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PubMed1988

The complement system in atherosclerosis.

Complement is a term referring to a collection of plasma proteins, specific cellular receptors and cell surface regulatory molecules. Activation of the complement system to completion results in the formation of C5b-9 terminal complexes. These complexes have been observed in human atherosclerotic lesions by immunohistochemistry. Although the structure(s) which activate complement in lesions have not been defined, cholesterol and oxysterols exhibit this property in vitro. Endothelial cell damage leads to complement activation and endothelial cells overlying atherosclerotic lesions have been observed to contain C3 and C5b-9 antigens. Cardiac myocytes stain for complement proteins (C3, C4 and C5b-9) following myocardial infarction. Infarct size and extent of inflammatory cell infiltrates are diminished by decomplementation prior to experimentally-induced myocardial ischemia. Following myocardial infarction and ulceration of atherosclerotic lesions in human patients there is an increase in circulating complement activation products and a decrease in the level of native C1 through C4 proteins. Thus, it appears that complement plays a role in atherogenesis and its sequelae. Little is known however, about the pathophysiological effects complement activation products exert on lesion development, for example through modulation of macrophage functions, or how complement activation is regulated in lesions. Implications for complement in atherogenesis are discussed.

Animals↗
PubMed2004

Complement and autoimmune glomerular diseases.

The renal glomerulus is the specialized structure in the kidney responsible for generating over 150 liters of plasma ultrafiltrate per day in humans. Certain characteristics of this structure favor involvement in autoimmune diseases. Formation of immune complexes in the glomerulus, either deposited from the circulation or generated in situ, can activate the complement system. Active products of this system include the anaphylatoxins C3a and C5a, C3b, which covalently associates with immune complexes, and the C5b-9 membrane attack complex. If complement is activated in a site accessible to blood constituents, such as in the subendothelial and mesangial regions, generated C3a, C5a and C3b can interact with their respective receptors on inflammatory cells to lead to an exudative lesion. In addition, intrinsic glomerular cells bearing relevant receptors may also be activated and can proliferate to contribute to the inflammation. In a privileged site such as the subepithelial region, complement activation products are not accessible to blood cells, and as such, the resultant pathology is noninflammatory. In this setting, effects of C5b-9 predominate, which include activation and injury of cells through still incompletely characterized pathways. Various means to alter the complement pathway are now available, including antibody inhibitors and recombinant proteins based upon naturally occurring complement regulators. The use of these agents, as well as mice in which individual components of the complement system have been deleted, has given a great deal of insight into how the complement system is involved in glomerular disease. The ability to manipulate the complement pathway is now a reality in a clinical setting, yet conclusive human studies are difficult to achieve.

Animals↗
PubMed2006

Cloning of a CD59-like gene in rainbow trout. Expression and phylogenetic analysis of two isoforms.

CD59, the major inhibitor of the complement membrane attack complex, is an 18-20 kDa glycoprotein, linked to the membrane via a glycosylphosphatidylinositol (GPI)-anchor. It restricts binding of C9 to the C5b-8 complex, preventing the formation of the complement membrane attack complex C5b-9. In this study we report the cloning of a second CD59-like gene in the rainbow trout, Oncorhynchus mykiss (referred to as CD59-2 and the previously deposited trout CD59-like gene as CD59-1). Trout CD59-2 is 56% identical to CD59-1 at the amino acid level. Both of trout CD59s show the highest identity score (54%) with putative CD59-like molecules from other teleost, and the overall identity with their mammalian orthologs is less than 30%. Trout CD59s are expressed in brain, heart, intestine, kidney, liver and spleen. Particularly, CD59-2 is abundant in trout brain, while CD59-1 seems to be absent in the trout spleen. Moreover, both of trout CD59 genes seems to be present as a single copy in trout genome.

Amino Acid Sequence↗
PubMed1997

Complement resistance of capsulated strains of Aeromonas salmonicida.

