[Clinical study of complement activation during cardiopulmonary bypass--analyses of complement activation pathway and transpulmonary leukosequestration].
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Pulmonary macrophages are attracted to inhaled particles through complement activation.
Pulmonary macrophages play a central role in clearing inhaled particles from the lung. Previously, we showed that inhaled asbestos fibers activate complement-dependent chemotactic factors on alveolar surfaces to facilitate macrophage recruitment to sites of fiber deposition. In the studies presented here, we have tested a variety of inorganic particles for complement activation in vitro and correlated these data with results on particle-induced macrophage accumulation in vivo. We found that significant chemotactic activity was activated in rat serum and concentrated lavaged proteins by chrysotile and crocidolite asbestos, iron-coated chrysotile asbestos, fiberglass, and wollastonite fibers, as well as by carbonyl iron and zymosan particles. Ash from the Mt. St. Helens volcano did not induce chemotactic activity in either the serum or lavaged proteins. Rats were exposed to brief aerosols of each of the particles listed above (except zymosan). All the particle types studied were deposited primarily at first alveolar duct bifurcations. In addition, all of the particles, except Mt. St. Helens ash, induced at 48 h postexposure significant accumulations of macrophages at these sites. Time-course studies of carbonyl iron particle exposure demonstrated that iron induced a rapid macrophage response, but both particles and phagocytic macrophages were cleared from alveolar surfaces within 8 days after exposure. The Mt. St. Helens ash induced no macrophage accumulation at any time postexposure. We conclude that particles with a wide variety of physical characteristics are capable of activating complement and consequently attracting macrophages, both in vitro and in vivo. We suggest that complement activation is a mechanism through which pulmonary macrophages can detect inhaled particles on alveolar surfaces.
Animals↗
Complement activation and cyto-immunological alterations of the respiratory mucosa.
The action of activated complement on the upper respiratory tract was studied using the registration of ciliary beating and the transmission and scanning electron microscopy of ciliated cell lesions. The alternative pathway of activation was done using (1) non-specific activators, i. e. zymosan, dextran sulfate and polymerised sIgA, and (2) specific activators, i. e. "Ag-sIgA" immune complexes on normal mucosa and contact between an antigen and the tracheal mucosa of an immunized animal. In all cases, a quick alteration of the ciliary beating rythm was registered as well as more or less extensive cytological destruction. Such results were obtained with or without adjunction of complement; this suggested the existence of complement locally. A new method to demonstrate the occurrence of complement was developed, and the results showed that complement was present in the trachea. The above results were corroborated (1) by EDTA inhibition of the two complement pathways which prevented stopping of the ciliary beating and eliminated most of the cytological lesions, whilst EGTA left the alternative pathway operative with consequent alterations, and (2) by using C6-deficient rabbits in which no alterations were found. This study demonstrated that under certain conditions, local sIgA may activate the complement, and this fact explains many aspects of these immunological reactions of the respiratory epithelium.
Animals↗
A comparison of the in-vitro antibacterial and complement activating effect of 'OpSite' and 'Tegaderm' dressings.
Two readily available semipermeable polyurethane dressings, 'OpSite' and 'Tegaderm', were tested for their in vitro ability to kill potential bacterial pathogens and activate complement C3. In bacterial killing tests, 'OpSite' was superior to 'Tegaderm' and in addition only 'OpSite' activated C3. It is concluded that in the practical situation, 'OpSite' could well confer a greater margin of safety.
Bacteria↗
In vitro complement activation by rabbit lymphocytes and thymocytes in autologous serum.
The activation of C3, previously demonstrated to occur during the isolation of lymphocytes from rabbit blood, has been investigated further by in vitro exposure of blood and lymph node lymphocytes and thymocytes to autologous serum. Activated C3 deposited on the lymphoid cell-surface was detected by (i) anti-C3, (ii) immune adherence reaction, and (iii) blocking of receptors for C3. An affinity shown by guinea-pig erythrocytes for activated complement was also investigated. Using EGTA, which inhibits the classical complement pathway while leaving the alternative pathway unaffected, it was shown that either pathway may be activated by rabbit cells depending on the temperature of incubation. The classical pathway was triggered at 4 degrees, probably by the reaction of cold auto-antibodies with lymphoid cell-surface determinants. At 37 degrees, however, comlement activation followed the alternative pathway in a similar manner to that reported by other workers with human lymphoblastoid cell lines.
