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PubMed1996

Complement-fixing islet cell antibodies in type-1 diabetes can trigger the assembly of the terminal complement complex on human islet cells and are potentially cytotoxic.

Forty-one sera of patients with IDDM (insulin-dependent diabetes mellitus) containing complement-fixing islet cell antibodies were analyzed for their ability to activate TCC (terminal complement complex). Eighteen sera were found to promote deposition of TCC on human islets of pancreatic cryostat sections with a nonhomogeneous pattern of distribution corresponding to that of insulin. Activation of TCC by IDDM serum and binding of this complex to islet cells was confirmed using purified islets. Flow cytometric analysis of islet cell treated with a TCC+ IDDM serum showed IgG binding to the cell surface. The same serum had a cytotoxic effect on islet cells in the presence of human C. These results obtained with a homologous system of C activation by IDDM sera suggest that TCC may contribute, at least in part, to the pancreatic beta cell damage.

Autoantibodies↗
PubMed2006

Genetic evidence for the involvement of Fcgamma receptor III in experimental autoimmune myasthenia gravis pathogenesis.

Immune complexes and classical complement pathway play vital roles in experimental autoimmune myasthenia gravis (EAMG). To analyze the role of immune complex receptors in EAMG, FcgammaRIII knockout (KO) mice were immunized with AChR and were found out to be resistant to EAMG induction. This was associated with reduced neuromuscular junction deposits, lymph node cell (LNC) IL-6 production and serum complement levels. EAMG resistance of anti-C1q Ab-administered mice was also associated with reduced LNC IL-6 production and neuromuscular junction deposits, indicating C1q involvement in EAMG resistance. The data provide the first direct genetic evidence for Fcgamma receptor involvement in EAMG pathogenesis.

Animals↗
PubMed1997

Sublytic terminal complement attack on myotubes decreases the expression of mRNAs encoding muscle-specific proteins.

Activation of inflammatory and cytotoxic complement effectors that include the C5b-9 complex plays an important pathogenic role in myasthenia gravis, an inflammatory autoimmune disease of the muscle. Altered muscle-specific gene expression has been observed in experimental myasthenic rats. In this study, we have examined the effect of sublytic C5b-9 on myotubes differentiated from C2C12 myoblasts, by generating C5b-9 with C7-deficient serum with or without C7. Within 2 h, C7-deficient serum plus C7, compared with C7-deficient serum alone, induced markedly decreased levels of mRNAs encoding alpha-actin, troponin I slow twitch isoform, acetylcholine receptor alpha, and muscle aldolase A, whereas the heat shock protein 83 mRNA level remained constant, by northern analysis. Because the half-life of the acetylcholine receptor alpha was estimated to be > 8 h, the C5b-9 effect was, in part, due to enhanced mRNA decay. Because C5b-9 also induced c-jun mRNA and reduced the myoD mRNA level, a possible inhibition of muscle gene transcription by C5b-9 was examined in myotubes transfected with troponin promoter-luciferase gene constructs. Luciferase activity was reduced to 50% in response to C5b-9 at 2 h. Thus, C5b-9 appears to inhibit the muscle-specific gene expression by stimulating mRNA decay and by decreasing the transcription process. The data also indicate a possible pathogenic role of C5b-9 in immune-mediated inflammatory muscle disorders in which complement activation has been implicated.

Animals↗
PubMed2006

The mammalian host response to borrelia infection.

Tick-borne relapsing fever (RF) and Lyme disease (LD) are spirochetal infections of humans caused by different Borrelia species in endemic areas throughout the world. Our laboratory is studying the response of mammalian hosts to borrelia infection in RF and LD. For this, we use mice and non-human primates infected with B. burgdorferi sensu stricto strain N40 (N40) and the Oz1 strain of Borrelia turicatae (Bt), agents of LD and RF in North America, respectively. Our results have revealed that outbred non-human primates are significantly less susceptible than outbred mice to persistent infection with N40. In contrast, the majority of mice inoculated with the RF agent B. turicatae clear the infection, with the notable exception of residual brain or blood infection in up to 25% of cases. Little if any tissue injury occurs in immunocompetent animals with either LD or RF. In contrast, impairment of specific antibody production results in significant tissue injury, most notably in the heart, in both LD and RF. The inflammatory infiltrate is rich in plasma cells, activated macrophages and T cells, and there is significant deposition of antibody and complement, including membrane attack complex, in inflamed tissues and spirochetes. Significant loss of cardiomyocytes with apoptosis and caspase activation was observed in the heart of immunosuppressed non-human primates infected with N40 and in B cell-deficient mice infected with B. turicatae. Unlike the heart, the brain of B cell-deficient mice infected with B. turicatae showed prominent microglial activation but no detectable tissue injury. Tissues from immunosuppressed non-human primates infected with N40 produce large amounts of immunoglobulin and the B cell chemokine CXCL13, both of which significantly correlate with the spirochetal load. We conclude that the main response of mammalian hosts in LD and RF is the production of specific antibody to clear the infection. Failure of this response leads to persistent infection, which can lead to tissue injury, most notably in the heart.

