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PubMed2001

Role of the complement system in ischaemic heart disease: potential for pharmacological intervention.

The complement system is an innate, cytotoxic host defence system that normally functions to eliminate foreign pathogens. However, considerable evidence suggests that complement plays a key role in the pathophysiology of ischaemic heart disease (IHD). Experimental models of acute myocardial infarction (MI) and autopsy specimens taken from acute MI patients demonstrate that complement is selectively deposited in areas of infarction. Furthermore, inhibition of complement activation or depletion of complement components prior to myocardial reperfusion has been shown to reduce complement-mediated tissue injury in numerous animal models. IHD remains a leading cause of patient morbidity and mortality. Considerable effort in recent years has therefore been directed by biotechnology and pharmaceutical industries towards the development of novel, human complement inhibitors. Proposed anticomplement therapeutic strategies include the administration of naturally occurring or recombinant complement regulators, anticomplement monoclonal antibodies, and anticomplement receptor antagonists. Although data regarding the effectiveness of anticomplement therapy in humans is limited at present, a number of novel anticomplement therapeutic strategies are currently in clinical trials. The role of complement in IHD and potential for pharmacological intervention is reviewed.

Anaphylatoxins↗
PubMed2006

A review of current knowledge of the complement system and the therapeutic opportunities in inflammatory arthritis.

The complement activation system, a key component of the innate immune system, protects the host from microorganisms such as bacteria, and other foreign threats including abnormal cells. However, it is also double-edged in that it can have negative effects in the host; excessive complement activation damages the host and can even kill in anaphylactic shock and septic shock. Regulation of the complement system is a useful strategy to control inflammatory diseases, including inflammatory arthritis. Rheumatoid arthritis is a common inflammatory disease worldwide. Many medicines are developed to control inflammation, including recently developed biological response modifiers such as anti-TNF and IL-6 agents. Nevertheless, in some patients disease remains difficult to control because of complications, side effects and tolerance of medicines. In inflammatory arthritis, including rheumatoid arthritis, there is abundant evidence implicating complement activation in humans and animal models. Therefore, anti-complement agents might be beneficial as part of clinical treatment. However, at present, there are still no applicable agents for therapeutic regulation of excessive complement activation in chronic disease. Novel agents in development might be useful as a strategy to control complement activation. Here I describe recent knowledge of the complement system in inflammatory arthritis, the recent developments in anti-complement agents and their considerable potential for the future.

Animals↗
PubMed2005

A role for the complement system in rheumatoid arthritis.

The production of autoreactive antibodies from self-reactive B cells results in the formation of immune complexes that deposit in tissue and fix complement, contributing to the pathogenesis of rheumatoid arthritis (RA). Earlier mouse models emphasize the importance of autoreactive antibodies formed against "self" proteins that serve as a source for T cell-mediated immune response, stemming from cross-reactivity and resulting in B cell activity. However, more recent models suggest the need for both autoantibodies and the initiation of the inflammatory cascade via the alternative complement pathway, which is unbridled as the cartilage lacks the usual regulatory proteins of the complement system. Furthermore, deficiencies in specific complement proteins could lead to an escape from negative selection by these self-reactive B cells. Moreover, the classical complement pathway establishes chemotactic gradients by which inflammatory cells follow and accumulate in the synovial fluid where they engulf immune complexes and release proteolytic enzymes. In addition, the processing of circulating immune complexes either via Fc receptor or CR1 and opsonization by complement fragments plays a key role in determining the fate of immune status. In addition, complement proteins are a major determinant in the size and solubility of an immune complex, which also affects clearance. The evidence regarding intra-articular activation of the complement system in RA provides the possibility to pharmacologically manipulate various parts of the complement system for therapeutic purposes and potential therapeutic targets for the control of inflammation and the prevention of joint destruction.

Animals↗
PubMedDate not supplied

Early recipient-donor switch of the complement type after liver xenotransplantation.