Animals↗
Complement activation by plasma separator membranes.
Because of their structural similarity to dialysis membranes, six plasma separator membranes were evaluated for the ability to activate complement, as judged by immunoconversion of the third component of complement in crossed immunoelectrophoresis. A polysulfone and two cellulose acetate membranes were relatively strong alternative pathway activators. Polypropylene, poly[vinylidine fluoride] and polyvinyl-chloride derivative membranes were weak activators in some sera. Membrane activation was inhibited in citrate-anticoagulated but not in heparin-anticoagulated plasma. The results of such in vitro screening should be of value in selecting materials and anticoagulation regimens for membrane plasma separators.
Complement Activation↗
Isolation of rat IgM to IgG hybridoma isotype switch variants and analysis of the efficiency of rat Ig in complement activation.
Sequential sublining was used in combination with enzyme-linked immunosorbent assays to isolate mu----gamma isotype switch variants of the rat IgM secreting mouse-rat B cell hybridoma line BA1.8. Switch variants to all four subclasses of IgG were obtained. The variant antibodies retained the antigen specificity of the parental IgM for the O18 (lipopolysaccharide) antigen of Escherichia coli. In sodium dodecyl sulfate-polyacrylamide gels the apparent molecular mass of the gamma heavy chains decreased in the order gamma 2b greater than gamma 1 greater than gamma 2c greater than gamma 2a. IgM, IgG1, IgG2a, IgG2b and IgG2c of the BA1.8 variant family and IgG2b, IgE and IgA of the previously described BA1.2 family were used for a comparative analysis of the capacity of rat Ig to activate complement. Efficient lysis of sheep erythrocytes coated with the O18 antigen was observed with IgM and all IgG subclasses, but no lysis was triggered by IgE or IgA. One hundred to 1000 IgG molecules were required to mediate the same hemolytic activity as one IgM molecule. The four IgG subclasses were equally efficient at mediating lysis by rat or human complement, while IgG2a was less efficient with guinea pig complement than the other three IgG subclasses. Antibody-triggered binding of C3 to pathogenic O18:K1 E. coli bacteria was measured using serum containing 125I-labeled C3. K1-encapsulated strains did not fix C3 efficiently in the absence of specific antibodies while acapsular mutants fixed C3 via the alternative pathway. IgM and all IgG subclasses triggered C3 binding to the K1 encapsulated bacteria. The capacity of IgM to mediate C3 fixation was not greater than that observed with IgG.
Animals↗
Modulation of complement activation on hemodialysis membranes by immobilized heparin.
To determine the effects of surface-associated heparin on the capacity of hemodialysis membranes to activate complement, cellulose acetate (CA) membranes that were untreated and CA membranes that had been coated with heparin (HCA) were incubated with C3-depleted serum repleted with radio-labeled C3. Next, the proteins in the supernatant and those eluted from the membranes were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. C3 activation was quantified by determining the radioactivity of the C3a-containing band in the gel. Total C3a generation (fluid phase C3a plus membrane-associated C3a) was three times greater in the presence of HCA compared with CA. Most (88%) of the C3a generated in the presence of HCA, however, was adsorbed onto the membrane surface. Consequently, there was more C3a in the CA supernatant than in the HCA supernatant. To determine the mechanism by which heparin enhanced alternative pathway activity, binding studies with radiolabeled factor B and factor H were performed. HCA bound 3.4 times more factor B and 20 times more factor H than did CA. The binding of these proteins, however, was not dependent on complement activation. Studies designed to test the functional activity of isolated factor H and factor B that had been adsorbed to the membrane showed that factor H was active on both CA and HCA, whereas factor B was active only on HCA. These data demonstrate that heparin immobilized onto CA hemodialysis membrane enhances C3 activation but produces low levels of C3a in the fluid phase because of high surface adsorption of the anaphylatoxin. Heparin appears to augment alternative pathway activity by favoring the interactions of factor B with other constituents of the amplification C3 convertase of the alternative pathway of complement.
