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PubMed1986

Complement activation by 19S IgM rheumatoid factor: relationship to disease activity in rheumatoid arthritis.

19S IgM rheumatoid factor (RF) in rheumatoid arthritis (RA) are polyclonal autoantibodies directed against the Fc piece of IgG. Rheumatoid patients with RF tend to have aggressive synovitis, nodules, and extraarticular manifestations. Although RF titer does not correlate with disease activity, RF activates complement (C) by the classical pathway. Thus, we postulated that selective stimulation of cell clones producing efficient C activating RF molecules might be associated with disease flares, independent of changes in serum RF concentration. To address the question, 42 patients with RA were evaluated prospectively. Serum RF concentration was measured by radioimmunoassay (RIA) and C activating activity by hemolytic assay. We then calculated the mean hemolysis (MH) of sensitized sheep erythrocytes (SRC) produced/ml of RF serum (MH/ml) and MH/microgram of RF as an expression of RF C activating properties (CAP). The following observations were made: RF CAP varied among the patients studied; RF CAP varied over time in individual patients; RF CAP differences varied in both groups independently from RF concentration; RF CAP correlated with both systemic and articular disease activity; and total RF concentration correlated with articular findings and nodules but less well with systemic disease activity.

Adult↗

PubMed1990

Isolation and characterization of a complement-activating lipid extracted from human atherosclerotic lesions.

The major characteristics of human atherosclerotic lesions are similar to those of a chronic inflammatory reaction, namely fibrosis, mesenchymal cell proliferation, the presence of resident macrophages, and cell necrosis. Atherosclerosis exhibits in addition the feature of lipid (mainly cholesterol) accumulation. The results of the present report demonstrate that a specific cholesterol-containing lipid particle present in human atherosclerotic lesions activates the complement system to completion. Thus, lipid could represent a stimulatory factor for the inflammatory reaction, whose underlying mechanistic basis may be, at least in part, complement activation. The complement-activating lipid was purified from saline extracts of aortic atherosclerotic lesions by sucrose density gradient centrifugation followed by molecular sieve chromatography on Sepharose 2B. It contained little protein other than albumin, was 100-500 nm in size, exhibited an unesterified to total cholesterol ratio of 0.58 and an unesterified cholesterol to phospholipid ratio of 1.2. The lipid, termed lesion lipid complement (LCA), activated the alternative pathway of complement in a dose-dependent manner. Lesion-extracted low density lipoprotein (LDL) obtained during the purification procedure failed to activate complement. Specific generation of C3a desArg and C5b-9 by LCA indicated C3/C5 convertase formation with activation proceeding to completion. Biochemical and electron microscopic evaluations revealed that much of the C5b-9 present in atherosclerotic lesions is membraneous, rather than fluid phase SC5b-9. The observations reported herein establish a link between lipid insudation and inflammation in atherosclerotic lesions via the mechanism of complement activation.

Aorta↗

PubMed1988

Selective lung leukosequestration after complement activation.

This study tests whether activated complement leads to a selective entrapment of polymorphonuclear leukocytes (PMN's) in the lungs. Awake sheep were infused for 5 min with zymosan-activated plasma (ZAP, 2.5 mg/ml) at a rate of 5 ml/min into the superior vena cava (IV, n = 4) or intra-arterially into the aortic arch or femoral artery (IA, n = 8). At the end of IV infusion, leukocyte counts fell from 8,862 to 1,631/mm3 (P less than 0.01). PMN counts across the lungs decreased by 74%. There were increases in plasma thromboxane (Tx) B2 from 114 to 2,733 pg/ml (P less than 0.01), mean pulmonary arterial pressure from 12 to 42 mmHg (P less than 0.01), and physiological shunt from 13 to 25% (P less than 0.05). Within 1 h lymph TxB2 levels had risen from 301 to 4,916 pg/ml (P less than 0.01), lung lymph flow (QL) rose from 3.7 to 11.1 ml/30 min (P less than 0.05), lymph-to-plasma protein ratio (L/P) remained unchanged at 0.63, and lymph protein clearance increased from 2.3 to 7.5 ml/30 min (P less than 0.05). Leukosequestration, quantitated by capillary PMN counting and by assaying the granulocyte marker myeloperoxidase, occurred relative to sham animals (P less than 0.05) in the lung and spleen but not in other organs. Intra-arterial ZAP infusion led to changes that were similar in magnitude and timing to the IV group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Inflammation in the lungs of rats after deposition of dust collected from the air of wool mills: the role of epithelial injury and complement activation.