Liver transplantation is an immunological peculiarity with respect to the resistance of the graft to humoral rejection. We undertook a kinetic analysis of molecules involved in humoral rejection for a period of one week following xenografting in the hamster to rat model system. A complement-dependent lymphocytotoxicity test (CDC) was used to detect anti-donor antibodies in the recipient rats. Complement was studied by two methods. Function of the classical complement pathway was evaluated with a hemolytic assay, and C3 was measured by radial immunodiffusion. Conversion of the major plasma proteins from recipient to donor profile was studied by zone electrophoresis on agarose. CDC showed antibody titers rose during the first week post-transplantation, and they were of complement-activating isotypes. Zone electrophoresis showed almost complete replacement of rat C3 by hamster C3 within 72 hours. Hemolytic assay of complement on day 6 post-transplant showed serum of the xenograft recipients could lyse erythrocytes sensitized with rat antibody with 80% of efficiency of normal rat serum. Our data show the effector molecules for humoral rejection, rat antibodies with anti-hamster specificity and a functional complement cascade, were present within the first week following transplantation. Rapid conversion of serum complement to hamster proteins maintains compatibility with the species-specific membrane inhibitors of complement activation expressed by the xenografted hepatocytes, and could limit complement-mediated damage.

Animals↗
PubMed2006

Porcine endothelial cells and iliac arteries transduced with AdenoIL-4 are intrinsically protected, through Akt activation, against immediate injury caused by human complement.

Vascular endothelial cells (ECs) can be injured in a variety of pathologic processes that involve activated complement. We reported previously that porcine ECs incubated with exogenous IL-4 or IL-13 are protected from cytotoxicity by human complement and also from apoptosis by TNF-alpha. The resistance to complement consists of an intrinsic mechanism that is lost a few days after cytokine removal. In our current study, we investigated whether transfer of the IL-4 gene into porcine ECs in vitro and into porcine vascular tissues in vivo would induce efficient and durable protection from human complement. We found that ECs transduced with adenoIL-4 or adenoIL-13 exhibited continuous production of the cytokine and prolonged protection from complement-mediated killing. IL-4 also protected ECs from activation: ECs incubated with IL-4 did not develop cell retraction and intercellular gaps upon stimulation with sublytic complement. The endothelium and subendothelium of pig iliac arteries that were transduced with the IL-4 gene were effectively protected from complement-dependent immediate injury after perfusion with human blood. However, after similar perfusion, the endothelium was immediately lost from arteries that were transduced with a control adenovirus. The protection was not due to up-regulation of the complement regulators decay accelerating factor, membrane cofactor protein, and CD59, or to reduced complement activation, but required the participation of Akt. Although our studies model protection in pig-to-primate xenotransplantation, our findings of IL-4 induction of Akt-mediated protection may be more broadly applicable to EC injury as manifested in ischemia-reperfusion, allotransplantation, and various vascular diseases.

Adenoviridae↗
PubMed1999

Complement activation by mycoloyl glycolipids from Mycobacterium tuberculosis and Rhodococcus ruber.

In this study, we examined complement activation by mycoloyl glycolipids (MGL) such as trehalose-6,6'-dimycolate (TDM), often termed cord factor, and trehalose-6-monomycolate from Mycobacterium tuberculosis and Rhodococcus ruber, and also examined the effect of complement binding to MGL on phagocytosis by human monocytes. TDM and TMM, but not glucose mycolate, mannose mycolate or fructose mycolate which differ from TMM only in carbohydrate moiety, exhibited complement activation. TDM and TMM of M.tuberculosis exhibited stronger complement activation than those of R.ruber, the mycolic acids of which are much shorter than those of M.tuberculosis. Neither mycolic acids nor trehalose, which are products of TDM and TMM by hydrolytic cleavage, exhibited no complement activation. TDM activated complement through the alternative pathway, since supplementation with C4-deficient serum completely restored classical pathway-mediated hemolytic activity of complement which had been previously consumed by TDM. Next, we examined the effects of TDM and TMM on phagocytosis by human monocytes. Coating of heat-killed Staphylococcus aureus cells with TDM or TMM did not enhance their phagocytosis by monocytes, while, in the presence of complement, phagocytosis of these cells increased significantly. These findings suggest that TDM and TMM act as virulence factors that enhance the entry of mycobacteria into phagocytes via binding of C3 through activation of the alternative complement pathway.

Adjuvants, Immunologic↗
PubMed1975

Diagnosis of bovine respiratory syncytial virus infection by complement fixation test.

