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PubMed1997

Biocompatibility: complement as mediator of tissue damage and as indicator of incompatibility.

The fully biocompatible surface is the host's own intact endothelium. Blood contact with a damaged or foreign endothelium, or with an artificial surface, will lead to a certain degree of activation of the defense systems. Complement is one of these systems which has a unique property to distinguish between 'self' and 'non-self'. Recent data using complement-specific inhibitors like soluble CR1 and monoclonal antibodies to C5 have shown that complement is not only associated with, but in fact contributes to, the whole body inflammatory reaction seen as a complication to cardiopulmonary bypass (artificial surfaces) and is responsible for the hyperacute rejection of xenografts (foreign endothelium). Complement activation, as measured by assays specific for neoepitopes exposed in the activation products, is a sensitive indicator of bioincompatibility. These assays have been increasingly important after a causal link between complement activation and tissue damage was demonstrated. Efforts have been made to improve the biocompatibility of artificial surfaces, including coating with heparin. This procedure not only improves coagulation compatibility, but also markedly reduces complement activation. Models to study complement compatibility in vitro and in vivo are described, and recommended complement activation assays reviewed.

Animals↗
PubMed1998

[Significance of the complement system for xenotransplantation: strategies for therapeutic intervention].

Hyperacute graft rejection triggered by the activation of the recipient's complement system represents the major obstacle to successful xenotransplantation. After the binding of preformed antibodies to vascular glycoproteins complement-induced activation and injury of endothelial cells with subsequent thrombosis leads to rapid destruction of foreign tissues. Inhibition of complement activation is therefore considered as a prerequisite for xenograft survival. Recent animal and cell culture experiments suggest that support of the physiological regulation of the complement system appears to be most promising. Besides the application of soluble complement inhibitors (e.g. soluble complement receptor 1, sCR1; C1 inhibitor) the genetic transfer of human membrane-bound complement regulatory proteins (e.g. DAF, CD59) offers new chances to protect the xenograft against the cytolytic complement attack. Results from the authors' experiments shall be included in a short overview to the issue.

Animals↗
PubMed1989

A knowledge-based system for automatic interpretation of an analytical profile of complement factors.

A comprehensive assay to evaluate the complement system includes functional tests of both classical and alternative pathways and immunochemical measurements of C3, C4, B, C1-INA, and C3d. The purpose of this analytical profile is to screen for rare hereditary deficiencies and acquired abnormalities of complement and to define the activation pathway in cases of complement consumptive processes. Based on several years' experience, a routine was established in our laboratory to report the data to the clinician, together with a computer-generated interpretive statement. This routine was formulated into a knowledge base by specifying a series of decision rules for each of the complement disorders. After the rules were tested and updated against some 400 complement profile analyses, reasonable analytical comments were produced by the system. This knowledge-based system for reporting and interpreting complement results offers several advantages: the interpretative work is facilitated and made more reliable; a consistent interpretative comment is generated that is recognized and therefore more meaningful for the clinician; the communication of analytical procedures and policy is enhanced.

Artificial Intelligence↗
PubMed1976

Increase of serum complement levels in cancer patients with progressing tumors.

Complement levels (CH50, C3, C4 and C1q) were determined in sera of 90 healthy subjects and 200 cancer patients. Complement levels of cancer patients were significantly higher than those of the healthy subjects, but there was a stage-linked increase of complement levels. Patients in remission had nearly normal complement levels, but patients with local tumor had increased complement levels, and a further increase was observed in patients with distant metastases. Treatment of these patients with radiotherapy or cytostatic drugs lowered the complement levels. At the terminal phase of the disease we also noted a drop in complement levels.

Adolescent↗
PubMed2001

Immune evasion of Borrelia burgdorferi by acquisition of human complement regulators FHL-1/reconectin and Factor H.

