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PubMed1982

Polymerization of the ninth component of complement (C9): formation of poly(C9) with a tubular ultrastructure resembling the membrane attack complex of complement.

The ninth component of complement (C9) has a marked propensity to polymerize. C9 polymers [poly(C9)] formed spontaneously in Veronal-buffered saline upon incubation of purified C9 for 64 hr at 37 degrees C or within 2 hr at 46--56 degrees C. Poly(C9) formed at 37 degrees C was visualized by electron microscopy as a tubular structure with an internal diameter of 110 A and a length of 160 A. Its ultrastructure suggested a dodecameric composition and resembled that of the membrane attack complex of complement. The wider end of the tubular structure was formed by an approximately 30-A-thick torus with inner and outer diameters of 110 A and 220 A, respectively. Because the dimensions of C9 within poly(C9) were 160 x 55 A (maximal) and 20 A (minimal) and because monomeric C9 has dimensions of approximately 80 x 55 A, it is proposed that monomeric C9 unfolds during polymerization into tubules. Polymerization also occurred upon treatment of C9 for 1 hr at 37 degrees C with 0.6 M guanidine . HCl, 0.1 M octyl glucoside, or 1.5% sodium deoxycholate. Guanidine . HCl-induced C9 polymers consisted of elongated highly curved strands 55--80 A wide, suggesting that these polymers were formed by globular C9 that had not unfolded.

Cell Membrane Permeability↗
PubMed1990

Involvement of membrane attack complex of complement in UV-B-induced acantholysis in pemphigus.

The initial acantholytic process induced by irradiation of UV-B on uninvolved skin of patients with pemphigus was immunohistologically studied using monoclonal antibodies that bind to antigenic determinants present in the C5b9 complex. Membrane attack complex of complement-related antigens in suprabasal intercellular sites could be detected after 5 hours of irradiation, at which time there was no acantholysis. At 24 hours, the staining intensity markedly increased and suprabasal clefts with acantholytic epidermal cells could be seen. In contrast, acantholysis did not develop in the absence of membrane attack complex formation at intercellular sites even 24 hours following UV-B irradiation. These findings suggest that UV-B can induce membrane attack complex assembly in the epidermis, which may itself be involved in the process of acantholysis and provide additional evidence for involvement of the complement system in pemphigus.

Acantholysis↗
PubMedDate not supplied

Inhibition of neutrophil adhesion and the membrane attack complex of complement synergistically prolongs cardiac xenograft survival.

BACKGROUND: Hyperacute xenograft rejection is affected by activation of the complement cascade. Split products of early complement components influence the localization, activation, and effector function of platelets, granulocytes, and lymphocytes, whereas the formation of the membrane attack complex (C5b-9) leads to direct cellular injury. In a unique strain of PVG rats deficient in the C6 component of complement, the terminal membrane attack complex is not formed. However, production of the chemotactic and vasoactive components C3a and C5a proceeds normally. Guinea pig cardiac xenografts in these C6-deficient rats have prolonged survival, and at the time of rejection the inflammatory infiltrate is composed primarily of neutrophils. NPC 15669, a member of a class of antiinflammatory agents called leumedins, is known to inhibit neutrophil adhesion. The purpose of this study was to determine whether inhibition of neutrophil recruitment in animals incapable of membrane attack complex formation would prolong cardiac xenograft survival. METHODS: Cardiac xenografts from male Hartley guinea pigs were heterotopically grafted into PVG (C-) and PVG (C+) male rats. Experimental animals received 20 mg/kg of NPC 15669 i.v. before cross-clamp release and 10 mg/kg of NPC 15669 intravenously on postoperative day 1. Control animals received intravenous saline solution only. RESULTS: Complement sufficient PVG (C+) rats rejected cardiac xenografts hyperacutely despite mode of treatment: PVG (C+) rats which received saline solution (n = 5) rejected their xenografts at 10.8 +/- 2.6 minutes, and those receiving NPC 15669 (n = 5) rejected at 13.9 +/- 5.3 minutes. Histologic examination showed edema, platelet aggregation, and hemorrhage but no cellular inflammatory infiltrate. As expected, complement-deficient PVG (C-) rats had markedly longer xenograft survival in the saline solution-treated group (n = 5) with graft function being sustained 14.7 +/- 6.1 hours. NPC 15669 treatment (n = 4) further prolonged graft function to 61.0 +/- 4.7 hours. In addition to edema, platelet aggregation, and hemorrhage, histologic analysis of these grafts at the time of rejection was characterized by an infiltration of neutrophils. CONCLUSIONS: We conclude that neutrophils play a critical role in cardiac xenograft rejection when complement activation is restricted. Combined inhibition of complement and neutrophil adhesion prolongs xenograft survival longer than inhibition of either component alone.