The complement resistance of Aeromonas salmonicida strains grown under conditions promoting capsule formation was investigated using well characterized strains and their isogenic mutants. Complement resistance was previously studied using the same strains growing under non-capsulating conditions. The serum resistant strains were found to activate complement, but rapidly degrade C3b preventing productive formation of the lytic complex C5b-9. Isogenic lipopolysaccharide rough mutants grown under non-capsulating conditions were serum sensitive, binding a large amount of C3b and leading to productive formation of C5b-9. When grown under conditions promoting capsule formation, these mutants were partially resistant to complement because less C3b is bound to them and also partially degraded, with a concomitant reduction in lytic C5b-9.

Aeromonas↗
PubMed1991

Reactions of the immune system in chronic degenerative neurological diseases.

Elements consistent with a cell mediated immune response were identified immunohistochemically in amyotrophic lateral sclerosis (ALS) spinal cord and Alzheimer disease (AD) hippocampus. T helper/inducer and cytotoxic/suppressor lymphocytes were detected in affected tissues in both diseases. In addition, abundant reactive microglia were found expressing the major histocompatibility glycoproteins HLA-A,B,C and HLA-DR, as well as receptors for the Fc chain (Fc gamma R1), for complement 3 and 4, and for vitronectin. In AD, the complement proteins C1q, C4d, C3d and C5b-9 were found on dystrophic neurites, neuropile threads and some neurofibrillary tangles. In ALS, the only complement proteins identified were C4d and C3d. The integrin ligands vitronectin and ICAM-1 were also identified in affected tissues in both diseases.

Alzheimer Disease↗
PubMed1994

C9-mediated killing of bacterial cells by transferred C5b-8 complexes: transferred C5b-9 complexes are nonbactericidal.

The formation of the C5b-9 complex on the outer membrane of complement-sensitive cells of Escherichia coli results in inhibition of inner membrane function and the death of the cell. Cells bearing a precursor of the C5b-9 site, the C5b-8 complex, suffer no loss in viability. Antibiotic-sensitive, complement-sensitive donor cells bearing precursor C5b-8 complexes were incubated with equal numbers of antibiotic-resistant, complement-sensitive acceptor cells that had not been exposed to a complement source. This cell mixture was incubated with 5 mM EDTA for 5 min and then with calcium chloride (20 mM) for various times. The excess calcium ion concentration was effectively reduced with additional EDTA, and the cell mixture was washed and resuspended in buffer. The viability of the acceptor cells was assayed by plating on antibiotic-containing media. C9 was added to the mixture, and the mixture was incubated for 10 min at 37 degrees C and then plated as described above. It was found that the acceptor cells were killed by the addition of purified C9 only after incubation with donor cells bearing C5b-8 sites during the transfer procedure. This indicates that precursor C5b-8 sites that support C9-mediated killing could be transferred between cells. No loss in viability was detected for acceptor cells subjected to the procedure described above in the presence of donor cells bearing complete C5b-9 complexes, formed prior to mixing with acceptor cells for the transfer procedure.

Bacteria↗
PubMed1998

Role of complement in in vitro and in vivo lung inflammatory reactions.

Complement is one of the integral buttresses of the inflammatory response. In addition to host defense activities, proinflammatory properties of several complement components are described. This overview elucidates the role of complement in inflammatory reactions in vitro and in vivo, focusing on the complement activation products, C5a, and the membrane attack complex, C5b-9. Using several approaches, the impact of these complement components in mechanisms relevant to neutrophil recruitment is emphasized. In addition, the participation of complement in endothelial superoxide generation and its essential requirement for full expression of lung injury is demonstrated, as are the involved intracellular signal transduction pathways. Understanding the mechanisms of complement-induced proinflammatory effects may provide a basis for future therapeutic blockade of complement and/or its activation products.

Complement Activation↗
PubMed1991

Binding of iron to the 5th component of human complement directs oxygen radical-mediated conversion to specific sites and causes nonenzymic activation.

