Allotypes of complement components in man.
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Animals↗
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Effect of the late complement components C5b-9 and of platelet-derived growth factor on the prostaglandin release of human synovial fibroblast-like cells.
We examined the prostaglandin E (PGE) synthesis of cultured adherent synovial fibroblast-like cells (SFC) from patients with osteoarthritis (OA) in the noninflammatory state as well as with rheumatoid arthritis (RA). In cells from RA patients the spontaneous PGE release was generally higher compared to that of OA patients, but decreased fast with time in culture. After cell passage, similar PGE baseline levels were seen in cells of the two patient groups. The cells could then be stimulated by the terminal complement components C5b-9 or C5b-8. PGE synthesis was also stimulated by the platelet-derived growth factor (PDGF), interleukin-1 (IL-1), or lipopolysaccharide (LPS). The amount of PGE synthesis after incubation with PDGF, LPS and IL-1 was comparable to that released after C5b-9. Thus, like other inflammatory mediators C5b-9 and PDGF trigger the increased PGE production by SFC and thus may participate in the development of synovial inflammation and contribute to the pathogenesis of RA.
Arthritis, Rheumatoid↗
Inhibition of terminal complement complex formation and cell lysis by monoclonal antibodies.
Three monoclonal antibodies (mabs), two against C5 and one against C6, were identified and characterized. They inhibited the generation of the terminal complement complex (TCC) in serum to over 90% as assayed by a sensitive ELISA based on a neoepitope-specific mab, which recognized TCC-integrated C9. The haemolytic function of the TCC was markedly reduced by all three mabs implying that they are directed to epitopes on C5 and C6 which are essential for TCC formation in both the fluid phase and on erythrocyte membranes. Since the generation of C5a was also impaired by these mabs, they may serve as tools in investigations of the sequelae of the generation of C5a and of TCC.
Antibodies, Monoclonal↗
Human platelet-initiated formation and uptake of the C5-9 complex of human complement.
We have studied the interaction of radiolabeled complement components with normal human platelets, platelets from a patient with paroxysmal nocturnal hemoglobinuria, and rabbit platelets in the absence of known complement activators or in the presence of cobra venom factor (CVF). When unwashed platelets in platelet-rich plasma, or washed platelets suspended in serum or autologous plasma, were incubated for 30 min, C3 and terminal components (C5, C8, and C9) were found to bind to them. The terminal components were shown to be bound as the C5-9 complex, rather than as individual proteins, by eluting them from the platelet membrane and examining their behavior on ultracentrifugation. They cosedimented at a rate characteristic of the stable C5-9 complex (22S). As many as 370-1,380 C5-9 complexes/platelet were calculated to have been bound during the incubation period. The complex so formed did not differ by ultracentrifugational criteria from that binding to rabbit platelets after CVF activation of complement. Though C3 was not included in the complex, it did not appear to be bound by nonspecific absorption. It could not be removed by washing but rather was eluted by the freeze-thaw technique used to elute the C5-9 complex. Incubation of radiolabeled components in platelet-free plasma did not result in C5-9 complex formation, indicating an initiating role for platelets in this reaction. In contrast to platelets, erythrocytes incubated in analogous plasma did not induce detectable C5-9 formation. Neither EDTA, phenylmethylsulfonylfluoride, nor epsilon-amino-N-caproic acid prevented platelet-initiated formation of C5-9, suggesting that the reaction may involve mechanisms of complement activation not previously described.
Aminocaproates↗
Complement lysis of human erythrocytes. Differeing susceptibility of two types of paroxysmal nocturnal hemoglobinuria cells to C5b-9.