Animals↗
PubMed1991

Blood dendritic cells carry terminal complement complexes on their cell surface as detected by newly developed neoepitope-specific monoclonal antibodies.

Blood dendritic cells carry the terminal complement complex (TCC) on their surface, as detected by three monoclonal antibodies (mAb). Two of these mAb were generated by immunizing mice with the terminal complement complex, whereas the third was generated by immunizing mice with blood dendritic cells. All three mAb are directed against neoepitopes on the C9 molecule, as assessed by binding and blocking experiments and studies with several forms of denatured C9 and C9-depleted serum. Only one of these mAb binds to soluble polymerized C9. All three mAb allow the quantification of human TCC in sensitive ELISA procedures and could be used as markers for the evaluation of the functions of non-lytic TCC on dendritic cells.

Animals↗
PubMed1994

Complement activation during cardiopulmonary bypass: effects of immobilized heparin.

The role of complement in biocompatibility reactions and the correlation between complement activation during cardiopulmonary bypass (CPB) and postperfusion syndrome have inspired attempts to improve the biocompatibility of extracorporeal blood oxygenation devices. Here we assessed the effect of immobilized heparin on the generation of C3a and terminal complement complexes during CPB. Thirty patients undergoing aortocoronary bypass were randomized to CPB with either heparin-coated (Duraflo II; Bentley, Irvine, CA) or noncoated control membrane oxygenators (Univox; Bentley). A standard dose of heparin (300 IU/kg) was given to the control group while the heparin dose was reduced to 30% (100 IU/kg) in the heparin-coated group. Significantly lower levels of terminal complement complexes were detected in the heparin-coated group by the end of CPB. From 28 +/- 5 AU/mL (heparin-coated group) and 26 +/- 3 AU/mL (control group, mean +/- standard error of the mean) the terminal complement complex levels increased to 391 +/- 35 AU/mL and 602 +/- 47 AU/mL, respectively (p < 0.002). This difference was still apparent 180 minutes after CPB. Although there was no difference in C3a levels between the two groups at the end of CPB, C3a levels were significantly lower in the heparin-coated group 30 minutes after CPB (194 +/- 18 ng/mL and 307 +/- 18 ng/mL in heparin-coated and control groups, respectively; p < 0.001). We conclude that the heparin-coated surface is more biocompatible with regard to complement activation than is the ordinary unmodified surface in extracorporeal circuits.

Biocompatible Materials↗
PubMed2001

Veno-venous bypass in liver transplantation: heparin-coated perfusion circuits reduce the activation of humoral defense systems in an in vitro model.

We studied the effects of bypass circuit surface heparinization on kallikrein-kinin, coagulation, fibrinolytic and complement activation in a closed model system for simulating veno-venous bypass (WBP) in orthotopic liver transplantation (OLT). The circuits were identical to those in routine use during clinical OLT in our institution. Fresh whole human blood diluted 1:2 with Ringer's acetate was circulated at a non-pulsatile flow (2 l/min) and at a constant temperature (37.5 degrees C) for 12 h. In 10 experiments, the entire inner surface of the circuits was coated with end-point attached heparin (HC). In the remaining 10, non-treated PVC tubing was used (NC). Components of the plasma kallikrein-kinin, coagulation, fibrinolytic and complement systems were analyzed using functional techniques (chromogenic peptide substrate assays) and enzyme immunoassays at baseline, 3 and 12 h. Significant activation of the initial (C3bc) and terminal (TCC) components of the complement system were found in both the NC and HC groups after 3 and 12 h: C3bc: NC: baseline = 4 (3.5-7.7), 3 h = 17.3* (12.5-27), 12h = 31* (17.7-63.6), HC: baseline = 4.9 (3.2-6.8), 3h = 9* (6-14.4), 12h = 13.7* (7.4-18.1). TCC: NC: baseline = 0.4 (0.2-0.6), 3h = 5*(0.8-11.9), 12 h: 13.1* (4.2-25.7). HC: baseline = 0.5 (0.1-0.6), 3 h = 0.6* (0.1-0.8), 12 h = 1.2* (0.3-2) AU/ml; median and range (*: p < 0.05). The C3bc and TCC concentrations were significantly higher in the NC group at 3 and 12 h, compared to the HC group: C3bc (NC vs. HC group): 3 h, p < 0.001; 12 h, p < 0.001. TCC (NC vs. HC group): 3h, p < 0.001; 12 h, p < 0.001. Significant increases in the values of thrombin-antithrombin complexes (p = 0.003), prothrombin fragment 1 + 2 (p = 0.006) and plasmin-alpha2-antiplasmin complexes (p = 0.016) were found in the non-coated group, but not in the heparin-coated group during the observation period, showing that the coagulation and fibrinolytic systems were activated in the non-coated circuits. We conclude that heparin-coating of the internal surface of the extracorporeal perfusion circuit used for WBP reduces activation of the plasma cascade systems in a closed venous system in vitro.