In a previous study assessing respiratory symptoms in individuals employed in wool textile mills in the north of England relations between symptoms of chronic bronchitis, breathlessness and wheeze, and rhinitis and current exposure to airborne mass concentration of dust were shown. As preliminary steps in defining the potential hazard associated with dust from the air of wool mills the ability of inspirable dust, collected from the air of wool textile mills, to cause inflammation when injected into the lungs of rats was determined. Dusts were collected from the beginning of wool processing (opening) in one factory and from the middle (combing) and late (backwinding) stages of the process in two other factories. Ability of the dusts to cause inflammation was assessed by instillation into the lungs of rats followed by bronchoalveolar lavage. All the dusts caused some inflammation which peaked on day 1 and did not persist beyond one week. A distinctive aggregation response of mononuclear cells in the lavage, however, had a different time course, peaking at day 7. An attempt was made to determine how the wool mill dusts caused inflammation and experiments showed that the dusts themselves had no inherent chemotactic activity but that they did have a pronounced ability to generate chemotaxins in serum and so could activate complement in lung fluid. In addition, dust collected from ledges in the mills had the ability to injure epithelial cells in vitro which could also contribute to inflammation. A role for endotoxin in the inflammatory activity of the dusts was not discounted and a leachate of the dust had the ability to cause inflammation when injected into the lungs of rats. Wool mill dust is likely to be a complex mixture of materials and these experiments represent a preliminary approach to understanding the biological activity of the whole unfractionated dust and further studies are in progress to define more accurately the toxic material(s) in the dust.

Animals↗

PubMed1986

Oxygen free radical generation during cardiopulmonary bypass: correlation with complement activation.

To determine the relationships among complement activation, pulmonary leukosequestration, and oxygen free radical generation, we prospectively studied 15 patients undergoing cardiopulmonary bypass for myocardial revascularization. Plasma levels of C3a, C4a, and hydrogen peroxide (a marker of oxygen free radical generation) were measured before, during, and after extracorporeal circulation. The results confirm that cardiopulmonary bypass activates complement via the alternate (C3a) pathway. This first phase of complement activation was accompanied by an increase in plasma H2O2 (from 80 +/- 8 to 155 +/- 13 microM/ml; p less than .001) and by pulmonary sequestration of polymorphonuclear leukocytes. Protamine administration after cardiopulmonary bypass further activated complement via the classical (C4a) pathway but was not accompanied by a change in plasma hydrogen peroxide. We hypothesize that both complement activation and excess oxygen free radical generation contribute to the pathophysiology of extracorporeal circulation.

Blood Cells↗

PubMed1990

Evacuation of microscopic air bubbles from Dacron reduces complement activation and platelet aggregation.

Complement activation by biomaterials may play an important role in vascular graft failure since the physiologically active polypeptides, C3a and C5a, have several relevant properties. C3a promotes platelet aggregation and release, and C5a activates neutrophils, which may stimulate platelet aggregation by liberation of platelet activating factor or by a direct neutrophil platelet interaction. Microscopic air bubbles (nuclei) are found in the surface roughness or pores of most biomaterials, and their number and size are related to the surface tension of the material. Therefore two interfaces can be postulated to exist when Dacron is exposed to blood: (1) a blood/biomaterial, and (2) a blood/air interface. These air nuclei in the surface and the biomaterial itself are capable of activating complement. The purpose of these experiments was to eliminate these surface nuclei from Dacron by a process termed denucleation and subsequently to determine the effect of this intervention on complement activation and platelet aggregation in vitro. Dacron was denucleated by pretreatment that involved serial rinsing with ethanol and degassed buffer that results in replacement of the air nuclei by buffer. Both control and denucleated pieces of Dacron (2, 4, and 6 cm2) were then incubated in human plasma. Each plasma sample was assayed for complement activation products (C3a, C5a, and C4a) by means of radioimmunoassays, and the degree of autologous platelet aggregation that resulted from the addition of a portion of each incubated plasma sample to an autologous platelet suspension was measured. There was a significant reduction in C3a and C5a in the plasma samples incubated with denucleated Dacron as compared to control Dacron (p less than 0.001, analysis of variance [ANOVA]).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1977

Complement activation by interaction of polyanions and polycations. III. Complement activation by interaction of multiple polyanious and polycations is the presence of C-reactive protein.