The complement fixation test by the microtiter method was applied to the serological diagnosis of bovine respiratory syncytial (RS) virus infection. When used as complement fixing antigens, untreated infected cell culture fluid, fluorocarbon-treated, and ether-treated materials showed no differences in antigenicity among them. The complement fixing antigenicity of bovine RS virus appeared in bovine kidney and Vero cell cultures for the first time 4 days after inoculation. Both the infectivity and complement fixing antigenicity reached a maximum 6 days after inoculation. In detecting complement fixing antibody from infected cattle, the most outstanding specific reaction was obtained when 5% fresh normal calf serum had been added to the diluent of complement. Neutralizing and complement fixing antibodies were examined in serum samples from two cattle in the course of experimental infection. It was found that both antibodies turned to be positive 2 weeks after inoculation. There was a linear correlation between neutralizing and complement fixing antibody titers, when serum samples from 40 natural cases were tested in the acute and convalescent stages. In addition, common antigenicity was demonstrated between the virus of bovine origin and the Long strain of human RS virus by complement fixation test.

Animals↗
PubMed1986

Kupffer cell complement receptor clearance function and host defense.

Kupffer cells are well known to be important for normal host defense function. The development of methods to evaluate the in vivo function of specific receptors on Kupffer cells has made it possible to assess the role of these receptors in host defense. The rationale for studying complement receptors is based on the proposed important role of these receptors in host defense and on the observation that the hereditary deficiency of a complement receptor is associated with recurrent severe bacterial infections. The studies reviewed here demonstrate that forms of injury that are associated with depressed host defense including thermal injury, hemorrhagic shock, trauma, and surgery also cause a decrease in complement receptor clearance function. This decrease in Kupffer cell receptor clearance function was shown not to be the result of depressed hepatic blood flow or depletion of complement components. Complement receptor function was also depressed following the phagocytosis of particulates that are known to depress Kupffer cell host defense function. Endotoxemia and bacteremia also were associated with a depression of complement receptor function. Complement receptor function was experimentally depressed in uninjured animals by the phagocytosis of IgG-coated erythrocytes. There was a close association between the depression of complement receptor clearance function and increased susceptibility to the lethal effects of endotoxin and bacterial infection. These studies support the hypotheses that complement receptors on Kupffer cells are important for normal host defense and that depression of the function of these receptors impairs host defense.

Animals↗
PubMed1987

Identical complement concentrations in blood obtained from central venous catheters, arterial lines, and antecubital phlebotomy.

In vitro complement activation has been detected during passage of blood through tubing used in hemodialysis and cardiopulmonary bypass surgery, in addition to tubing being investigated for vascular grafts. Because tubing from arterial lines and central venous catheters are composed of similar materials and are used when blood is withdrawn from patients for complement assays, a study was undertaken to assess the degree of complement activation in blood obtained from these sites. Complement activation was determined by a terminal complement complex enzyme-linked immunosorbent assay (ELISA), C1rC1s-C1 inhibitor complex ELISA, and 50% complement hemolytic activity (CH50) assay. Blood simultaneously obtained from the arterial lines and central venous catheters had identical terminal complement complex, C1rC1s-C1 inhibitor complex, and CH50 levels when compared with blood withdrawn by antecubital phlebotomy. Because blood may be obtained from the arterial lines and central venous catheters for complement assays, the pain and possible bruising from antecubital phlebotomy could be eliminated. Furthermore, blood may now be withdrawn from indwelling catheters without fear of in vitro complement activation causing a misinterpretation of results.

Arteries↗
PubMed1979

Complement response after experimental bacterial infection in various nutritional states.

In malnourished rats, nutritionally rehabilitated rats at various stages, and in well nourished rats, levels of serum complement after bacterial infection caused by Staphylococcus aureus, as well as tuberculin reactivity, were examined. The elevation of complement showed a peak 2--3 days after infection, herein called the first complement response. A reelevation occurred at a later stage, 7--14 days after infection, and is referred to as the second complement response. The first complement response was observed in all the rats after Staphylococcus aureus infection but it was greater in well nourished rats. In malnourished rats, only the first complement response was observed and the tuberculin reaction and second complement response were lacking. After 1 week of nutritional rehabilitation, 40% of the rats showed recovery of tuberculin responses and both the first and second complement responses were observed. Nutritionally rehabilitated rats treated longer than 2 weeks, together with the well nourished control rats, showed positive tuberculin reactivity. The second complement response was also observed in such rats when bacterial infection was severe but not with mild infection.