Animals↗
PubMed1987

The membrane attack complex of Xenopus laevis complement.

Rabbit erythrocyte membranes lyzed by Xenopus laevis serum exhibited a typical ultrastructural complement lesion with an inner diameter of 80 +/- 9 A. The protein pattern associated with lyzed membrane is compared to a similar human preparation.

Animals↗
PubMed1993

The cerebrospinal-fluid soluble form of Alzheimer's amyloid beta is complexed to SP-40,40 (apolipoprotein J), an inhibitor of the complement membrane-attack complex.

The amyloid fibrils deposited in Alzheimer's neuritic plaque cores and cerebral blood vessels are mainly composed of aggregated forms of a unique peptide, 39-42 amino acids long, named amyloid beta (A beta). A similar, although soluble, A beta ('sA beta') has been identified in cerebrospinal fluid, plasma and cell supernatants, indicating that it is normally produced by proteolytic processing of its precursor protein, amyloid precursor protein (APP). Using direct binding experiments we have isolated and characterized an 80 kDa circulating protein that specifically interacts with a synthetic peptide identical with A beta. The protein was unmistakably identified as SP-40,40 or ApoJ, a cytolytic inhibitor and lipid carrier, by means of amino acid sequence and immunoreactivity with specific antibodies. Immunoprecipitation with anti-SP-40,40 retrieved soluble A beta from cerebrospinal fluid, indicating that the interaction occurs in vivo.

Amino Acid Sequence↗
PubMed1979

Proteolytic transformation of SC5b-9 into an amphiphilic macromolecule resembling the C5b-9 membrane attack complex of complement.

Proteolysis of fluid-phase SC5b-9 left a major part of the macromolecule intact and caused transition of the molecule from a hydrophilic to an amphiphilic state. The transformed complex exhibited neoantigens characteristic of the C5b-9 membrane attack complex of the complement. It yielded an SDS gel electrophoresis pattern that was similar, but not identical to that of the proteolysed, membrane attack complex. The proteolytically altered SC5b-9 complex bound lipid and incorporated into artificial lipid vesicles to yield a membrane-bound structure resembling the C5b-9 complement lesion.

Antigens↗
PubMed2002

Modulation of leukocyte recruitment and IL-8 expression by the membrane attack complex of complement (C5b-9) in a rabbit model of antigen-induced arthritis.

The complement system is thought to be a major physiological mediator of injury in a number of diseases including rheumatoid arthritis (RA). The membrane attack complex (MAC) of complement has been detected in RA tissue, suggesting that the MAC may be relevant to the pathogenesis of the disease. Deposition of sublytic concentrations of the MAC has been shown to promote the expression of proinflammatory mediators. In the present study, we utilized rabbits deficient in the complement protein C6 to elucidate the role of the MAC in mediating the pathogenesis of antigen-induced arthritis. Swelling, leukocyte accumulation, IL-8 expression, proteoglycan, and hydroxyproline content were assessed. Analysis of synovial tissue demonstrated a significant decrease in leukocyte influx and a parallel decrease in tissue associated IL-8 in joints of C6-deficient animals as compared to C6-sufficient animals. However, this did not correlate with the preservation of connective tissue. The results derived from this study provide evidence that the MAC has an important function in mediating leukocyte recruitment in antigen-induced arthritis but does not play a direct role in connective tissue breakdown.