It was earlier found that hydroxyl radicals (OH.) generated in a fluid phase system, convert human C5 to an activated, C5b-like form without cleavage. For the conversion catalytic amounts of divalent iron were necessary; upon their oxidation OH. are generated. In view of the extraordinary reactivity of OH. their specific effect on C5 was surprising. It has now turned out that C5 binds iron, about 13-15 Fe ions per molecule C5. C5 was fully bound to iron-loaded Chelating Sepharose and in this way removed form the medium. Only at the sites where iron is bound, is OH. generation possible. The half-life of OH. is extremely short and hence the radicals can act on C5 only in the immediate environment of the binding sites for iron. In this way the oxidative change of C5, induced by the radicals, is restricted to some sites on the molecule determined by the iron binding. The hydroxyl radical scavenger, dimethylsulfoxide (DMSO), is unable to interfere with the conversion of C5 by OH. generated on iron-Sepharose, it does not reach the site of reaction in that system. In fluid phase systems DMSO does inhibit the conversion of C5 to C5b-like C5.

Binding Sites↗
PubMed1992

Effects of complement activation in the isolated heart. Role of the terminal complement components.

The mechanisms of the complement-mediated myocardial injury associated with ischemia and reperfusion have not been elucidated fully. Complement activation may directly mediate injury through actions of the anaphylatoxins C3a and C5a or generation of the membrane attack complex C5b-9. A model was developed to examine the direct effects of complement activation on heart function, assess myocardial tissue damage, and determine which complement components mediate tissue injury. Isolated rabbit hearts were perfused with Krebs-Henseleit buffer by using a modified Langendorff apparatus. Human plasma was added to the perfusate as a source of complement. Rabbit tissue activates human complement. Treatment with 6% normal plasma resulted in complement activation as assessed by the generation of Bb, C3a, C5a, and SC5b-9. Functional changes in cardiac performance became apparent 7-15 minutes after plasma addition and developed fully over the next 20-30 minutes. The effects were dependent on the complement titer and included 1) an increase in the end-diastolic pressure, 2) a decrease in the developed pressure, 3) an increase in the coronary perfusion pressure, and 4) an increase in lymphatic fluid formation. These effects were not elicited when an inhibitor of complement activation (FUT-175) was present or when heat-inactivated plasma was used. The effects of complement activation on myocardial function could not be reproduced by treatment with recombinant human C5a, zymosan-activated plasma, or plasma selectively depleted of C8. Myocardial tissue accumulated sodium and calcium and lost potassium as a result of complement activation. Activation caused the release of creatine kinase from myocytes and an increase in the radiolabeled albumin space of the hearts. The data demonstrate that complement activation caused decrements in myocardial function and increased the coronary perfusion pressure and lymphatic fluid flow rate. The effects were not mediated by the anaphylatoxins but were dependent on the distal complement component C8, suggesting that C5b-9 was responsible for the physiological changes. Complement activation directly mediated tissue injury in a manner consistent with plasmalemmal disruption as a result of C5b-9 formation. The data suggest that the C5b-9 complex, which is known to form under conditions of ischemia, may contribute directly to myocardial cell injury.

Animals↗
PubMed1993

The sheep analogue of human CD59: purification and characterization of its complement inhibitory activity.

An inhibitor of the membrane attack complex of complement was isolated from the membranes of sheep erythrocytes. Fast protein liquid chromatography (FPLC) and affinity purification procedures for this sheep complement-inhibiting protein (SCIP) both yielded a pure protein with an apparent M(r) of 19,000 under reducing and non-reducing conditions. Incubation of the denatured protein with neuraminidase and Endo-F reduced the apparent M(r) to 18,000 and 15,000 respectively, while treatment with O-deglycosidase or phosphatidylinositol-specific phospholipase C (PIPLC) did not affect the apparent M(r). SCIP was detectable on erythrocytes and lymphocytes but not on platelets and could partially be removed by PIPLC treatment. Deglycosylation of the pure protein markedly reduced and PIPLC treatment abolished its activity. A monoclonal antibody (mAb) raised against sheep complement-inhibiting protein (SCIP) enhanced the susceptibility of sheep erythrocytes to lysis by homologous complement. SCIP inhibited complement after the stage of C5b-7 formation. Amino-terminal protein sequence was obtained and was shown to be similar to that of human CD59. All these features suggest that SCIP is the sheep equivalent of human CD59. Human CD59 has been reported to be species selective in that it inhibits complement from relatively few species. However, SCIP efficiently inhibited lysis of guinea-pig erythrocytes by complement from a wide range of species tested indicating that it is a potent and non-selective inhibitor of the membrane attack complex of complement (MAC).

