Relationships between complement activation, complement binding, and EBV absorption by human hematopoietic cell lines.
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Binding Sites↗
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The ontogeny of complement activity. Complement titers in the developing chick embryo during graft-versus-host reactions.
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Animals↗
Assays for complement activation.
Complement is a major biologic mediation system that functions in host defense against microorganisms and other pathogens and also aids in the elimination of damaged and abnormal cells. This is accomplished by its ability to mediate the destruction of pathogens and altered cells directly through cytolytic and cytotoxic properties, as well as indirectly by its ability to augment the actions of various effector cells, which in turn destroy or inactivate these substances. Its second major action in vivo is the production of an acute inflammatory response that, by altering blood-vessel permeability, contracting smooth muscles, and promoting an influx of leukocytes, aids in the localization of the injurious process responsible for complement activation and retards its spread and dissemination throughout the body. The actions of the activated complement system upon pathogens and altered cells, as well as its phlogistic properties, are the direct consequence of the actions of complement protein-protein complexes, enzymes, peptides, and cleavage products on the activator, on biologic membranes, and on various effector and other tissue cells. Complement activation is a frequent phenomenon in infectious diseases, autoimmune diseases, and many other conditions having an inflammatory component. Because of the importance of this system in contributing to the resolution of the disease process, monitoring of the status of the system in patients is frequently indicated. Monitoring of the complement status is also appropriate in numerous other diseases, such as those with an inflammatory component, in which complement activation occurs secondarily but in which it is frequently responsible for confining the injurious process and aiding in its resolution. A number of techniques are available to assess the status of the complement system in samples obtained from patients. Among these are a group of newer tests that specifically detect complement activation. They quantitate activation-dependent complement cleavage products, antigenic changes, or protein-protein complexes. These tests are quantitative, highly sensitive, and extremely specific; furthermore, most can be employed with samples obtained from patients. Because all of the biologic actions of the complement system require complement activation, such newer activation-specific assays permit the precise evaluation of the status of this system in human diseases. Further extension of their use to additional patients and other disease complexes will undoubtedly increase the understanding of the biologic importance of the complement system in human disease processes.
Complement Activation↗
Complement and atherogenesis: binding of CRP to degraded, nonoxidized LDL enhances complement activation.
Complement activation occurs in temporal correlation with the subendothelial deposition of LDL during early atherogenesis, and complement also plays a pathogenetic role in promoting lesion progression. Two lesion components have been identified that may be responsible for complement activation. First, enzymatic degradation of LDL generates a derivative that can spontaneously activate complement, and enzymatically degraded LDL (E-LDL) has been detected in the lesions. Second, C-reactive protein (CRP) colocalizes with complement C5b-9, as evidenced by immunohistological studies of early atherosclerotic lesions, so the possibility exists that this acute phase protein also fulfills a complement-activating function. Here, we report that addition of LDL and CRP to human serum did not result in significant C3 turnover. Addition of E-LDL provoked complement activation, which was markedly enhanced by CRP. Binding of CRP to E-LDL was demonstrated by sucrose flotation experiments. Binding was Ca(2+)-dependent and inhibitable by phosphorylcholine, and the complement-activating property of E-LDL was destroyed by treatment with phospholipase C. These results indicated that CRP binds to phosphorylcholine groups that become exposed in enzymatically degraded LDL particles. Immunohistological studies complemented these findings in showing that CRP colocalizes with E-LDL in early human atherosclerotic lesions. Thus enzymatic, nonoxidative modification of tissue-deposited LDL can be expected to confer CRP-binding capacity onto the molecule. The ensuing enhancement of complement activation may be relevant to the development and progression of the atherosclerotic lesion.
C-Reactive Protein↗
Immunoadsorption therapy and complement activation.
Complement activation was studied in six patients treated with immunoadsorption columns Ig-ADSOPAK for myasthenia gravis. Mean therapy duration was 18.6 months (range 4-28 months). Prior and after each procedure, concentrations of C3 and C4 were examined, hemolytic activity of complement by a classic pathway (CH50) was determined, as well as terminal complement complex (TCC). After each immunoadsorption procedure, a decrease of C3 and C4 was noted (median 21.19% and 19.68%, respectively). The CH50 and TCC follow-up showed statistically significant complement activation. Median of TCC accrual was 60.21% and median of CH50 decrease was 23.24%. No clinical manifestations of complement activation were present. With increasing number of procedures a marked decrease of TCC activation was observed in five patients, which was statistically significant in three of them (p < 0.05). This finding may indicate an immunomodulating effect of long-term adsorption therapy. With increasing number of procedures, an inhibition in complement system reactivity occurs. This result, however, has to be confirmed on a larger group of patients.