Animals↗
PubMed1985

Monoclonal antibodies which react with lymphocyte-lysed target cells and which cross-react with complement-lysed ghosts.

Monoclonal antibodies were raised against a human natural killing system and screened against targets lysed either by human lymphocytes in antibody-dependent cellular cytotoxicity (ADCC), or by human complement. Two monoclonals were identified which bound specifically to both types of killed targets. More detailed studies with one antibody showed that it inhibited ADCC, both as intact antibody and as the F(ab')2 fragment. Intact antibody enhanced natural (NK) killing, although the F(ab')2 fragment inhibited NK killing. The data support the hypothesis that lymphocyte-mediated killing involves a complex analogous in nature to the complement membrane attack complex. In addition, the antibodies provide evidence to suggest that this complex has antigenic determinants in common with the complement membrane attack complex, and indicate the possibility that the two systems are derived from a common ancestor.

Animals↗
PubMed2001

Streptococcal inhibitor of complement (SIC) inhibits the membrane attack complex by preventing uptake of C567 onto cell membranes.

Streptococcal inhibitor of complement (SIC) was first described in 1996 as a putative inhibitor of the membrane attack complex of complement (MAC). SIC is a 31 000 MW protein secreted in large quantities by the virulent Streptococcus pyogenes strains M1 and M57, and is encoded by a gene which is extremely variable. In order to study further the interactions of SIC with the MAC, we have made a recombinant form of SIC (rSIC) in Escherichia coli and purified native M1 SIC which was used to raise a polyclonal antibody. SIC prevented reactive lysis of guinea pig erythrocytes by the MAC at a stage prior to C5b67 complexes binding to cell membranes, presumably by blocking the transiently expressed membrane insertion site on C7. The ability of SIC and clusterin (another putative fluid phase complement inhibitor) to inhibit complement lysis was compared, and found to be equally efficient. In parallel, by enzyme-linked immunosorbent assay both SIC and rSIC bound strongly to C5b67 and C5b678 complexes and to a lesser extent C5b-9, but only weakly to individual complement components. The implications of these data for virulence of SIC-positive streptococci are discussed, in light of the fact that Gram-positive organisms are already protected against complement lysis by the presence of their peptidoglycan cell walls. We speculate that MAC inhibition may not be the sole function of SIC.

Bacterial Proteins↗
PubMed1995

Induction of cellular procoagulant activity by the membrane attack complex of complement.

In addition to their well-recognized role in immune defense, there is a growing recognition that the proteins of the complement system impact directly on vascular homeostatic mechanisms, evoking cellular responses that serve to both promote adherence of blood cells to the walls of blood vessels, and the formation of fibrin through the enzyme mechanisms of the coagulation system. This clot-promoting or 'procoagulant' activity initiated through the complement system entails both receptor-mediated as well as receptor-independent pathways of cell activation. In this review, we will focus specifically upon the role that is now thought to be played by the membrane attack complex of the complement system (MAC) in the induction of the procoagulant properties of human platelets and endothelium.

Blood Coagulation↗
PubMed2000

Resistance against the membrane attack complex of complement induced in porcine endothelial cells with a Gal alpha(1-3)Gal binding lectin: up-regulation of CD59 expression.