Amino Acid Sequence↗
PubMedDate not supplied

Sulfonated dextran inhibits complement activation and complement-dependent cytotoxicity in an in vitro model of hyperacute xenograft rejection.

In the present study, we demonstrate that a substituted soluble dextran derivative bearing 73% carboxylic groups and 15% benzylamide sulfonate groups, termed CMDBS25, inhibits complement activation and complement-mediated damage in an in vitro model of xenogeneic rejection. Incubation of porcine aortic endothelial cells with normal human serum resulted in time-dependent complement consumption as assessed by C3a generation in the fluid phase and deposition of activated complement fragments C3, C5 and of C5b-9 on target cells. The presence of C5b-9 membrane attack complex was associated with 51Cr release from prelabelled endothelial cells. The addition of 5-25 mg of CMDBS25/ml under the experimental conditions used, inhibited complement activation and C3a generation in a dose-dependent fashion. CMDBS25 (25 mg/ml) totally suppressed iC3b, C5 and C5b-9 cytolytic complex deposition on cells and inhibits by 42% lysis of target endothelial cells. Native dextran had no effect. Our observations document the anti-complementary properties of sulfonated dextran derivatives and their potential as therapeutic agents for the prevention of complement-dependent hyperacute xenograft rejection.

Animals↗
PubMed1993

Pathogenesis of glomerulonephritis.

This review summarizes current understanding of the mechanisms which mediate immune glomerular injury in glomerulonephritis. Non-inflammatory lesions resembling minimal change disease and membranous nephropathy, respectively, are induced by non-complement fixing antibodies to glomerular epithelial cell (GEC) membrane antigens (minimal change disease) and GEC membrane insertion of the C5b-9 membrane attack complex of complement (membranous nephropathy). The cellular mechanisms of these effects are unclear but may involve GEC activation and release of local mediators, such as proteases or oxidants, or GEC detachment from underlying basement membrane. Inflammatory types of glomerular lesions are mediated by circulating inflammatory cells (neutrophils, platelets, macrophages) or by resident glomerular cells (mesangial cells) or both. Neutrophil-mediated injury involves local release of GBM degrading proteases or GBM halogenation induced by the interaction of neutrophil-derived myeloperoxidase with H2O2 and a halide. Neutrophil induced glomerular injury is augmented by platelets. Recent evidence establishes that mesangial cell proliferation in glomerulonephritis is mediated by complement and platelets. Mesangial cell proliferation is accompanied by increased expression of PDGF and PDGF receptor proteins and the genes for these proteins resulting in an autocrine mechanism of cell proliferation. Mesangial cell proliferation is also accompanied by increased release of neutral proteinase in sites of basement membrane damage. Mesangial cell proliferation precedes up-regulation of genes for extracellular matrix components in several models and may be important in the pathogenesis of glomerulosclerosis.

Animals↗
PubMed1986

Complement lysis of U937, a nucleated mammalian cell line in the absence of C9: effect of C9 on C5b-8 mediated cell lysis.

Previous studies have demonstrated that in general, nucleated cells are more resistant to killing by serum complement than are erythrocytes. During studies aimed at defining the mechanisms of nucleated cell resistance, we found that the human histiocytic cell line U937 was easily lysed by homologous serum. U937 cells were also killed by serum depleted of C9, but not by serum depleted of C8, implying that the C5b-8 complex was sufficient to cause lysis of these cells. Enumeration of complexes on the cell surface demonstrated that approximately 40-fold more complexes were required to lyse U937 cells in the absence of C9 than in the presence of an excess of C9. Examination of the effects of small amounts of C9 on lysis of U937 cells by the C5b-8 complex demonstrated that at very low doses, C9 inhibited C5b-8 mediated lysis. The use of radiolabeled anti-C8 antibody showed that C5b-8 complexes were eliminated from the surface of U937 cells at 37 degrees C, and C9 at the dose causing inhibition of lysis accelerated the elimination of complexes. These results suggest that the increased lytic potential resulting from binding of small amounts of C9 to C5b-8 complexes is outweighed by enhanced elimination of complexes resulting in decreased cell death.