Adult↗
Anti-inflammatory effect of intravenous immunoglobulin mediated through modulation of complement activation.
Complement activation by immune complexes is well-known. In the course of autoimmune disease, acute and chronic complement activation is the primary inducer of inflammation and tissue damage. Polyclonal, polyspecific intravenous immunoglobulin (IVIg) preparations are a therapy of choice in a variety of autoimmune and inflammatory diseases. This review describes mechanisms by which IgG reduces complement activation or interferes with the action of proinflammatory complement-derived proteins. The known interference of IVIg with the biological activity of complement-derived proinflammatory proteins does not affect the generation of these potentially dangerous products, but can limit their devastating effects. Therefore, we embarked on studies on IVIg's potential to attenuate complement activation and thus to prevent further generation of such dangerous molecules. We present here a revised view of how the central event of complement activation--namely, complement amplification--operates on a molecular level and how IVIg, with its physiological autoantibodies directed against some complement proteins, is able to downregulate amplification of complement C3 activation. Finally, we summarize results of a study in which clinical effects of IVIg and attenuation of complement activation were assessed. We propose that the anti-inflammatory effect of IVIg in a wide range of autoimmune diseases might be explained, at least in part, by attenuation of complement amplification.
Animals↗
Ulex europaeus agglutinin II (UEA-II) is a novel, potent inhibitor of complement activation.
Complement is an important mediator of vascular injury following oxidative stress. We recently demonstrated that complement activation following endothelial oxidative stress is mediated by mannose-binding lectin (MBL) and activation of the lectin complement pathway. Here, we investigated whether nine plant lectins which have a binding profile similar to that of MBL competitively inhibit MBL deposition and subsequent complement activation following human umbilical vein endothelial cell (HUVEC) oxidative stress. HUVEC oxidative stress (1% O(2), 24 hr) significantly increased Ulex europaeus agglutinin II (UEA-II) binding by 72 +/- 9% compared to normoxic cells. UEA-II inhibited MBL binding to HUVEC in a concentration-dependent manner following oxidative stress. Further, MBL inhibited UEA-II binding to HUVEC in a concentration-dependent manner following oxidative stress, suggesting a common ligand. UEA-II (< or = 100 micromol/L) did not attenuate the hemolytic activity, nor did it inhibit C3a des Arg formation from alternative or classical complement pathway-specific hemolytic assays. C3 deposition (measured by ELISA) following HUVEC oxidative stress was inhibited by UEA-II in a concentration-dependent manner (IC(50) = 10 pmol/L). UEA-II inhibited C3 and MBL co-localization (confocal microscopy) in a concentration-dependent manner on HUVEC following oxidative stress (IC(50) approximately 1 pmol/L). Finally, UEA-II significantly inhibited complement-dependent neutrophil chemotaxis, but failed to inhibit fMLP-mediated chemotaxis, following endothelial oxidative stress. These data demonstrate that UEA-II is a novel, potent inhibitor of human MBL deposition and complement activation following human endothelial oxidative stress.
Binding, Competitive↗
A modification of cellulose that facilitates the control of complement activation.
Complement activation by Cuprophan hemodialysis membranes has been linked to a variety of pathological sequelae (neutropenia and various cardiopulmonary manifestations) seen in the clinical setting. The modification of reactive surface hydroxyl groups on regenerated cellulose with various dicarboxylic-acid anhydrides has been found to significantly limit the complement-activating potential of these materials. Of the anhydrides tested, maleic anhydride appears to display the most dramatic and consistent diminution of complement activation compared to unmodified cellulose (0-10% of control values for C3b deposition and C3a/C5a production). Current evidence suggests that this maleated derivative facilitates the factor-H control of C3 and C5 convertase activity and thus may help limit complement activation by normal regulatory mechanisms. In addition, this modification may help limit the production of other inflammatory mediators that may result in diminished levels of cellular activation.
Biocompatible Materials↗
The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation.