Endothelial cells (EC) play central roles in vascular physiology and pathophysiology. EC activation results in proinflammatory activities with production of cytokines and expression of adhesion molecules. However, we have shown before in a model of xenotransplantation that prolonged stimulation of porcine EC with human anti-porcine IgM natural Abs can activate the cells to become resistant against cytotoxicity by the membrane attack complex of complement (MAC). Now we report the major characteristics of induction and maintenance of resistance elicited in porcine EC with Bandeiraea simplicifolia lectin that binds terminal gal alpha(1-3)gal. Lectin-treated cells underwent little or no cytotoxicity and PGI2 release when exposed to MAC. Induction of resistance required incubation of the EC with lectin for 4 h but was not fully manifested until 16 h later. Most of the initially bound lectin remained on the cell surface for >60 h. EC-bound lectin did not inhibit binding of IgM natural Abs or activation and binding of C components, including C9, but a C-induced permeability channel of reduced size was present. Induction of resistance required protein synthesis, developed slowly, and was associated with up-regulation of expression of mRNA for the MAC inhibitor CD59 and membrane-associated CD59 protein. Resistance lasted at least 3 days, and the cells regained normal morphology and were metabolically active. This induced resistance may have a physiologic counterpart that might be amenable to pharmacologic manipulation in vascular endothelium pathophysiology.

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↗
PubMed1995

The membrane attack complex of complement mediates peripheral nervous system demyelination in vitro.

The present study used cocultures of rat dorsal root ganglia (DRG) and peritoneal macrophages to define the role of activated complement components during demyelination. The complement cascade was activated in vitro by treatment of the cultures with natural rat serum and lipopolysaccharides. Complement activation was examined by detection of the membrane attack complex of complement (MAC) with an antibody directed against rat C5-9. Detection of MAC in vitro by immunoelectron microscopy was associated with morphological changes of the myelin sheath. The sheath's regular structure was disrupted. Myelin lamellae were split and showed signs of decompaction. These changes were followed by a selective macrophage attack on myelin sheaths resulting in demyelination. Schwann cell viability was not affected by complement activation. Axons and sensory ganglion cells also survived this attack. The specificity of the complement effect was tested in experiments using treatment regimens with natural rat serum or lipopolysaccharides alone. In these experiments, no morphological changes of the myelin sheath were observed as well as no macrophage attack on myelin.

Animals↗
PubMed1986

Assembly of the membrane attack complex of complement on small unilamellar phospholipid vesicles.

Light-scattering intensity was shown to be a reliable, direct, and quantitative technique for monitoring the assembly of the membrane attack complex of complement (proteins C5b-6, C7, C8, and C9) on small unilamellar phosphatidylcholine vesicles. The assembly on vesicles occurred in a simple fashion; complexes of C5b-7 bound noncooperatively to the vesicles, and final assembly of C5b-9 did not induce vesicle aggregation or fragmentation. When C5b-6 and C7 were mixed in the presence of vesicles but at molar protein/vesicle ratios of less than 1, there was quantitative binding of C5b-7 to the vesicles with no concomitant aggregation of C5b-7. If C7 was added at a slower rate, quantitative binding was obtained at molar C5b-7/vesicle ratios of up to 5. The latter observations (a) were consistent with the proposal that C5b-7 aggregation and membrane binding were competitive events and (b) defined conditions under which light-scattering intensity measurements could monitor C5b-9 assembly on vesicles without contribution from the fluid-phase assembly. The C8/C5b-7 ratio in the phospholipid-C5b-8 complex was 0.97 +/- 0.12, and the maximum ratio of C9/C5b-8 in the final complex was 16.2 +/- 2.0. One C9 molecule associated rapidly with each phospholipid-C5b-8, followed by slower incorporation of the remaining C9 molecules. The initial velocity of the slow phase of C9 addition was easily saturated with C9 and gave an activation energy of 37 kcal/mol. This was identical with the value measured for the analogous process in the fluid-phase assembly.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement C7↗
PubMed1994

Blocking antibodies specific for human albumin interfere with the hemolytic activity of the membrane attack complex of complement.