Cell Line↗
PubMed1988

Complement fixation by pemphigus antibody. V. Assembly of the membrane attack complex on cultured human keratinocytes.

Previous studies have shown that pemphigus vulgaris (PV) IgG will fix early complement components (C1q, C4, and C3) to cultured murine epidermal cell surfaces and that PV IgG and complement alter epidermal cell membrane integrity. The present study was undertaken to determine if assembly of terminal complement components (C5, C6, C7, C8, and C9) and expression of C5b-9 neoantigens occur when PV IgG interacts with human keratinocyte (HuK) cell surface antigens in the presence of a source of complement. Monoclonal antibodies specific for C5, C6, C7, C8, C9, and C5b-9 neoantigens were screened for reactivity to the individual complement components in an assembled complex of human C5b-9 on rabbit red blood cell ghosts. Monoclonal antibodies (tissue culture supernatants) that bound to antigenic determinants accessible in the C5b-9 complex were selected for this study using immunofluorescence methods. HuK treated with PV IgG fixed C5, C6, C7, C8, C9, and C5b-9 neoantigens in a characteristic speckled pattern, while normal IgG did not. Heat inactivation or EDTA treatment of the complement source, or substitution of C2-depleted serum abolished C5, C6, C7, C8, C9, and C5b-9 neoantigen staining. PV IgG and complement also resulted in significant cytotoxicity to cell membranes as assessed using an ethidium bromide-fluorescein diacetate assay. These results suggest that PV IgG will activate the membrane attack complex of the complement system on HuK cell surfaces, resulting in cytotoxicity to cell membranes, further implicating complement in the pathogenesis of pemphigus.

Autoantigens↗
PubMed1985

The membrane attack complex of complement: relation of C7 to the metastable membrane binding site of the intermediate complex C5b-7.

Isolated C7 (m.w. 120,000) in 1% deoxycholate (DOC) forms dimers with an apparent m.w. of 230,000 and a DOC-binding capacity of 82 mol per mol of dimer. Dimerization of C7 also occurs in the presence of DOC-phospholipid mixed micelles and eventuates in the insertion of C7 dimers into the lipid bilayer upon the removal of the detergent. C5b-7 complex formation in the fluid phase or on lipid vesicles likewise involves polymerization. C5b-7 sedimented with 17-40S, which suggests a dimeric to hexameric composition. In avidin-biotin binding experiments in which two differentially labeled forms of C5b,6 (biotinyl 125I-C5b,6, and 131I-C5b,6) were used in equimolar amounts to assemble C5b-7, more than 50% of the biotinyl 125I-C5b,6-containing complexes also contained 131I label; again suggesting that C5b-7 consisted of oligomers rather than monomers. The conformation of C7 in C5b-7 and in dimeric C7 appeared similar by the following criteria. On formation of C5b-7 from C5b,6 and C7, a 20% increase in beta-pleated sheet structure was observed by circular dichroism spectroscopy, and a similar change occurred on dimerization of isolated C7. Tryptic and thermolytic digests of C5b-7 and C7 dimers containing 125I-C7 were analyzed by autoradiography after SDS-polyacrylamide gel electrophoresis and were found to contain similar peptides that were distinct from those in the digests of monomeric C7. Direct evidence showing that the metastable membrane binding site of the C5b-7 complex resides in the C7 subunit was obtained by using the conjugates of C5b,6 and colloidal gold. Viewed in the electron microscope, these conjugates were aggregated upon the addition of isolated C7. In contrast, when conjugates of C7 and colloidal gold were treated with soluble C5b,6, no such aggregates occurred, but instead, individual C5b-7 complexes were observed arranged around single gold particles, resulting in star-like structures. The results strongly suggest that structures of C7 are responsible for the expression of the membrane binding site of metastable C5b-7.