To understand immune evasion mechanisms of Borrelia burgdorferi we compared serum-resistant B. afzelii and serum-sensitive B. garinii isolates for their capacity toacquire human complement regulators. Here we demonstrate that the two borrelial genospecies show different binding of the two important human complement regulators, FHL-1/reconectin and Factor H. All serum-resistant B. afzelii isolates bound FHL-1/reconectin and also Factor H, and all analyzed serum-sensitive B. garinii isolates showed no or a significantly lower binding activity. Using recombinant deletion mutants, the binding domains were localized to the C terminus of FHL-1/reconectin to short consensus repeats 5-7. The borrelial binding proteins were located in the surface of the bacteria as demonstrated by immunofluorescence staining of intact, serum-exposed bacteria and by enrichment of outer membrane proteins. The surface-attached complement regulators maintained complement regulatory activity as demonstrated in a cofactor assay. By ligand blotting two different borrelial binding proteins were identified that were responsible for the surface attachment of FHL-1/reconectin and Factor H. These borrelial complement regulators acquiring surface proteins (CRASP) were further characterized as either CRASP-1, a 27.5-kDa molecule which preferentially binds FHL-1/reconectin and which was present in all serum-resistant borreliae, or CRASP-2, a 20/21-kDa protein which interacts preferentially with Factor H and the expression of which was more restricted, being detected in four of the six isolates analyzed. In summary, we describe a new immune evasion mechanism of B. burgdorferi, as these bacteria acquire human complement regulators to control complement activation on their surface and to prevent formation of toxic activation products.

Adsorption↗
PubMed1986

Complement-activating abilities of defined antinuclear antibodies.

A complement-fixing immunofluorescence assay on HEp-2 cells was used to assess the ability of various antinuclear antibodies (ANA) to activate complement. Sera which contained only specific antibodies to nuclear RNP, SS-B/La, centromere, Sm antigen, double-stranded DNA, and/or nuclear histone were selected. Relative abilities of various ANA to activate complement were determined from the ratio of titers of C3, C4, or properdin-fixing ANA to the IgG ANA titers. Nuclear RNP-anti-RNP complexes activated and deposited significantly more complement C3 than other ANA (P less than 0.02). Antibodies to SS-B/La, centromere, and Sm activated more complement than anti-DNA or antihistone (P less than 0.02). Antihistone antibodies activated the least complement. These studies demonstrate that different ANA have significantly different orders of complement-activating capabilities when bound to their respective nuclear antigens.

Antibodies, Antinuclear↗
PubMed1993

Complement activation by Pseudomonas aeruginosa biofilms.

In chronic infections, such as the bronchopulmonary Pseudomonas aeruginosa infection in cystic fibrosis (CF) patients, bacteria persist despite an intact host immune defense and frequent antibiotic treatment. An important reason for the persistence of the bacteria is their capacity for the biofilm mode of growth. In this study we investigated the role of biofilms in activation of complement, a major contributor to the inflammatory process. Complement activation by P. aeruginosa was examined in a complement consumption assay, production of C3 and factor B conversion products assessed by crossed immuno-electrophoresis, C5a generation tested by a PMN chemotactic assay, and terminal complement complex formation measured by ELISA. Two of the four assays showed that P. aeruginosa grown in biofilm activated complement less than planktonic bacteria, and all assays showed that activation by intact biofilms was submaximal. Factor B conversion was of low magnitude indicating the importance of the classical pathway. Complement activation by P. aeruginosa was inhibited by polymyxin B indicating that lipopolysaccharide (LPS) was the main mediator of complement activation. Immune complexes and massive influx of neutrophils are known to cause inflammatory changes in the lungs. P. aeruginosa persisting in biofilms may contribute to the constant inflammation taking place in the lungs of CF patients.

Chemotaxis, Leukocyte↗
PubMed2004

New advances in measurement of complement activation: lessons of systemic lupus erythematosus.

Activation of the complement system plays a fundamental role in the pathogenesis of systemic lupus erythematosus (SLE). For the past several decades, quantifying this process has focused primarily on determination of serum C3 and C4, although the utility of these assays for diagnosis and monitoring disease activity is still debated. During this same timespan, knowledge of the complement system has exploded, with identification of more than 30 proteins, an abundance of newly recognized functions, and even a third pathway of activation. These advances suggest that it is appropriate to revisit the complement system as a potential source of biomarkers for SLE. This paper reviews briefly the role of complement in SLE and other inflammatory diseases, discusses conventional methods for complement measurement and their drawbacks, and focuses on recent advancements in harnessing the complement system for monitoring SLE. Specifically, novel assays that measure cell-bound complement activation products are introduced and their utility as biomarkers of SLE disease activity is discussed.