Although enhanced sensitivity of erythrocytes to complement-mediated lysis is a hallmark of paroxysmal nocturnal hemoglobinuria (PNH), subpopulations of erythrocytes in such patients vary significantly in this respect. One PNH erythrocyte subpopulation (termed type III) comprises exquisitely sensitive cells, whereas type II PNH erythrocytes are intermediate in complement sensitivity between PNH type III and normal human erythrocytes. Differences in the action of the terminal complement components that would account for the differing lytic behavior of types II and III PNH erythrocytes have been proposed but not directly demonstrated. The present studies, making use of carefully selected cases with pure populations of type II or type III erythrocytes, confirm a prior observation that antibody-coated PNH erythrocytes of both types II and III display comparably supranormal C3 binding in whole human serum. However, when lysis was induced by the isolated C5b-9 membrane attack mechanism, bypassing the requirement for C3 binding, only type III PNH cells exhibited greater than normal lysis. This finding suggests that type III PNH erythrocytes have an additional membrane abnormality not present in type II cells. Thus, the differing lytic behavior of these two cell types in whole serum may reflect the additive effects on type III cells of both exaggerated C3 binding and enhanced sensitivity to C5b-9, whereas the more moderate lysis of type II PNH cells may be determined mainly or entirely by the earlier-acting mechanism producing augmented C3 binding. The failure of guinea pig C8 and C9, as opposed to human C8 and C9, to reveal the true lytic sensitivity of PNH-III E in our earlier study is illustrated, and its implications briefly discussed.
Animals↗
Membrane receptors on neutrophils.
Neutrophils recognise humoral immunologic reactants through 'receptors' on their surface membrane. Most widely studied and probably of greatest biologic significance are the immunoglobulin (Fc), and complement (primarily C3b and C5a) receptors which enable the cell to ract with, and be stimulated by, antigen-antibody, or antigen-antibody-complement complexes and their products. This interaction with the putative receptors and the consequent cell activation occurs most optimally on surfaces and plays a critical role in the mammalian host defense system.
Antibody Specificity↗
Complement, serum bactericidal activity, and disseminated gram-negative infection.
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Blood Bactericidal Activity↗
Activation of the complement attack mechanism in the fluid phase and its control by C567-INH: lysis of normal erythrocytes initiated by zymosan, endotoxin, and immune complexes.
Addition of zymosan-serum complexes to guinea pig erythrocytes in guinea pig complement-EDTA was found to result in substantial lysis of the bystander cells in the presence of polycations such as poly-L-lysine of 178,000 daltons. Involvement of the alternative C pathway was shown, and the optimum time, temperature, and eruthrocyte and polycation concentrations were defined; a surprising efficiency was observed at low temperature and high cell concentrations. Several lines of evidence indicated that this hemolysis was mediated via the C567 complex of the C system and modulated by serum inhibitors of C567 (C567-INH): lysis was observed only with zymosan-serum complexes possessing C-consuming activity; it was not observed in C5-depleted guinea pig serum but was restored upon addition of purified C5; the addition of partially purified C567-INH insubstantially depressed hemolysis; and poly-L-lysine which is known to neutralize C567-INH in solution resulted in substantial enhancement of hemolysis. We also sought to determine whether the addition of complement activators directly to erythrocyte-serum mixtures could result in the hemolysis of bystander erythrocytes. It was found that zymosan, endotoxin, antigen-antibody complexes, and aggregated human gamma-globulin each could initiate such bystander lysis under appropriate conditions. Lysis again was favored by increased erythrocyte concentrations, low temperatures, and the presence of polycations such as poly-L-lysine, and was found to be mediated via the C system. C567-INH blocked cytolysis whereas poly-L-lysine potentiated hemolysis by neutralization of C567-INH. These experiments emphasize the propensity for C567 formation and lysis of bystander erythrocytes during C activation generally, the role of C567-INH in the control of this lysis, and the susceptibility of these interactions to modulation by highly charged macromolecules.
Animals↗
The properdin pathway: mechanisms of complement activation and analogies to the classical pathway.
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Complement C1↗
[Interaction between the complement and the coagulation systems].
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Blood Coagulation↗
Studies on the inhibition of C56-initiated lysis (reactive lysis). V. The roleof C567-INH in the regulation of complement-dependent haemolysis initiated by cobravenom factor.