Blood Coagulation Factors↗
PubMed1992

Meningococcal septicaemia in a C6-deficient patient and effects of plasma transfusion on lipopolysaccharide release.

Patients whose blood is deficient in the terminal component of complement have an increased susceptibility to meningococcal infection. However, mortality from meningococcal infection is lower in these patients than in immunocompetent subjects. We studied a C6-deficient patient with meningococcal sepsis who received fresh frozen plasma (FFP). The patient's initial plasma endotoxin, C6, and terminal-complement-complex concentrations were low, but rose sharply after treatment with FFP. Samples of the patient's serum taken shortly after admission did not cause endotoxin release from Escherichia coli J5 in vitro, but endotoxin-releasing activity was restored in serum samples taken after infusion of FFP. It is possible that C6-deficient patients have reduced mortality from meningococcal infection because their serum cannot cause acute release of endotoxin from the invading organism and extensive tissue damage is thus avoided.

Adult↗
PubMed2006

Comparison of inflammatory responses after off-pump and on-pump coronary surgery using surface modifying additives circuit.

BACKGROUND: Cardiac surgery is followed by various degrees of inflammation, which have harmful consequences. Because of the central role of extracorporeal circulation (EC), off-pump coronary bypass surgery is deemed preferable. Do different modalities of EC challenge this view? METHODS: Four groups of similar patients underwent coronary surgery: (group 1) on-pump, EC with closed surface modifying additives (SMA) circuit and no pump suckers (n = 20); (group 2) on-pump, EC with open SMA circuit and pump suckers (n = 20); (group 3) off-pump (beating heart) and heparin 3 mg/kg (n = 20); (group 4) off-pump (beating heart) and heparin 1 mg/kg (n = 20). Interleukins (IL)-6, IL-8, IL-10, myeloperoxidase, elastase, and terminal complex of the complement (TCC) were analyzed at various times: at induction (time I); after heparin (time II); after complete revascularization (time III); after protamine (time IV); and 24 hours later (time V). RESULTS: The TCC was significantly higher in groups 1 and 2 at time III. The pattern of IL-6 was the same for the four groups. No significant difference in myeloperoxydase content was noted; however, elastase was significantly higher in the two EC (on-pump) groups. CONCLUSIONS: Except for the complement system and elastase, on-pump surgery with SMA-coated circuits did not elicit any greater inflammatory response than off-pump surgery.

Adult↗
PubMed1995

Reduced complement activation and improved postoperative performance after cardiopulmonary bypass with heparin-coated circuits.

A randomized controlled trial that involved 30 patients undergoing elective coronary artery bypass grafting was done to determine the effect of heparin-coated circuits and full heparinization on complement activation, neutrophil-mediated inflammatory response, and postoperative clinical recovery. Peak concentrations of terminal complement complex were 38% lower (p = 0.004) in 15 patients treated with heparin-coated circuits (median 775 micrograms/L, interquartile range 600 to 996) compared with those in 15 patients treated with uncoated circuits (median 1249 micrograms/L, interquartile range 988 to 1443). Although no significant intergroup differences in concentrations of polymorphonuclear neutrophil elastase were found, a positive correlation (rs = 0.74, p < 0.0007) was calculated between peak concentrations of terminal complement complex and polymorphonuclear neutrophil elastase. Differences in patient recovery were analyzed with use of a score composed of fluid balance, postoperative intubation time, and the difference between rectal temperature and skin temperature. The score was significantly lower in patients treated with heparin-coated circuits (p = 0.03), whereas its components showed no intergroup significance. We conclude that the use of heparin-coated circuits with full systemic heparinization results in improved biocompatibility, as assessed by complement activation, and leads to an improved postoperative recovery of the patient.