Complement activation with formation of biologically potent mediators like C5a and the terminal C5b-9 complex (TCC) contributes essentially to development of inflammation and tissue damage in a number of autoimmune and inflammatory conditions. A particular role for complement in the ischaemia/reperfusion injury of the heart, skeletal muscle, central nervous system, intestine and kidney has been suggested from animal studies. Previous experiments in C3 and C4 knockout mice suggested an important role of the classical or lectin pathway in initiation of complement activation during intestinal ischaemia/reperfusion injury while later use of factor D knockout mice showed the alternative pathway to be critically involved. We hypothesized that alternative pathway amplification might play a more critical role in classical pathway-induced C5 activation than previously recognized and used pathway-selective inhibitory mAbs to further elucidate the role of the alternative pathway. Here we demonstrate that selective blockade of the alternative pathway by neutralizing factor D in human serum diluted 1 : 2 with mAb 166-32 inhibited more than 80% of C5a and TCC formation induced by solid phase IgM and solid- and fluid-phase human aggregated IgG via the classical pathway. The findings emphasize the influence of alternative pathway amplification on the effect of initial classical pathway activation and the therapeutic potential of inhibiting the alternative pathway in clinical conditions with excessive and uncontrolled complement activation.
Antibodies, Monoclonal↗
Protection of human nasal respiratory epithelium from complement-mediated lysis by cell-membrane regulators of complement activation.
Complement in the respiratory tract protects the host from invading micoorganisms and other inhaled insults, but may damage normal tissue. Recently we reported that human respiratory epithelium from the nose to the alveoli expresses three cell-membrane regulators of complement activation: membrane cofactor protein (MCP, CD46), decay accelerating factor (DAF; CD55), and CD59. In this study we investigated whether two of these complement-regulatory proteins, DAF and CD59, protect human nasal epithelial cells from complement-mediated lysis. Treatment of nasal epithelial cells in suspension with 50% or 100% normal human serum (NHS) lysed small percentages of cells (8% and 16%, respectively). Addition of complement activators, rabbit serum antinasal epithelial cells (anti-NEC), or lipopolysaccharide (LPS) increased cell lysis in the presence of 50% NHS in a dose-dependent manner up to 50% and 35% lysis, respectively. Human serum deficient in C3 or C7 did not lyse nasal epithelial cells even in the presence of anti-NEC. To assay the contribution of DAF and CD59 to cell protection against lysis, nasal epithelial cells in suspension were treated with appropriate blocking antibodies. Both anti-DAF and anti-CD59 markedly increased the susceptibility of human nasal epithelial cells to lysis by complement. At 50% NHS, anti-DAF and anti-CD59 antibodies increased epithelial cell lysis from 8% to 24% and 67%, respectively. A similar pattern of response to complement was demonstrated by monolayers of substrate-anchored cultured cells. These results indicate that DAF and CD59 protect human nasal epithelial cells from complement-mediated lysis; however, intense activation of complement may overcome this protection, leading to cell death and tissue injury. We speculate that imbalance between complement regulation and complement activation in the human respiratory tract in disease may result in tissue injury and impaired tissue function.
Adolescent↗
Consecutive enzyme cascades: complement activation at the cell surface triggers increased tissue factor activity.
Complement activation at the cell surface initiates cell damage through a series of reactions occurring at the cell membrane and, after assembly of the terminal membrane attack complex, produces leakage of cytoplasmic contents from the cell. It has been documented that chemical or physical damage to cell membranes can cause a rapid increase in the expression of tissue factor procoagulant activity. In this study, antibody-mediated complement activation at the cell surface resulted in increased tissue factor activity, which correlated with cytolysis, as measured by 51-chromium release. Therefore, complement fixation on the cell surface can have a direct and immediate stimulatory effect on the coagulation cascade at the point of its initiation, with formation of a fibrin clot requiring only three consecutive proteolytic reactions after immunologically mediated cell damage.
Antibodies↗
Hyperacute xenograft rejection in the swine-to-human donor-recipient combination. In vitro analysis of complement activation.