Biocompatible Materials↗
Complement activation by female protein, the hamster homologue of human C-reactive protein.
The capacity of Syrian hamster female protein (FP), a phosphorylcholine (PC)-binding pentraxin, to activate complement was tested in an in vitro system consisting of PC-coupled sheep red blood cells and guinea pig serum as the complement (C) source. FP was demonstrated to fix complement as reflected by hemolysis. Such hemolysis was eliminated by heat treatment (56 degrees C, 30 min) of guinea pig serum and inhibited by PC chloride but not dinitrophenyl lysine. The inability of C4-deficient guinea pig serum to provide lytic activity indicated that lysis proceeded through the classical hemolytic pathway.
Acute-Phase Proteins↗
Complement activation during systemic lupus erythematosus. C3a and C5a anaphylatoxins circulate during exacerbations of disease.
To determine whether activated complement components appear in the circulation of patients with systemic lupus erythematosus (SLE), we measured C5a and C3a by radioimmunoassay. Mean C5a concentration in the plasma of acutely ill SLE patients was 46.0 ng/ml, compared with 17.1 ng/ml in normal controls (P less than 0.01). Mean C3a concentration in patients with severe disease was 526 ng/ml, compared with 134 ng/ml in controls (P less than 0.01). In patients with moderately active SLE, the mean C3a concentration, but not the mean C5a concentration, was also elevated. In addition, C3a was elevated in 15 or 21 patients with active SLE, whereas low levels of C3 or C4 were noted in only 7 of these 21 patients. We conclude that the measurement of complement-derived anaphylatoxins may be useful in the management of patients with SLE. In addition, we suggest that these circulating mediators may contribute to the pathogenesis of vascular injury in patients with the disease.
Complement Activation↗
The subclass profile and complement activating potential of anti-alpha-gliadin antibodies in coeliac disease.
In a randomly selected group of coeliac patients, alpha-gliadin antibodies (AGA) of subclasses IgG1 and IgG3 were significantly elevated (p less than 0.01) in comparison to both normal and disease control groups. This result was, however, influenced by increased total AGA levels in the coeliac patients. AGA subclass profiles of cohorts of coeliac and normal controls matched for total IgG AGA were therefore compared. It was found that IgG3 AGA levels were higher in the coeliac group (p = 0.006) while IgG4 titres were higher in the control group (p = 0.005). Titres of IgG1 and IgG2 AGA did not differ between the two groups. Because of the marked differences between the ability of IgG3 and IgG4 to activate complement, alpha-gliadin-specific complement fixation was measured. Using randomly selected coeliac and normal sera, the patient group activated highly significantly greater quantities of complement than controls (p less than 0.01). Furthermore, when samples matched for total IgG AGA were compared, sera from coeliac patients were again found to activate greater amounts of complement than sera from controls (p = 0.024). Thus AGA in coeliac sera are both structurally and functionally distinguishable from AGA in normal control sera.
Adolescent↗
Association of complement activation and elevated plasma-C5a with adult respiratory distress syndrome. Pathophysiological relevance and possible prognostic value.
Clinical and experimental observations suggest that aggregation of polymorphonuclear granulocytes (PMN) in response to activated complement (C) might contribute to the genesis of the adult respiratory distress syndrome (ARDS), aggregating PMN causing pulmonary dysfunction by becoming lodged in the lung as leucoemboli. PMN-aggregating activity can be detected in C-activated plasma and reflects C5a levels. In 61 patients at risk for ARDS a strong and highly significant correlation was found between the presence of PMN-aggregating activity in the plasma and the development of ARDS; this correlation was also significant when patients with sepsis were excluded from analysis. In patients followed prospectively detection of elevated C5a seemed to be a useful predictor of ARDS. Since corticosteroids have been shown to inhibit PMN aggregation both in vitro and in vivo, the evidence for a role for PMN aggregation in the genesis of ARDS supports the use of corticosteroids in this disorder.