Body Temperature↗
PubMed1994

Functional and antigenic similarities between a 94-kD protein of Schistosoma mansoni (SCIP-1) and human CD59.

Schistosomiasis is a parasitic disease affecting approximately 200 million people, primarily in the third world. Schistosoma mansoni, one of the causative agents of this disease, parasitize the human mesenteric and portal blood systems while successfully evading host immune responses. During parasite penetration into the mammalian host and shortly afterwards, the larvae rapidly convert from being sensitive to being resistant to C-mediated killing. Treatment of the C-resistant parasitic forms with trypsin renders the parasite susceptible to C attack, thus indicating the presence of C inhibitory protein(s) on the parasite surface. We describe here an intrinsic schistosome C inhibitory protein (SCIP-1) that exhibits antigenic and functional similarities with the human C-inhibitor CD59. Like CD59, SCIP-1 is capable of inhibiting formation of the C membrane attack complex (MAC), probably by binding to C8 and C9 of the C terminal pathway. In addition, SCIP-1 is apparently also membrane-anchored via glycosyl phosphatidylinositol as it can be specifically released with phosphatidylinositol-specific phospholipase C. Soluble SCIP-1, partially purified from Nonidet P-40 extracts of schistosome tegument is capable of inhibiting hemolysis of sensitized sheep erythrocytes and of rabbit erythrocytes by human C. Anti-human CD59 antibodies block this activity of SCIP-1 and in addition, upon binding to intact parasites, render them vulnerable to killing by human and guinea pig C. SCIP-1 is located on the surface of C-resistant forms of the parasite, i.e., 24-h cultured mechanical schistosomula and in vivo-derived adult worms as revealed by immunofluorescence and immunogold electron microscopy studies. These results identify one of the mechanisms schistosomes use to escape immune attack.

Animals↗
PubMed1987

Immunohistochemical studies of reflux nephropathy. The role of extracellular matrix, membrane attack complex, and immune cells in glomerular sclerosis.

Renal tissue obtained from 8 patients with reflux nephropathy was studied by immunofluorescence with well-defined mono- and polyclonal antibodies to extracellular matrix, intermediate filament proteins, membrane attack complex of complement (MAC), and immune cells. In both unscarred and scarred areas of the tissue, intrinsic components of the human glomeruli, such as Type IV collagen, laminin, and fibronectin, accumulated in the expanded mesangium of the glomeruli. Those components were diminished or absent in the hyalinized glomeruli. Type III collagen was occasionally localized to the mesangium and synechiae in the glomeruli and was frequently observed within the nearly hyalinized glomeruli. MAC was co-deposited with C3, C5, C9, and properdin in the sclerotic area of the glomeruli, along with a decrease in the reactivity of podocytes with anti-vimentin antibody. Numerous suppressor/cytotoxic T cells were identified in the glomeruli and widened interstitum. Monocytes/macrophages also infiltrated the glomeruli. The present study suggests that accumulation of extracellular matrix, activation of the complement system, and infiltration of suppressor/cytotoxic T cells and monocytes/macrophages are closely associated with the glomerular obsolescence and the progression of reflux nephropathy.

Adolescent↗
PubMed1992

Surface epithelium related activation of complement differs in Crohn's disease and ulcerative colitis.

IgG1 and activated complement are colocalised on the colonic epithelial brush border in active ulcerative colitis. To investigate whether such deposition is specific for ulcerative colitis, we examined ethanol fixed mucosal specimens from 18 patients with Crohn's colitis and 14 with terminal ileitis by indirect two colour immunofluorescence staining. Monoclonal antibodies to the IgG subclasses and to neoepitopes of activated complement C3b and the terminal complement complex were used in combination with rabbit antiserum to C1q, C4c or cytokeratin. Granular deposition of C3b and terminal complement complex were observed at the luminal face of the surface epithelium in 10 of 18 patients with Crohn's colitis. Specimens from eight of 14 patients with ileal involvement were intensely stained for activated complement (primarily C3b) within the surface mucus layer. No epithelial IgG, C1q or C4c deposition was observed. The results suggest that early and late phase complement activation takes place at the luminal face of the epithelium in Crohn's disease. The absence of colocalised IgG and complement components involved in the classical activation pathway (C1q and C4c), however, suggest that other immunopathological mechanisms (the alternative pathway?) are primarily involved in Crohn's disease in contrast with ulcerative colitis.

Adolescent↗
PubMed2002

Structure and function of complement C5 convertase enzymes.