Animals↗
PubMed1981

Humoral immune killing of nucleated cells: mechanisms of complement-mediated attack and target cell defense.

The killing or lysis of nucleated cells, erythrocytes, bacteria, and other targets (e.g., liposomes) by antibody and complement is the result of complex series of actions and interactions between antibody, components of the complement system, and the cell. The complement attack mechanism has strict qualitative and quantitative requirements. For efficient activity, sufficient amounts of antibody must bind to the cell, the antibody must be of the complement-fixing type, and sufficient amounts of complement components must be activated and fixed to the surface of the target cells. Nucleated cells of different types differ in their sensitivity to the cytotoxic action of complement. This difference in sensitivity may be attributed to differences in metabolic properties and/or the chemical and physical composition of the cells. Since complement action occurs primarily on or in the cell membrane, the properties of the cell which may affect the outcome of complement-mediated attack should be linked to cell membrane function and integrity. The relationship between the susceptibility of nucleated cells to complement-mediated killing and the chemical and metabolic properties of the cells will be discussed in this review.

Animals↗
PubMed1981

[Comparative studies on doses of complement for detection of sperm immobilizing antibody in serum, cervical mucus and seminal plasma (author's transl)].

In Isojima's sperm immobilization test, the complement is one of the most important factors which influence on sensitivity of the test. Previously we reported that more than 10 CH50 of guinea pig serum complement was necessary in the reaction to obtain the best result for measuring the sperm immobilizing antibody in the serum. This time, the influences of various test specimens on complement activities for the sperm immobilization test were studied and the necessary amounts of complement to detect the sperm immobilizing antibody in serum, cervical mucus and seminal plasma were compared. In the sperm immobilization test, the following results were obtained: 1. The amount of complement (guinea pig serum) added was 11.9 CH50, and after 60 minutes incubation at 32 degrees C in veronal buffer (VB2+), 2.0 +/- 0.3 (M +/- SD) of CH50 was consumed. 2. When human serum, cervical mucus and seminal plasma were added to the reaction as specimens, the complement consumptions (M +/- SD) were more 0.2 +/- 0.3 CH50, 0.2 +/- 0.2 CH50 and 3.3 +/- 0.8 CH50 than that of VB2+ buffer respectively. 3. When the washed human spermatozoa were added, the consumed amounts of complement (M +/- SD) were dose dependent; 3.5 +/- 0.7 CH50 for 100 X 10(4) spermatozoa, 7.3 +/- 0.3 CH50 for 200 X 10(4) spermatozoa and 15.7 +/- 2.2 CH50 for 400 X 10(4) spermatozoa. 4. In our sperm immobilization test, the net consumptions of complement (M +/- SD) were 5.0 +/- 0.7 CH50 for specimen of serum, 4.9 +/- 0.8 CH50 for specimen of cervical mucus and 11.1 +/- 1.2 CH50 for specimen of seminal plasma. 5. Complement doses necessary to obtain the most sensitive sperm immobilization tests were 10 CH50 for both serum and cervical mucus specimens, and 15 CH50 for seminal plasma specimen.

Animals↗
PubMed1994

Mutations participating in interallelic complementation in propionic acidemia.