Binding Sites↗
PubMed1987

Immunohistochemical localization of C5b-9, S-protein, C3d and apolipoprotein B in human arterial tissues with atherosclerosis.

The terminal C5b-9 neoantigens of the complement complex, S-protein (Vitronectin), C3c, C3d and apolipoprotein B were localized on 16 aortic fibrous plaques, 8 aortic intimal thickenings, 4 fatty streaks intimae, 12 coronary fibrous plaques, 3 coronary intimal thickenings, 6 femoral and 5 basilar fibrous plaques, using an indirect and double-staining immunoperoxidase method. The granular specific deposits were localized in the fibrous cap and deeper parts of the plaque or in the deeper intima and inner-third media of intimal thickenings and fatty streaks intimae, in relation to the degree of atherosclerotic involvement. The different localization of C5b-9 and S-protein demonstrated by the double-staining technique is more suggestive for the assembly of the complex into the arterial wall and not for its preformed passage from circulation. The relation of these immune deposits to the degree of fibrosis and necrosis and their presence from the initial stages through to the advanced lesions could ascribe a role to the complement system in atherosclerosis.

Apolipoproteins B↗
PubMed1998

Identity of the residues responsible for the species-restricted complement inhibitory function of human CD59.

The membrane-anchored glycoprotein CD59 inhibits assembly of the C5b-9 membrane attack complex (MAC) of human complement. This inhibitory function of CD59 is markedly selective for MAC assembled from human complement components C8 and C9, and CD59 shows little inhibitory function toward MAC assembled from rabbit and many other non-primate species. We have used this species selectivity of CD59 to identify the residues regulating its complement inhibitory function: cDNA of rabbit CD59 was cloned and used to express human/rabbit CD59 chimeras in murine SV-T2 cells. Plasma membrane expression of each CD59 chimera was quantified by use of a 5'-TAG peptide epitope, and each construct was tested for its ability to inhibit assembly of functional MAC from human versus rabbit C8 and C9. These experiments revealed that the species selectivity of CD59 is entirely determined by sequence contained between residues 42 and 58 of the human CD59 polypeptide, whereas chimeric substitution outside this peptide segment has little effect on the MAC inhibitory function of CD59. Substitution of human CD59 residues 42-58 into rabbit CD59 resulted in a molecule that was functionally indistinguishable from native human CD59, whereas the complementary construct (corresponding residues of rabbit CD59 substituted into human CD59) was functionally indistinguishable from rabbit CD59. Based on the solved solution structure of CD59, these data suggest that selectivity for human C8 and C9 resides in a cluster of closely spaced side chains on the surface of CD59 contributed by His44, Asn48, Asp49, Thr51, Thr52, Arg55, and Glu58 of the polypeptide.

Amino Acid Sequence↗
PubMed1990

[Chronic urticaria and acquired complement deficiency due to a nephritic factor (C3NeF)].

Several studies have suggested that complement activation processes are frequently involved in the pathogenesis of urticaria. We report clinical evolution and studies of complement-mediated functions in a 47-year-old previously described patient presenting with chronic urticaria, in whom we found persistent low complement hemolytic activity (65-75% of normal values), depressed levels of third complement component (C3, between 55% and 65%) and of factor B (between 60% and 75%), together with C1, C4, C2, C5, C5b neoantigen and fluid phase terminal complement (SC5b-9) complex within the normal range, pointing to activation of the alternative pathway. A circulating low affinity C3 nephritic factor (C3NeF), known to enhance cleavage of human serum C3, was detected. The urticarial lesions, which were initially pruritic and persisted for less than 24 hours, became subsequently fixed and burning, and were accompanied by fever and arthralgia. Skin biopsy specimens showed moderate leukocytoclastic vasculitis. Response to varied treatment regimens, including antihistamines and colchicine, was poor. Therapy with oral corticosteroids produced some improvement. The association of chronic urticaria with C3NeF without clinical and biological signs of membranoproliferative glomerulonephritis and partial lipodystrophy has not to our knowledge been reported before. This observation raises the question of a possible role of C3NeF in the pathogenesis of urticaria.

Chronic Disease↗