Activation of the alternative pathway of complement by a factor from cobra venom (CVF) can lead to lysis of unsensitized erythrocytes (E) of some species. In these studies we observed that alterations in CVF-induced lysis could be produced by manipulation of C567-INH, a naturally occurring inhibitory activity which acts on fluid phase C567 complexes. Venom lysis of sheep and guinea-pig E was markedly inhibited by serum fractions having C567-INH activity. Microgram quantities of poly-L-lysine (PLL), molecular weight 180,000, a polycation which is a functional antagonist to C567-INH in serum, potentiated CVF lysis of sheep and guinea-pig E, and permitted the lysis of human E, which are otherwise not suscepticle to CVF lysis. The potentiation of venom lysis by PLL seemed not to be due to alterations in the target cell membrane; furthermore, it in turn was reversed by substances with C567-INH activity. This suggests that the generation of fluid phase C567 complexes contributes to the CVF-induced lysis of erythrocytes of these species, and that the haemolytic potential of fluid phase C567 generated during alternative pathway activation by this means is regulated by C567-INH.
Ammonium Sulfate↗
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. I. Generation of the activated complex.
A complex formed between cobra venom factor (CVF) and isolated human factor B (B) was found to be converted by trypsin to a stable enzyme, CVF-B which cleaved the third component (C3) and the fifth component (C5) of human complement. The formation of CVF-B by trypsin required divalent cations, whereas the formation of the lytic factor from human serum occurred even in the presence of EDTA. CVF-B purified by gel filtration could initiate the hemolysis of unsensitized guinea pig erythrocytes when incubated with human complement components C5 to C9 in 0.01 M EDTA buffer. C3 was not required for the lysis of guinea pig erythrocytes initiated by CVF-B because of the beta1C precipitation line formed between human serum and anti-beta1C antibody did not inhibit the hemolysis by CVF-B in agarose gel. Treatment of beta1C and beta1F globulins in whole human serum with CVF-B in the presence of 0.01 M EDTA converted them to components with higher mobilities on immunoelectrophoresis.
ABO Blood-Group System↗
The C5b-9 complex: subunit composition of the classical and alternative pathway-generated complex.
The membrane attack complex of complement (C5b-9) is identical in composition regardless of which pathway of activation was instrumental in its formation. Band V protein was consistently a subunit of the soluble complex. Since band V protein is not required for complement-dependent cytolysis, it probably represents a membrane site equivalent in serum of the nascent C5b-9 complex.
Centrifugation, Density Gradient↗
Hereditary complement deficiencies in Israel.
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Complement Activation↗
Terminal complement complexes and C1/C1 inhibitor complexes in rheumatoid arthritis and other arthritic conditions.
Terminal complement complex (TCC) and C1r-C1s-C1 inhibitor complex (C1/C1 INH) concentrations were measured in plasma and synovial fluid from patients with arthritis and related to other measures of disease activity. Both TCC and C1/C1 INH concentrations were significantly increased in patients with rheumatoid arthritis (RA) compared with patients with osteoarthritis (plasma and synovial fluid, P less than 0.05) and normal subjects (plasma only, P less than 0.001). In the patients with RA, there was no correlation between plasma or synovial fluid TCC concentrations and IgM rheumatoid factor, immune complex or C1/C1 INH levels. However, in 10 patients with seronegative RA, C1/C1 INH and immune complex levels correlated significantly in synovial fluid (r = 0.69, P less than 0.05) although not in plasma (r = 0.52). Plasma and synovial fluid TCC and C1/C1 INH concentrations did not differ in rheumatoid patients with severe compared with mild joint disease (categorized by the Ritchie score). These results confirm a role for complement activation in RA but suggest that several mechanisms are involved in its pathogenesis.
Adult↗
Haemolytic assays in agarose plates for components of the classical complement pathway: interference by the alternative pathway.
It has been observed that when serum C6 is measured by the haemolytic radial diffusion technique a heat labile factor limits the size of the haemolytic rings. This reduction is haemolysis has been shown to be due to alternative pathway activation of C6 in the agarose plate; and that the heat labile factor is Factor B of the alternative pathway. This phenomenon is of practical importance when assaying for C6; however, it does not explain the observations of a C6 inactivator reported by Nelson & Biro (1968).
Antigen-Antibody Complex↗