Biomarkers↗
PubMed1979

Complement activation following intravenous contrast material administration.

Untoward reactions to iodinated contrast material (ICM) continue to be a significant medical problem. Complement components were assayed in patients having reactions to evaluate the possibility of complement activation in these reactions. Reactor group samples were drawn from patients during the contrast reactions and then 2 weeks later to provide the equivalent of preinjection baseline samples, Control patient values were determined from blood samples drawn from patients before and 20 minutes after ICM injections without reaction. There were consistent falls in total hemolytic complement (CH50) as well as C3, C4, and C5 in both the control group and the reactor group. These falls in the complement reached statistical significance only for CH50 in the reactor group. The results indicate that complement activation occurs after ICM injection. This activation can occur independent of clinical reactions; however, falls in total hemolytic complement and low hemolytic complement titers prior to ICM infusion may be related to the presence of anaphylactoid symptoms.

Adolescent↗
PubMed1994

An indirect effect of an antibody on complement deposition and lysis of differently sensitized surrounding cells.

Lysis of papain-treated group A and B erythrocytes by human complement was studied by an anti-A (BRIC. 131) and an anti-B (BRIC. 30) IgM monoclonal antibody in 51Cr release assays. The indirect effect of membrane-bound antibody, i.e. its influence on complement binding to sensitized surrounding cells, was examined in a cold target competition test in which sensitized, non-labelled cells are present along with sensitized labelled cells and complement. The mode by which anti-A antibodies indirectly suppressed lysis of sensitized B cells up to 20-fold was studied by following C1q and C3b binding. C1q binding to both types of erythrocytes was not altered in mixed populations of erythrocytes in the presence of both antibodies. Binding of C3b to a mixture of both cell types was, however, suppressed, when both antibodies were present. C3b deposition in mixed cell populations did not reach a significantly higher extent than deposited to one type of erythrocyte alone. This was consistent with the results from competitive lysis and suggests that the anti-A captured most C3b at high anti-A concentrations and deprived the similarly sensitized B erythrocytes of complement. We think that this phenomenon is not due to an uneven removal of complement regulatory proteins from A and B erythrocytes by papain. Instead, the phenomenon might be due to an inherent property of anti-A mAb to better produce nucleation sites for C3 convertases which, upon binding factor B, better compete for the limiting factor D. A mathematical analysis of cold target competition experiment (containing 2430 individual measurements) also shows that the distribution of complement between the competing A and B erythrocyte population is uneven, since it predicts that in any given antibody combination the majority of complement is bound to A erythrocytes. This is consistent with the measured average percentage of lysis.

ABO Blood-Group System↗
PubMed2006

CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens.

The complement system serves an important role in clearance of pathogens, immune complexes, and apoptotic cells present in the circulation. Complement fragments deposited on the particle surface serve as targets for complement receptors present on phagocytic cells. Although Kupffer cells, the liver resident macrophages, play a dominant role in clearing particles in circulation, complement receptors involved in this process have yet to be identified. Here we report the identification and characterization of a Complement Receptor of the Immunoglobulin superfamily, CRIg, that binds complement fragments C3b and iC3b. CRIg expression on Kupffer cells is required for efficient binding and phagocytosis of complement C3-opsonized particles. In turn, Kupffer cells from CRIg-deficient mice are unable to efficiently clear C3-opsonized pathogens in the circulation, resulting in increased infection and mortality of the host. CRIg therefore represents a dominant component of the phagocytic system responsible for rapid clearance of C3-opsonized particles from the circulation.

Animals↗
PubMed2005

Activation of the spinal cord complement cascade might contribute to mechanical allodynia induced by three animal models of spinal sensitization.