Cell Aggregation↗
Effect of time, temperature and anticoagulants on in vitro complement activation: consequences for collection and preservation of samples to be examined for complement activation.
The effects of time, temperature, ethylene-diamine-tetra-acetic acid (EDTA), citrate and heparin on in vitro complement activation were examined in enzyme immuno assays (EIA) for detection of C3 activation products and the terminal complement complex (TCC). In vitro complement activation occurred during coagulation since baseline concentrations of activation products were considerably higher in serum than in plasma. EDTA was more efficient than citrate and heparin in inhibiting in vitro activation. Minimal activation was observed in all preparations when samples were kept at 4 degrees C for up to ten days, whereas a very rapid increase in activation products occurred even in EDTA plasma when the temperature was elevated. Based on the data obtained, guidelines for the collection and preservation of samples to be examined for complement activation are given.
Blood Preservation↗
Mechanisms of complement activation by crystalline cholesterol.
The mechanism by which cholesterol crystals activate complement in human serum has been studied. Crystals treated with serum and washed with buffer contain a fixed C3/C5 convertase. Its generation is dependent on the presence of divalent cations (and of factor B). The cholesterol-fixed convertase is subject to decay and can be regenerated by factors B and D. C2 in combination with C1 is not essential but enhances the convertase formation. These findings indicate that it is predominantly the alternative C3/C5 convertase C3bBb(P) that assembles on cholesterol during exposure to human serum. By the use of different antisera and immunofluorescence a C3 fragment, probably C3b, was demonstrated on serum-treated crystals. Its fixation is resistant to washing with urea, and with buffers of differing pH: by hydroxylaminolysis the C3 fragment dissociates from the crystals. This indicates a covalent ester bond linking the labile binding site of activated C3 to the hydroxyl group of cholesterol. Cholesterol acetate does not fix C3 nor acquire a C3-cleaving activity upon contact with serum. In addition, cholesterol crystals bind factor I (C3b inactivator) and in this way may facilitate fixation and amplification of the alternative C3/C5 convertase.
Cholesterol↗
Complement activation by aluminium and zirconium compounds.
The activation of complement by a number of metal compounds, previously found to induce chronic inflammation, was investigated. Results obtained were compared with complement activation by inulin and zymosan. It was shown that complement activation by these metal compounds did not necessarily involve either the classical or the alternative pathways. Some of these compounds were unable to activate complement in the absence of detectable plasminogen. The results obtained indicate a relationship between the ability of these compounds to induce chronic inflammation in the guinea-pig and to activate complement.
Aluminum↗
[Biological effects and the mechanism of complement activation--interaction among complement, coagulation, fibrinolysis and kinin generation system].
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Animals↗
Compartmental distribution of complement activation products in artificial kidneys.
The compartmental distribution of the human anaphylatoxins C3a and C5a has been defined during simulated hemodialysis performed with various types of hemodialyzers. New cuprophan hollow fiber dialyzers were found to activate human complement very readily in vitro, while re-used cuprophan dialyzers displayed only modest complement activating potential. The C3a and C5a antigens, formed as a result of complement activation in these dialyzers, accumulated predominantly in the blood path and were not adsorbed extensively on the membrane surface or transported into the dialysate compartment. Cellulose acetate membranes also produced complement activation in vitro, but to a lesser degree than new cuprophan hollow fibers. However, these membranes exhibited a significant capacity to bind the anaphylatoxins to their surface. Polyacrylonitrile membranes appeared to be unique in that they not only failed to activate complement significantly, but they rapidly adsorbed large quantities of C3a and C5a. These findings demonstrate that hemodialysis membranes may differ with regard to their complement activating potential as well as their ability to remove circulating anaphylatoxins from the blood path. Clinical measurements of anaphylatoxin production during hemodialysis reflect these dynamic events.
Complement Activation↗
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↗