Interactions between heparin and protamine previously were found to result in activation of the complement (C) system. In the present investigation, this interaction was shown to result in the binding of purified C1, and this was markedly enhanced in the presence of C-reactive protein (CRP). CRP also enhanced C consumption during heparin-protamine interactions in whole serum, and in the presence of CRP depletion of C components C1-3 was observed. Similar C1 binding and C consumption in the presence of CRP were seen upon the interaction of multiple additional polyanions including DNA, ENA, hyaluronic acid, chondroitin sulfate, and dextran sulfate with the polycations protamine sulfate and poly-L-lysine. These effects were observed with CRP concentrations well within the range found in normal human sera and considerably less than those found in most acute phase sera. We suggest, therefore, C activation by polyanion-polycation interactions in the presence of CRP may be important to certain reactions of host defense and inflammation.

Anions↗

PubMed1988

Complement activation by vascular prostheses and its role in progression of arteriosclerotic lesions.

This study, using C3a, C4a, and C5a assay and crossed immunoelectrophoresis in vitro and in vivo, was designed to determine whether vascular prostheses activate the complement system. The degree of complement activation and the pathway of activation were also studied. The complement levels (C3, C4, CH50) in different arterial diseases were measured, and the relationship of complement levels to serum lipids in patients with arteriosclerosis obliterans (ASO) was also investigated, in order to clarify a relationship between the complement system and arteriosclerosis or other arterial diseases. Bovine graft, dacron, and PTFE activated the complement system in vitro. In order of the degree of complement activation, bovine graft ranked first, followed by dacron and PTFE. The patient group with acute arterial occlusion showed high C3 and C4 levels. The healthy elderly group showed higher C3 and C4 levels than the healthy persons in their twenties. In ASO patients, C3 levels correlated with serum lipid levels. Judged from the relation of complement activation by vascular prostheses to the progression of arteriosclerotic changes, vascular prostheses should be assessed with regard to complement activation.

Arterial Occlusive Diseases↗

PubMed1991

Complement activation during prolonged extracorporeal membrane oxygenation.

Short-term cardiopulmonary bypass activates the complement system, possibly resulting in pulmonary dysfunction from granulocyte aggregation and pulmonary endothelial damage. These effects may be inhibited by steroids. Prolonged extracorporeal membrane oxygenation (ECMO) is used for newborn respiratory failure, but the effects of ECMO on complement activation are unknown. Twenty-one newborn infants with respiratory failure treated with ECMO were randomly assigned to group I (control, no steroids) or group II (30 mg/kg intravenous methylprednisolone before ECMO). Depletion assays of C3 and C5 were performed in each group at intervals before and during ECMO (declining values indicate complement activation). The groups were compared for complement levels, survival, time on ECMO and on the ventilator, and total hospitalization time. Steroids significantly shortened the time on ECMO and time on the ventilator after ECMO but did not affect survival or total hospitalization time. Steroids also enhanced activation of C3 and C5. Complement activation occurs during ECMO. Steroid administration paradoxically causes earlier complement activation but shortens ECMO and ventilator times. Complement activation during ECMO is of questionable significance. The benefits of steroids during ECMO may be mediated through other mechanisms.

Birth Weight↗

PubMed1989

Biocompatibility of urinary catheters. Effect on complement activation.

The ability of 2 brands of urinary catheters to activate the complement system in vitro as a marker of biocompatibility was investigated. Pieces of a silicone/latex catheter and an all-silicone catheter were incubated in human serum. Complement activation was tested in 2 enzyme immunoassays, one evaluating C3 activation and the other the terminal complement complex (TCC) formation. The silicone/latex catheter caused considerably more complement activation in both assays than did the all-silicone one. The findings are in agreement with previous results of tissue toxicity tests. The methods presented may prove valuable for the practical purpose of testing the biocompatibility of urinary catheters.

Biocompatible Materials↗

PubMed1988

Complement activation is not required for IgG-mediated suppression of the antibody response.