The present series of experiments examined whether the complement cascade might play a key role in the expression of mechanical allodynia. Soluble complement receptor 1 (sCR1) was used to block the activation of the membrane attack pathway of the complement cascade. In doing so, sCR1 prevents the formation of the biologically active end products C3a, C5a, and membrane attack complexes (MACs). Intrathecal sCR1 had no effect on the behavioral responses of control groups. In contrast, blockade of this pathway abolished the expression of mechanical allodynia induced by peripheral nerve inflammation (sciatic inflammatory neuropathy model), partial sciatic nerve injury (chronic constriction injury model), and intrathecal injection of human immunodeficiency virus type 1 gp120, a viral envelope protein that activates glia. The fact that enhanced nociception was prevented or reversed in all 3 paradigms suggests that complement might be broadly involved in spinally mediated pain enhancement. The mechanisms whereby complement activation might potentially affect the functioning of microglia, astrocytes, and neurons are discussed. The complement cascade has not been previously implicated in spinal sensitization. These data suggest that complement activation within the spinal cord might contribute to enhanced pain states and provide additional evidence for immune regulation of pain transmission.

Animals↗
PubMed2000

Complement activation promotes muscle inflammation during modified muscle use.

Modified muscle use can result in muscle inflammation that is triggered by unidentified events. In the present investigation, we tested whether the activation of the complement system is a component of muscle inflammation that results from changes in muscle loading. Modified rat hindlimb muscle loading was achieved by removing weight-bearing from the hindlimbs for 10 days followed by reloading through normal ambulation. Experimental animals were injected with the recombinant, soluble complement receptor sCR1 to inhibit complement activation. Assays for complement C4 or factor B in sera showed that sCR1 produced large reductions in the capacity for activation of the complement system through both the classical and alternative pathways. Analysis of complement C4 concentration in serum in untreated animals showed that the classical pathway was activated during the first 2 hours of reloading. Analysis of factor B concentration in untreated animals showed activation of the alternative pathway at 6 hours of reloading. Administration of sCR1 significantly attenuated the invasion of neutrophils (-49%) and ED1(+) macrophages (-52%) that occurred in nontreated animals after 6 hours of reloading. The presence of sCR1 also reduced significantly the degree of edema by 22% as compared to untreated animals. Together, these data show that increased muscle loading activated the complement system which then briefly contributes to the early recruitment of inflammatory cells during modified muscle loading.

Animals↗
PubMed1975

Serum complement profiles in infants and children.

The purpose of this study was to examine normal serum values for the complement components, C3, C4, and C5, and total hemolytic complement (CH50) activity in 163 healthy infants and children, in the age range from birth through 14 years. There were statistically significant relationships of C3, C4, and C5, but not CH50 with age. None of the complement components or CH50 could be differentiated by sex or race. Tolerance limits for high and low values were projected for each complement measurement for 75%, 90%, and 95% of the general population. Our data confirm the differences in complement levels between children and adults and demonstrate a wide range of values within each group, reflecting the biologic variability of complement measurements. These results emphasize the importance of establishing normal pediatric values in any laboratory that measures complement profiles in various diseases of childhood.

Adolescent↗
PubMed2000

Inhibition of complement alternative pathway function with anti-properdin monoclonal antibodies.

Complement activation products appear to contribute to the pathology of several acute and chronic inflammatory conditions. The relative contributions of the classical and alternative complement pathways to these pathologies have, in large part, been undefined. Considerable progress has been made recently in identifying inhibitors of complement activation and demonstrating that such molecules can attenuate inflammation in various models of disease. However, most of these complement inhibitors affect aspects of both the classical and alternative pathways. In an effort to better define the role of the alternative complement pathway in complement-mediated inflammatory conditions, we have developed monoclonal antibodies that specifically inhibit alternative pathway function. These blocking antibodies bind human properdin with high avidity and prevent its interaction with the alternative pathway C3 convertase. This results in a cessation of alternative pathway function in several in vitro assay systems. When tested in a model of cardiopulmonary bypass, in which human blood passes through tubing, a selected antiproperdin antibody caused nearly complete inhibition of the C3a and C5b-9 formation that was seen in untreated blood. Moreover, the anti-properdin agent resulted in a dramatic reduction of neutrophil and platelet activation in the bypass model. Surprisingly, the monoclonal antibody also caused a significant inhibition of C5b-9 generation when classical pathway activators, such as heparin-protamine or immune complexes, were added to human blood. These latter data suggest that the alternative pathway contributes significantly to the formation of complement activation products in blood when the classical pathway is initially triggered.