Earlier, we showed that antibodies specific for human serum albumin are able to bind to erythrocyte-associated albumin and inhibit complement mediated hemolysis. In the present study we determine if inhibition is occurring at the membrane attack phase of complement activation or at an earlier step. We show that although cell-bound anti-albumin antibodies do not inhibit binding and activation of C3 or uptake of C9, they do appear to cause cells to become refractory to lysis by the membrane attack complex as they inhibit both the kinetics and the extent of hemolysis in a reactive lysis system which employs preformed C5b6 plus C7, C8, and C9. We believe that this is the first report of inhibition of the hemolytic activity of the membrane attack complex by antibodies bound to an erythrocyte surface antigen.

Animals↗
PubMed2003

The membrane attack complex of complement contributes to plasmin-induced synthesis of platelet-activating factor by endothelial cells and neutrophils.

Thrombolytic agents, used to restore blood flow to ischaemic tissues, activate several enzymatic systems with pro-inflammatory effects, thus potentially contributing to the pathogenesis of ischaemia-reperfusion injury. Platelet-activating factor (PAF), a phospholipid mediator of inflammation, has been implicated in the pathogenesis of this process. We previously showed that the infusion of streptokinase (SK) induces the intravascular release of PAF in patients with acute myocardial infarction (AMI), and that cultured human endothelial cells (EC) synthesized PAF in response to SK and plasmin (PLN). In the present study, we investigated the role of the membrane attack complex (MAC) of complement in the PLN-induced synthesis of PAF. In vivo, we showed a correlation between the levels of soluble terminal complement components (sC5b-9) and the concentrations of PAF detected in blood of patients with AMI infused with SK. In vitro both EC and polymorphonuclear neutrophils (PMN), incubated in the presence of PLN and normal human serum, showed an intense staining for the MAC neoepitope, while no staining was detected when they were incubated with PLN in the presence of heat-inactivated normal human serum. Moreover, the insertion of MAC on EC and PMN plasmamembrane elicited the synthesis of PAF. In conclusion, our results elucidate the mechanisms involved in PAF production during the activation of the fibrinolytic system, showing a role for complement products in this setting. The release of PAF may increase the inflammatory response, thus limiting the beneficial effects of thrombolytic therapy. Moreover, it may have a pathogenic role in other pathological conditions, such as transplant rejection, tumoral angiogenesis, and septic shock, where fibrinolysis is activated.

Cells, Cultured↗
PubMed1989

Increased urinary excretion of C5b-9 distinguishes passive Heymann nephritis in the rat.

Increased urinary excretion of C5b-9 distinguishes passive Heymann nephritis from other forms of experimental glomerulonephritis in the rat. In the passive Heymann nephritis (PHN) model of membranous nephropathy (MN) subepithelial deposits form from anti-Fx1A antibody reacting with antigen expressed on the glomerular epithelial cell membrane followed by membrane patching and shedding of immune complexes. Immune complex deposits are accompanied by deposits of C5b-9 which is required for the mediation of proteinuria. We tested the hypothesis that C5b-9 assembly on the epithelial cell membrane might result in C5b-9 excretion in the urine, which would distinguish this autoimmune mechanism of MN from other processes that result in subepithelial immune complex deposits. Using monoclonal antibodies developed to rat C6 and a rat C5b-9 neoantigen, in a sensitive ELISA assay, elevated urinary excretion of rat C5b-9 was documented in PHN associated with on-going glomerular immune deposit formation. No urinary C5b-9 was detectable in MN induced by an exogenous antigen (cationized IgG) despite equivalent glomerular C5b-9 deposits, or in models of nephrotoxic nephritis, subendothelial immune complex nephritis, anti-mesangial cell membrane antibody-induced nephritis or two non-immune nephropathies. Infusion of preformed C5b-9 in proteinuric animals excluded glomerular filtration of C5b-9 as a contributing mechanism to urinary C5b-9 excretion. We conclude that in the rat, increased urinary excretion of C5b-9 is a marker of MN induced by antibody to a glomerular epithelial cell antigen. Urine C5b-9 excretion reflects active glomerular immune deposit formation and distinguishes MN induced by this mechanism from other forms of MN as well as from other glomerular diseases with equivalent glomerular C5b-9 deposits.

Animals↗