Complement activation is central to the rejection of discordant xenografts. In order to assess the respective roles of direct and alternative pathways, an in vitro model of hyperacute rejection in the swine-to-human donor-recipient combination was designed, using a complement-dependent cytotoxicity test with swine endothelial cells in culture as targets, and fresh human serum as the source of xenogeneic antibodies and complement. The cytotoxic activity of the sera was evaluated by a colorimetric assay using (3-[4,5-dimethyldiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT). Pure human serum lysed 58 +/- 5% of swine endothelial cells. Selective inhibition of the direct pathway by adding EGTA to the serum reduced cytolysis to 51 +/- 2% (P < 0.01 versus normal serum). Similarly, when using C1q-deficient human sera, only 37 +/- 7% of swine endothelial cells were killed (P < 0.001 versus normal serum). When the alternative pathway was selectively inhibited by heating for 20 min at 50 degrees C, the lytic activity of human serum dropped to 42 +/- 5% (P < 0.001 versus normal serum). Factor B-deficient human serum could only lyse 42 +/- 10% of porcine endothelial cells (P < 0.001 versus normal serum). Syngeneic normal swine serum and heat-inactivated serum were not cytotoxic. Mixing serum with deficient direct pathway and serum with deficient alternative pathway restored the cytotoxicity to normal levels. Similarly, the cytotoxic activity of deficient serum supplemented with purified C1q or factor B at physiological concentrations reached that of normal human serum. In this model of in vitro hyperacute rejection, both pathways of complement activation are involved, suggesting that regimens designed to inhibit hyperacute rejection of swine xenografts into humans should take into account the dual activation of complement in this donor-recipient combination.
Acute Disease↗
Blood substitution and complement activation.
Complement activation was studied in 45 patients undergoing total hip arthroplasty under epidural anesthesia. The patients were randomly allocated to three groups. In Group I blood loss was replaced with microaggregate-poor erythrocyte concentrate (SAGM-ERC) plus 3% dextran-60 as plasma substitute, and postoperative analgesia was maintained with intramuscular ketobemidone. In Group II blood loss was replaced as in Group I, but epidural anesthesia was prolonged 12 h postoperatively and kept at a level of T4 with 0.5% bupivacaine. In Group III blood loss was replaced with non-frozen stored plasma plus SAGM-ERC, and postoperative analgesia was maintained with ketobemidone as in Group I. All groups received pre- and postoperative thrombo-prophylaxis with dextran. The plasma concentration of C3a-des-arginine (C3a-desArg) was measured by radioimmunoassay preoperatively, immediately after operation and 3, 6 and 18 h postoperatively. No significant differences in plasma C3 and C4 were found between the groups. C3a-desArg was significantly (P less than 0.01) increased up to 6 h postoperatively in Group III compared with both the preoperative value and Groups I and II. It is demonstrated that infusion of plasma can enhance or initiate endogenous complement activation. Blood component therapy with SAGM-ERC and 3% dextran-60, on the other hand, did not significantly increase the plasma level of C3a-desArg irrespective of the type of postoperative analgesia.
Aged↗
Usefulness of detection of complement activation products in evaluating SLE activity.
Complement activation products, such as C1rs-C1inh, specific for the activation of the classical pathway, C3b(Bb)P, specific for the activation of the alternative pathway and SC5b-9, specific for common terminal pathway of the complement cascade, were measured in healthy donors and in patients with clinically active and inactive systemic lupus erythematosus (SLE). Plasma levels of C3b(Bb)P and SC5b-9 were moderately, those of C1rs-C1inhibitor (C1rs-C1inh) were markedly elevated in patients with clinically inactive SLE, compared with healthy controls. The difference between active and inactive stages of the disease was best reflected by C3b(Bb)P plasma concentration (P<0.001), which also showed the highest correlation with the SLEDAI (Rs=0.41 P<0.001) and which was the most useful in distinguishing active and inactive sample pairs as well. The difference between SC5b-9 levels in the active and inactive stages was also significant (P=0.007), while that of C1rs-C1inh did not differ significantly (P=0.136). The correlation of the SLEDAI with SC5b-9 was 0.3 (P=0.015), while with C1rs-C1inh it was 0.21 (P=0. 089). These findings suggest that the measurement of complement activation products, especially that of the alternative pathway, are sensitive markers of the activity of SLE and can be used for clinical purposes.
Adult↗
The ischaemic leg as a source of complement activation.
Complement activation before and after surgical resection was studied in 40 patients with ischaemic legs (17 with acute and 23 with chronic ischaemia). Plasma anaphylatoxin concentrations (C3a and C5a) and anaphylatoxin inhibitor (AI) activity were studied pre-operatively, and 1 h, 24 h and 1 week postoperatively. Increased plasma anaphylatoxin concentrations were found pre-operatively. Anaphylatoxin levels in plasma had returned to normal one week postoperatively. Patients with acute ischaemia had higher plasma C3a and C5a pre-operatively and during the first 24 h postoperatively than patients with chronic ischaemia. Anaphylatoxins increase vascular permeability, smooth muscle contraction and histamine release from mast cells. Their enhanced activity might be one of the explanations for respiratory, hepatic and renal insufficiency before surgical resection in patients with extensive ischaemia.