Antibodies, Monoclonal↗
PubMed1996

Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv.

Activation of the complement system contributes significantly to the pathogenesis of numerous acute and chronic diseases. Recently, a monoclonal antibody (5G1.1) that recognizes the human complement protein C5, has been shown to effectively block C5 cleavage, thereby preventing the generation of the pro-inflammatory complement components C5a and C5b-9. Humanized 5G1.1 antibody, Fab and scFv molecules have been produced by grafting the complementarity determining regions of 5G1.1 on to human framework regions. Competitive ELISA analysis indicated that no framework changes were required in the humanized variable regions for retention of high affinity binding to C5, even at framework positions predicted by computer modeling to influence CDR canonical structure. The humanized Fab and scFv molecules blocked complement-mediated lysis of chicken erythrocytes and porcine aortic endothelial cells in a dose-dependent fashion, with complete complement inhibition occurring at a three-fold molar excess, relative to the human C5 concentration. In contrast to a previously characterized anti-C5 scFv molecule, the humanized h5G1.1 scFv also effectively blocked C5a generation. Finally, an intact humanized h5G1.1 antibody blocked human complement lytic activity at concentrations identical to the original murine monoclonal antibody. These results demonstrate that humanized h5G1.1 and its recombinant derivatives retain both the affinity and blocking functions of the murine 5G1.1 antibody, and suggest that these molecules may serve as potent inhibitors of complement-mediated pathology in human inflammatory diseases.

Amino Acid Sequence↗
PubMed1999

C1-inhibitor attenuates hyperacute rejection and inhibits complement, leukocyte and platelet activation in an ex vivo pig-to-human perfusion model.

Xenotransplantation may be a future alternative due to increased shortage of organs. Classical complement activation is central in hyperacute rejection in pig-to-human combinations. We investigated the effects of C1-inhibitor (C1-INH), a regulator of the complement and contact systems, on hyperacute rejection. Pig kidneys were perfused with fresh human blood to which either C1-INH (n = 6) or human serum albumin (n = 6) was added. The survival of the C1-INH perfused kidneys (mean 327 min) was significantly longer (p < 0.00001) than the controls (79 min). C1-INH substantially inhibited complement activation (C1rs-C1-INH complexes, C4bc, C3bc and terminal complement complex) (p < 0.001 for all) compared with the marked complement activation in the controls. No contact activation was found. Leukocytes and platelets were substantially activated (counts, myeloperoxidase, beta-thromboglobulin, thrombospondin, soluble P-selectin) in the control group, and this activation was markedly reduced by C1-INH (p < 0.02 for all). Immunohistochemistry showed less C1q, C3, TCC, IgG and fibrin deposition in the C1-INH group. C1-INH may be useful to attenuate hyperacute rejection, probably through inhibition of complement. The reduced activation of neutrophils and platelets may mainly be secondary to inhibition of complement.

Animals↗
PubMed2003

Research on complement: old issues revisited and a novel sphere of influence.

Immunology in recent years has taken a somewhat surprising turn, expressed by a renewed interest in innate immunity. Especially intriguing is the regulatory role exerted by the innate components on the adaptive response, with Toll receptors and complement components being the most investigated. This function has been firmly established for complement protein CR2 (CD21) as part of the BCR co-receptor CD19/CD21/CD81. New findings are now providing a broader picture of complement and its tuning of the immune response; for example, complement proteins have been implicated in the control of T-cell-mediated responses. We will review some of these data here and summarize new discoveries in areas of research on more traditional topics within the complement literature, such as complement and renal diseases, and the therapeutic use of C1-Inhibitor. We cover papers selected from studies presented at the XIX International Complement Workshop, held in Palermo in September 2002, and published within the past six months.

Animals↗