Feedback suppression of the antibody response by IgG is known to be dependent on intact Fc regions. However, it is not clear which of the Fc-mediated effector functions is required. In the present report we have studied whether ability or inability of the IgG antibodies to activate the complement system was of consequence for their immunosuppressive effect. First, a monoclonal IgG1-anti-2,4,6-trinitrophenyl (TNP) antibody, unable to activate complement via the classical or alternate pathway, was shown to be able to inhibit more than 90% of the in vivo sheep erythrocyte-specific antibody response in mice when TNP coupled to sheep erythrocytes was used as antigen. Second, we investigated the immunosuppressive ability of a non-complement-activating mutant IgG2a-anti-TNP monoclonal antibody. The mutant differs from the wild type by a single amino acid substitution in the CH2 domain leading to inability to fix complement factor C1q. However, the mutant has the same affinity for antigen and the same Fc receptor-binding capacity as the wild type antibody. It is demonstrated that the mutant was as efficient as the wild type antibody in inhibiting an in vitro antibody response to TNP-coupled sheep erythrocytes. These findings confirm the non-determinant specificity and Fc dependence of IgG-mediated suppression, and show that the Fc-mediated effector mechanism is independent of complement activation. The results instead suggest binding to Fc receptors as a necessary step in feedback immunosuppression and favor inactivation of B cells by cross-linking of Fc and antigen receptors on their surface rather than elimination of antigen by complement-dependent phagocytosis as the effector mechanism.

Animals↗

PubMed1992

Differences of two Borrelia burgdorferi strains in complement activation and serum resistance.

Complement activation and serum resistance of the Borrelia burgdorferi strains B31 (American strain) and PKo (European strain) were compared. In 25% (v/v) normal human serum (NHS) free of B. burgdorferi-specific antibodies the cells of the PKo strain were high activators of complement as indicated by rapid and strong C9 consumption, by deposition of up to 336763 C9 molecules per cell and by the formation of the terminal complement complex on the cell surface. By comparison, complement activation by the B31 strain was low with 5.4-fold less C9 deposited per cell. The addition of B. burgdorferi-specific antibodies to NHS either as purified IgG or heat-inactivated patient sera, had no influence on the results with both strains. After an incubation period of 2h at 37 degrees C in 25% (v/v) NHS most cells of the PKo strain had lost their viability as indicated by cell immobilization and failure to multiply in subcultures. In addition, extensive cell fragmentation and bleb formation were observed in the electron microscope. In contrast, the B31 strain remained alive and morphologically intact after the same incubation with NHS. We conclude from our results that complement activation and serum resistance are properties which differ considerably between isolated strains of B. burgdorferi.

Antibodies, Bacterial↗

PubMed1989

Different oxygenators for cardiopulmonary bypass lead to varying degrees of human complement activation in vitro.

Complement activation was studied in vitro with six different membrane and bubble oxygenators for cardiopulmonary bypass. There was a similar increase in terminal (C5 to C9) activation with all oxygenators (p less than 0.001), ranging from 281% (117% to 444%) to 453% (225% to 680%) after 60 minutes (median and 95% confidence intervals). C3 activation was not observed with a hollow fiber membrane and a soft shell bubble oxygenator. On the other hand, a capillary membrane, a sheet membrane, a nonporous membrane, and a hard shell bubble oxygenator all induced a similar increase in C3 activation (p less than 0.01), ranging from 107% (23% to 346%) to 272% (88% to 395%) after 60 minutes. The differences in C3 activation could not be explained by the blood contact materials or any other single factor known to induce activation, which suggests that overall complement activation during cardiopulmonary bypass is a multifactorial effect. The tubing set per se induced only minor C3 activation but contributed to the overall formation of terminal complement complex. The study further indicates that an arterial line blood filter prevents activated neutrophils from being reinfused to the patient and should be used regardless of type of oxygenator.

Cardiopulmonary Bypass↗

PubMed1991

Neutrophil polarization and immunoelectrophoresis assays in the study of complement activation by biomaterials.

The neutrophil polarization assay, a technique used to measure chemotaxis, was adapted to examine complement activation. Complement activation in serum which had been incubated with metallic and polymeric biomaterials was examined using the neutrophil polarization assay and immunoelectrophoresis assay. In agreement with previous publications, nylon activated the complement cascade, but PTFE did not. The neutrophil polarization assay was found to be the most sensitive technique for examining complement activation by endotoxin but the immunoelectrophoresis assay is the technique most sensitive for detecting complement activation by cobalt powder. In both assays, complement activation was not detected in serum incubated with chromium powder. However, serum incubated with silver and nickel powder stimulated neutrophils to polarize indicating that these powders may activate complement.

Biocompatible Materials↗

PubMed1988

Lack of complement activation by human IgA immune complexes.