Aged↗
Plasmin activity and complement activation during storage of citrated platelet concentrates.
Platelet concentrates were studied for evidence of plasmin activity and complement activation during a 7-to-10-day storage period. When measured by an amidolytic activity assay, plasmin reached a level of 845 +/- 540 nkats/L on day 7 (n = 9). Fibrin(ogen) degradation product (FDP) levels became markedly elevated on the tenth day of storage, rising to 45 +/- 22 micrograms/ml (n = 5). Antiplasmin levels decreased in platelet concentrates by 18% +/- 6% (n = 5) over 7 days, but there was no significant decrease in stored platelet-poor plasma (-1.7%, n = 5, p = 0.5). The amount of plasminogen in platelet concentrate converted to plasmin was estimated to be less than 3% by assay of total plasminogen. Supernatant plasma from stored platelet concentrates was examined for the presence of the complement activation peptides C3a and C5a. From day 0 to day 10 of storage, mean C3a levels rose from 327 ng/ml to 6690 ng/ml. An equivalent increase in C3a levels, from 336 ng/ml at day 0 to 6866 ng/ml at day 10, was also observed in stored platelet-poor plasma. C5a was not detected (less than 10 ng/ml) at any point during the storage period; however, we noted a small decrease of borderline significance (p = 0.04) in total C5 from day 0 (117 micrograms/ml) to day 10 (108 micrograms/ml). Only trace amounts of C3 fragments were found on stored platelets, and there was no evidence of the membrane attack complex. These findings indicate the presence of plasmin activity and conversion of C3 during storage of platelet concentrates.
Blood Platelets↗
Surfactant protein A regulates complement activation.
Complement proteins aid in the recognition and clearance of pathogens from the body. C1, the first protein of the classical pathway of complement activation, is a calcium-dependent complex of one molecule of C1q and two molecules each of C1r and C1s, the serine proteases that cleave complement proteins. Upon binding of C1q to Ag-bound IgG or IgM, C1r and C1s are sequentially activated and initiate the classical pathway of complement. Because of structural and functional similarities between C1q and members of the collectin family of proteins, including pulmonary surfactant protein A (SP-A), we hypothesized that SP-A may interact with and regulate proteins of the complement system. Previously, SP-A was shown to bind to C1q, but the functional significance of this interaction has not been investigated. Binding studies confirmed that SP-A binds directly to C1q, but only weakly to intact C1. Further investigation revealed that the binding of SP-A to C1q prevents the association of C1q with C1r and C1s, and therefore the formation of the active C1 complex required for classical pathway activation. This finding suggests that SP-A may share a common binding site for C1r and C1s or Clq. SP-A also prevented C1q and C1 from binding to immune complexes. Furthermore, SP-A blocked the ability of C1q to restore classical pathway activity to C1q-depleted serum. SP-A may down-regulate complement activity through its association with C1q. We hypothesize that SP-A may serve a protective role in the lung by preventing C1q-mediated complement activation and inflammation along the delicate alveolar epithelium.
Adjuvants, Immunologic↗
Oligomeric structures required for complement activation of serum mannan-binding proteins.
Serum mannan-binding protein (S-MBP) comprises a series of homooligomers, and activates complement when it binds to appropriate carbohydrate ligands. In this study, the structural requirements necessary for complement activation were examined for rat, rabbit, and human S-MBPs. On SDS-PAGE under non-reducing conditions, the S-MBPs gave three major bands: large, middle, and small oligomers. Since three subunits (23-25 kDa) form a triple helix (the base structural unit) at the collagen-like domain within the S-MBP molecule, it was estimated that human and rabbit S-MBPs comprise a mixture of pentamers, tetramers, and trimers of the respective structural units. In contrast, rat S-MBP is composed of tetramers, trimers, and dimers. The large and middle oligomers were almost equal in their ability to activate complement, whereas the small oligomers had very low or no activity. Upon digestion with bacterial collagenase, the large and small oligomers were degraded almost completely. In contrast, the middle oligomers remained largely intact, and the surviving middle oligomers retained complete ability to activate complement. The degraded product, trimers of the carbohydrate recognition domain (CRD), did not show any complement activating activity. These data indicate that not only the structural integrity of the S-MBP collagen-like domain and CRD, but also a unique conformational structure present in the middle oligomers are critically important for carbohydrate-mediated complement activation.
Animals↗