Deficiency of propionyl-CoA carboxylase (PCC; alpha 4 beta 4) results in the rare, autosomal recessive disease propionic acidemia. Cell fusion experiments have revealed two complementation groups, pccA and pccB, corresponding to defects of the PCCA (alpha-subunit) and PCCB (beta-subunit) genes, respectively. The pccBCC group includes subgroups, pccB and pccC, which are thought to reflect interallelic complementation between certain mutations of the PCCB gene. In this study, we have identified the mutations in two pccB, one pccC, and two pccBC cell lines and have deduced those alleles participating in interallelic complementation. One pccB line was a compound heterozygote of Pro228Leu and Asn536Asp. The latter mutation was also detected in a noncomplementing pccBC line. This leaves Pro228Leu responsible for complementation in the pccB cells. The second pccB line contained an insertional duplication, dupKICK140-143, and a splice mutation IVS + 1 G-->T, located after Lys466. We suggest that the dupKICK mutation is the complementing allele, since the second allele is incompatible with normal splicing. The pccC line studied was homozygous for Arg410Trp, which is necessarily the complementing allele in that line. For a second pccC line, we previously had proposed that delta Ile408 was the complementing allele. We now show that its second allele, "Ins.Del," a 14-bp deletion replaced by a 12-bp insertion beginning at codon 407, fails to complement in homozygous form. We conclude that the interallelic complementation results from mutations in domains that can interact between beta-subunits in the PCC heteromer to restore enzymatic function. On the basis of sequence homology with the Propionibacterium shermanii transcarboxylase 12S subunit, we suggest that the pccC domain, defined by Ile408 and Arg410, may involve the propionyl-CoA binding site.

Alleles↗
PubMed1975

Alternate complement pathway induction of aggregation and release of 5-hydroxytryptamine and adenosine diphosphate by rabbit platelets.

The present studies investigated patterns of rabbit platelet aggregation and release of 5-hydroxytryptamine (5HT) utilizing nine variables: three different types of challenge, soluble antigen and antibody (AG-AB), zymosan (Z), an agent known to activate the alternate complement pathway (ACP), and Z preincubated in lightly heparinized plasma so as to become coated with complement (ZC); three different types of platelet-rich plasma (PRP), lightly heparinized PRP in which both complement pathways are active, ethylene glycol tetraacetic acid-PRP (EGTA-PRP) in which only the ACP is active, and ethylene diamine tetraacetic acid PRP (EDTA-PRP), which inhibits both complement pathways; three different types of inhibitors, cobra venom factor (CoF), which causes activation of C3 proactivator (C3PA) to C3 activator (C3A) and fluid phase decomplementation of C3 and C5 through C9, adenosine monophosphate (AMP), a specific antagonist of ADP, and tosyl arginine methyl ester (TAME), an inhibitor thought to act not only on the first component of complement, but also on a platelet membrane site of mediating complement-induced platelet injury as well as on C3PAse. In heparinized PRP, both AG-AB and Z produced biphasic aggregation and prompt and extensive 5HT release. A brief lag period noted with both AG-AB and Z challenge was not observed with ZC challenge, indicating that this lag period represented time required for generation of the necessary complement-dependent membrane-injuring activity. Prior decomplementation by CoF entirely prevented both aggregation and release by either AG-AB or Z but by ZC, indicating first that fluid-phase ACP activation did not produce platelet injury, and second that ZC had on its surface an activity capable of producing immediate biphasic aggregation and prompt 5HT release without the further participation of later acting complement components. Both AMP and TAME eliminated the second phase of aggregation and diminished or eliminated 5HT release with all three challenges, suggesting that both inhibitors might be operative on similar or identical platelet membrane receptors mediating complement-dependent platelet injury. In EGTA-PRP, AG-AB and Z produced delayed monophasic aggregation and delayed and diminished 5HT release, whereas ZC produced immediate although monophasic aggregation but delayed and diminished 5HT release. This suggested that all three challenges were capable of producing ACP-mediated platelet injury.

Adenosine Diphosphate↗
PubMed1994

Immunologic assessment of host defense impairment in patients with septic multiple organ failure: relationship between complement activation and changes in neutrophil function.

BACKGROUND: The pathogenesis of gram-negative sepsis-induced multiple organ failure (MOF) remains to be elucidated. METHODS: Blood samples were obtained from eleven patients with septic MOF, three patients with sepsis, three patients who underwent operation, and three healthy volunteers. In these patients the relationship between changes in polymorphonuclear neutrophil (PMN) function and complement activation was investigated. RESULTS: PMNs from patients with sepsis exhibited enhanced endothelial cell adhesion, enhanced chemotaxis, increased oxygen radical generation, and increased lysosomal enzyme release. Although PMNs from patients with septic MOF also exhibited enhanced adhesion and chemical mediator production, chemotaxis was markedly depressed. Complement activation in septic MOF was indicated by decreases in total complement activity and complement component 4 (C4) and increases in C3a and C4a des-Arginine. Increases in plasma concentrations of circulating immunoglobulin G immune complexes and decreases in PMN Fc gamma R expression suggest that the classic pathway is the main pathway of complement activation. On the other hand, we could not detect decreases in C4 or increases in C4a des-Arginine in patients with sepsis, suggesting that the alternate pathway is the main pathway of complement activation. Increases in serum concentrations of the membrane attack (SC5b-9) complex also suggested that activated complement itself may participate in organ injury in patients with septic MOF. Moreover, PMN up-regulation of surface inhibitory factors of complement activation likely allows these neutrophils to survive and function. CONCLUSIONS: The combination of changes in PMN function and complement activation appears to be intimately associated with the pathogenesis of septic MOF.

