Fluosol are used after its incubation with serum, activated C3 and factors Bb and H are bound to the Fluosol particles in a time-dependent fashion, which suggests that complement activation with Fluosol, as does that with zymosan, occurs on the surface of the particles. Paradoxically, it is found, both by the measurement of Fluosol-bound C3d and by fluid-phase C5a, that lower concentrations of Fluosol cause greater amounts of complement activation, which suggests a complex interaction of activators and inhibitors that changes as the available surface area is decreased. Studies performed with bystander red cell-bound C3d demonstrated in vivo complement activation occurring in six patients receiving Fluosol as an adjunct to chemotherapy for colon cancer. In two patients, there was a marked increase in red cell-bound C3d after Fluosol infusion; these two patients also developed adverse reactions during Fluosol infusion. These studies suggest that the Fluosol surface plays a major role in the initiation and regulation of complement activation that is seen during Fluosol infusion.

Adenocarcinoma↗
PubMed1993

Test for ability of decay-accelerating factor (DAF, CD55) and CD59 to alleviate complement-mediated damage of xeno-erythrocytes.

We investigated the susceptibility to human complement (C) of xeno-erythrocytes into which phosphatidylinositol (PI)-anchored human C regulatory protein, decay-accelerating factor (DAF) or CD59 had been incorporated. Erythrocytes of sheep (Esh), swine (Esw), dog (Edg), and guinea pig (Egp), unsensitized with human natural antibody (Ab), were used as xeno-target. C-mediated lysis of erythrocytes (E) was induced in both classical and alternative pathways in parallel with the density of the sensitized Ab, except for Egp. The efficacy of DAF/CD59-mediated protection of the xeno E from human C, however, differed among these E species. In both classical and alternative pathways, Esh or Esw, which are non-activator surfaces, were protected by the incorporated DAF or CD59, DAF being more effective than CD59. On the other hand, CD59 was more effective than DAF in both pathways in protection of Egp, which is an alternative pathway activator. To elucidate this different behaviour of DAF and CD59, C3 step inhibition by the incorporated DAF or CD59 was measured. DAF was effective in the suppression of classical pathway-mediated C3 deposition in Esh, Esw and Egp, but not in Edg, while CD59 exhibited negligible effects in this regard. Next, inhibition of the lysis by CD59 was tested by haemolytic assay. CD59 did not block the C5b-8-mediated lysis in any xeno E. It also barely blocked C5b-9-mediated lysis, except in the case of Egp, in which CD59 partly blocked C9 attack. Membrane constituents on targets other than the incorporated complement inhibitors may be a crucial factor in the induction of cytolysis and, presumably, in hyperacute rejection.

Animals↗
PubMed1979

Substrate modulation as a control mechanism in the activation of plasma multienzyme systems.

Since plasma is a homogenous fluid its biochemical systems need special control mechanisms to prevent their unlimited and continuous activity. In general, enzymic activity is not preformed but generated by trigger processes. Activation is then enhanced by cascade reactions. It can be controlled by enzyme inhibitors, by enzymes which destroy co-factors, or by spontaneous decay or enzyme complexes involved in the system. In addition, in some reactions of the complement and Hageman factor-dependent systems the necessity of substrate modulation controls the extent of activation. Thus, factor B of the properdin system is activatable by factor D only when bound to the activated third component of complement, and C3b fragment; similarly C2 is activated and forms the C3 converting complex, C42, only when bound to C4b prior to its cleavage by C1; C5 can be activated by either of the two convertases only when bound to surface-fixed C3b; and the mutural activation of Hageman factor and pre-kallikrein on surfaces proceeds efficiently only when HMW-kininogen is present which complexes with pre-kallikrein and possibly with Hageman factor.

Complement C3↗
PubMed1987

The late onset form of C1 esterase-inhibitor deficiency presenting as food allergy.

Two cases of late onset recurrent angioedema associated with deficiency of C1 esterase inhibitor are described. Both patients had life-threatening episodes of angioedema that they had related to the ingestion of certain foodstuffs. This was not confirmed by food challenges or by food allergy skin testing, although both patients had embarked on strict exclusion diets before the diagnosis of C1 esterase-inhibitor deficiency. Clinicians should be aware of the entity of late onset angioedema caused by C1 esterase deficiency mimicking food allergy and hence delaying the diagnosis of this potentially lethal condition.