Complement activation may play an important role in renal injury associated with glomerular deposition of IgA immune complexes. The ability of naturally occurring human IgA immune complexes (IgA-IC) and covalently cross-linked human IgA oligomers (X-IgA) to activate complement were examined in vitro and in vivo. Large-sized IgA-IC were isolated from a patient's serum by affinity purification (Jacalin-Sepharose) and gel chromatography. Stable X-IgA were prepared by chemical cross-linking with a heterobifunctional reagent, N-succinimdyl 3-(2-pyridyl-dithio) propionate (SPDP). Treatment of fresh normal human serum with large amounts of either IgA-IC or X-IgA failed to activate C3. The C3 consumption was measured immunochemically by the decrease of the B antigen on the native C3 and by the generation of iC3b. Addition of these complexes to serum did not result in cleavage of factor B. Administration of human IgA-IC or X-IgA to mice, killed after 6 h, resulted in glomerular deposition of IgA. Despite the presence of intense glomerular IgA deposits no C3 was detected. Collectively, these findings suggest that neither soluble nor renal localized human IgA complexes activate complement.

Animals↗

PubMed1989

Accentuated complement activation in patient plasma during the adult respiratory distress syndrome: a potential mechanism for pulmonary inflammation.

The adult respiratory distress syndrome (ARDS) represents an acute inflammatory lung disorder, characterized by both refractory hypoxemia and a mortality rate approaching 95%. Researchers have proposed that activation of the complement (C) system may play a role in the development of the pulmonary inflammation associated with ARDS. The purpose of this investigation was to determine whether complement activation occurs to a greater extent in patients with ARDS than in patients without ARDS, thereby providing a potential mechanism for the acute inflammation seen in ARDS. In this study, we assessed plasma complement activation by measuring complement activation by-products: C1rC1s-C1 inhibitor complex and C3b-P complex, generated subsequent to activation of the classical and alternative pathways, respectively, and also the terminal complement complex, formed after activation of either the classical or alternative complement pathway. Multivariate discriminant analysis revealed that these three complement activation complexes could distinguish patients with ARDS from those without ARDS (p less than 0.04). Furthermore, these three complexes provided a more sensitive discriminator of ARDS than did plasma levels of C3a desarginine (p greater than 0.30), C5a desarginine (p greater than 0.41) and total hemolytic complement activity (CH50) (p greater than 0.72). We conclude that a temporal association exists between the complement activation and the development of ARDS. Therefore, we suggest that complement activation by-products be included in the armamentarium for ARDS.

Adult↗

PubMed1987

The IgA-binding lectin jacalin induces complement activation by inhibition of C-1-inactivator function.

Jacalin, a D-galactose-specific lectin from jackfruit, interacts with human IgA and one or two other serum proteins. Incubation of jacalin with fresh human serum was shown to result in activation of the complement system. Therefore the mechanism of complement activation by jacalin was studied. Jacalin was extracted from jackfruit seeds (crude preparation) and purified to homogeneity by affinity chromatography on IgA-Sepharose to yield a pure preparation of jacalin. Both crude and pure jacalin were able to activate complement, accompanied by conversion of C3. Consumption of C1, C4 and C-1-inactivator (C-1-In) indicated involvement of the classical pathway. Aggregated IgG (AIgG) caused partial (38%) and jacalin induced complete consumption of C1-In functional activity. It was found upon Ouchterlony analysis that jacalin forms a precipitation line with purified C-1-In. In addition binding of 125I-C-1-In to jacalin-Sepharose was observed, and this binding was inhibitable by either secretory IgA or D-galactose. Next to binding of jacalin to C-1-In, jacalin was also shown to inhibit the functional activity of C-1-In. These results indicate that jacalin induces complement activation by inhibition of C-1-In function and thereby facilitates the activation of precursor C1 in either the absence or presence of low amounts of C1 activators.

Complement C1 Inactivator Proteins↗

PubMed1979

Complement activation by parasites. A review.

Activation of complement by parasites (living parasites or purified parasite antigens) is involved in several mechanisms of the host parasite relationship. In most of the experiments performed in vitro, complement activation was found to be lethal for the parasites, but sometimes it could be essential for the development of parasitemia. Both classical and alternative complement pathways may be activated by parasites; the classical pathway nearly always requires the involvement of antibodies whereas the alternative pathway is activated directly by products released by the parasites or present in their teguments. Activation of complement, especially via the alternative pathway may also be a prerequisite for cellular adherence to parasites which can then cause their death.

Animals↗