Adult↗
PubMed1996

Serum complement determinations in patients with quiescent systemic lupus erythematosus.

OBJECTIVE: To determine whether complement component analyses during a period of inactive disease can define clinically important subgroups and predict morbidity in patients with systemic lupus erythematosus (SLE). METHODS: We identified 277 patients with SLE whose disease became clinically inactive at some point after diagnosis. Serum samples were obtained at that time and tested for total complement activity (CH100) and antigenic levels of C1q, C1r, C1s, C3 and C4. Results of complement determinations were correlated with demographic characteristics and clinical findings in the followup period (mean observation period 4.25 years). RESULTS: We identified 25 (9%) patients with multiple complement determinations below the normal range. 24 other patients (8.5%) had a very low level of a single complement component. The group with multiple complement determinations below the normal range was much more likely than the normocomplementemic SLE controls to progress to renal insufficiency. In other respects, complement component determinations were neither reflective nor predictive of clinical course. CONCLUSION: In this group of patients with inactive SLE, complement component analyses did not generally correlate with longterm outcome; however, multiple low complement component determinations during disease quiescence was associated with increased risk of renal insufficiency.

Autoantigens↗
PubMed1997

Diving decompression fails to activate complement.

The present study evaluated complement activation during decompression after air dives in a hyperbaric chamber. Intravascular bubbles were quantified by Doppler ultrasound scoring. Eighteen subjects completed 92 dives, of which 74 produced bubbles. Complement activation was assessed by plasma C3a des Arg and red-cell-bound C3d before and after each dive. These parameters of in vivo complement activation failed to show significant activation. In vitro complement activation susceptibility tests on pre-dive sera were performed to explore their association with in vivo complement activation and intravascular bubbles. Such tests failed to identify a distinct complement-sensitive group and did not correlate with in vivo complement activation during the dives and/or intravascular bubble appearance. Two subjects developed decompression sickness but were not different from the rest of the group regarding in vitro complement sensitivity or complement activation during dives.

Adult↗
PubMed1976

Humoral immunostimulation. VI. Increased calcium uptake by cells treated with antibody and complement.

When L cells were treated with anti-L cell antibody in medium depleted of complement, rapid increases in calcium uptake were obtained over a wide range of antiserum concentrations. Concomitant cell growth and viability studies demonstrated that stimulation of cell growth occurred at higher dilutions of antiserum whereas cytotoxicity occurred at lower dilutions. The stimulatory and toxic effects of antibody on cell growth were potentiated by complement as was the enhancement in calcium uptake. Sera deficient in C1R, C2,4D, C4, C3-C9 did not increase the calcium uptake response to antibody whereas augmentation did occur with C6-deficient serum. A specific role for complement was further indicated by the ability of purified complement components to restore the response to complement in complement-deficient sera. C3 with C3-C9 deficient serum, but not C2, C5, and C6 with C3-C9 deficient serum restored augmentation effects. Taken together with the results of previous studies it is apparent that complement augments both calcium and nucleoside uptake and that the effect is primarily via the classical complement pathway through C3. Substrate saturation studies demonstrated that antibody activated the facilitated diffusion of calcium altering the Vmax but not the Km of transport whereas addition of complement altered both the Vmax and Km. These findings suggest that one of the early effects of enhancing antibody upon tumor cell metabolism in vitro is to stimulate uptake of calcium. In view of the suspected role of Ca++ in cell proliferation the increase in cell-associated calcium may be important in the subsequent proliferative response.

Antigen-Antibody Reactions↗