Aged↗
PubMed1994

In vivo effects of monoclonal antibodies that functionally inhibit complement regulatory proteins in rats.

The present work was designed to evaluate the effects of functional suppression of complement regulatory proteins in vivo. Male Wistar rats were anesthetized with Nembutal and were intravenously injected with 1 mg/kg of F(ab')2 or Fab fraction of either monoclonal antibody 5I2, which inhibits the function of rat counterpart of mouse Crry/p65, or monoclonal antibody 6D1, which inhibits the rat counterpart of CD59. Mean arterial pressure was continuously measured for 30 min. When 5I2 was injected, there was a biphasic change of mean arterial pressure, namely, the rapid increase immediately after the injection (approximately 2 min, phase 1) and the subsequent fall and slow recovery (approximately 4-30 min, phase 2). These effects were completely abrogated by pretreatment of rats with cobra venom factor. Pretreatment with carboxypeptidase inhibitor, which inhibits inactivation of anaphylatoxins C3a and C5a, induced enhanced reduction of blood pressure. Circulating leukocytes and platelets were rapidly decreased 5 min after antibody injection and became normal by 2 h. Hematocrit and erythrocyte count were continuously increased up to 2 h after injection, suggesting that there was hemoconcentration due to increased vascular permeability. Immunofluorescence study revealed binding of antibody fragments and rat C3 along the capillaries of lung, heart, and liver 5 min after injection. In contrast to 5I2, F(ab')2 fraction of 6D1, though localized to the same areas and in similar amounts, had no significant effect on the parameters measured. These data suggest that the rat counterpart of mouse Crry/p65 plays a vital role in vivo by preventing the activation of autologous complement on vascular endothelium.

Animals↗
PubMed2006

Effect of oral diacerein (DAR) in an experimental hip chondrolysis model.

We aimed to reproduce the articular cartilage structural changes in a joint exposed to a metallic implant as in the adolescent pinned hip with persistent joint penetration and secondly, to test the effect of an interleukin inhibitor, diacerein (DAR) in the ensuing articular cartilage lesion. Twenty immature beagles were submitted to a surgical K-wire implantation in the hip with the material left in the joint space for 6 months. Twelve animals were sacrificed for histological and biochemical tests. Eight animals were sacrificed at 10 months (half of them treated with DAR) and analyzed by scanning electron microscopy (SEM) and biochemistry of the articular cartilage. Preoperative and monthly C3 and C4 complement and immunoglobulins serum levels were determined. The histological and the electrophoretic profile changes were significative at 6 months. At 10 months the migration profile (CaCl2) recovered to normal levels in the operated hip and the SEM scores for the acetabulum were similar to the non operated control hip after treatment. The serum level of IgA was elevated at the 4th and 6th month postoperatively. The persistence of a metallic implant resulted in degenerative changes parallel to that described for hip chondrolysis as a complication of in-situ pinning; and the cartilage lesion improved with DAR treatment.

Acetabulum↗
PubMed1997

Suppression of alternative complement pathway activity by radiographic contrast media.

The authors examined the effect of four different kinds of contrast media (ionic/non-ionic, monomer/dimer) on the activation of the complement (C) system (haemolytic activity and anaphylatoxin generation) in vitro. In addition, the authors compared the effect of contrast media on inulin-mediated generation of the anaphylatoxin derivative C3a des Arg in sera from urticarial reactors and their non-reacting controls. It was observed that the incubation of commercial iohexol, ioxaglate, iodixanol and meglumin amidotriz solutions in normal human serum (NHS) resulted in a dose-dependent decrease in the haemolytic activity of the alternative C pathway. Contrary to expectations the contrast media did not activate C in NHS. Instead, inulin-induced generation of C3a des Arg was inhibited by all the four contrast media. The strongest inhibitor was ioxaglate, an ionic dimer. No significant difference between the urticarial reactors and non-reactors in the inhibition of C3a des Arg generation was observed. In analyzing the mechanism of C inhibition we found that the contrast media solutions, particularly the ionic ones, prevented formation of the alternative pathway C3 convertase, C3bBb, by inhibiting the binding of factor B to surface-associated C3b molecules. The results suggest that the previously observed decrease in haemolytic C titres by contrast media is due to direct suppression of C activity rather than activation-induced consumption.

Complement C3-C5 Convertases↗