The multisubunit enzymes of the complement system that cleave C5 have many unusual properties, the most striking of which is that they acquire their specificity for C5 following cleavage of another substrate C3. C5 convertases are assemblies of two proteins C4b and C2a (classical or lectin pathways) or C3b and Bb (alternative pathway) and additional C3b molecules. The catalytic complexes (C4b, C2a or C3b, Bb) are intrinsically unstable ( t (1/2)=1-3 min) and the enzymes are controlled by numerous regulatory proteins that accelerate this natural decay rate. Immediately after assembly, the bi-molecular enzymes preferentially cleave the protein C3 and exhibit poor activity toward C5 (a K (m) of approx. 25 microM and a C5 cleavage rate of 0.3-1 C5/min at V (max)). Efficient C3 activation results in the covalent attachment of C3b to the cell surface and to the enzyme itself, resulting in formation of C3b-C3b and C4b-C3b complexes. Our studies have shown that deposition of C3b alters the specificity of the enzymes of both pathways by changing the K (m) for C5 more than 1000-fold from far above the physiological C5 concentration to far below it. Thus, after processing sufficient C3 at the surface of a microorganism, the enzymes switch to processing C5, which initiates the formation of the cytolytic membrane attack complex of complement.

Animals↗
PubMed1998

Permanent CD8(+) T cell depletion prevents proteinuria in active Heymann nephritis.

Active Heymann nephritis (HN) is a rat model of human idiopathic membranous nephropathy in which injury is thought to be mediated by membrane attack complex of complement (MAC) activated by antibody (Ab) to glomerular epithelial cells. Recent work has shown that HN develops in C6-deficient rats which cannot assemble MAC, and that infiltration of activated cytotoxic CD8(+) T cells and macrophages into glomeruli coincides with proteinuria. This study examined the role of CD8(+) T cells in mediating glomerular injury in HN by permanent CD8(+) cytotoxic T cell depletion via adult thymectomy (ATx) and anti-CD8 mAb. Groups of rats were depleted of CD8(+) T cells either before immunization for HN or 6 wk after immunization when Ab responses and glomerular IgG deposition were well established. These were compared with groups of HN, ATx/HN, and complete Freund's adjuvant (CFA) controls. Neither group of CD8(+) T cell-depleted rats developed proteinuria, although there was normal development and deposition of Ab. CD8(+) T cell-depleted rats developed neither T cell or macrophage infiltrates nor their effector cytokines, which are present in glomeruli of rats with HN. Examination of lymph node (LN) draining sites of immunization showed these findings were not explained by altered immune events within these LNs. It was concluded that CD8(+) cytotoxic T cells are essential to the mediation of glomerular injury in HN and may be relevant to the pathogenesis and treatment of membranous nephropathy.

Animals↗
PubMed1998

Heparin-coated bypass circuits: effects on inflammatory response in pediatric cardiac operations.

BACKGROUND: This study was designed to investigate whether clinical signs of the inflammatory response in pediatric cardiac patients are reduced by heparin-coated cardiopulmonary bypass circuits and how this could be explained by differences in the pathophysiologic mechanisms involved. METHODS: In a randomized, prospective study 19 patients underwent cardiopulmonary bypass either with Carmeda BioActive Surface bypass circuits (n = 9) or with identical noncoated circuits (control, n = 10). Clinical parameters were recorded during the first 48 hours after the start of operation. Blood samples for determination of terminal complement complex, soluble form of E-selectin, and beta-thromboglobulin were obtained perioperatively up to 24 hours after operation. RESULTS: All clinical and inflammatory mediators showed a tendency in favor of the group with heparin-coated circuits. When analyzed on a point-by-point basis there were significant differences in postoperative central body temperature, soluble E-selectin levels, and beta-thromboglobulin levels (all p < 0.05). CONCLUSIONS: These data suggest that the use of heparin-coated cardiopulmonary bypass offers clinical benefit and tends to reduce the release of inflammatory mediators.

Anticoagulants↗
PubMed1994

New insights into mechanisms of immune glomerular injury.

Although glomerular disease remains the most common cause of end-stage renal disease worldwide, major advances have been made recently in understanding the cellular and molecular mechanisms that mediate these disorders. The nephrotic syndrome in noninflammatory lesions such as minimal change or focal sclerosis and membranous nephropathy results from disorders of the glomerular epithelial cell that can be simulated in animal models by antibodies to various epithelial cell membrane epitopes. Clarification of how these antibodies affect epithelial cells to induce a loss of glomerular barrier function should substantially improve understanding of the pathogenesis of minimal change or focal sclerosis. In membranous nephropathy, proteinuria is mediated primarily by the C5b-9 complex through similar mechanisms that also involve glomerular epithelial cells as targets. Inflammatory glomerular lesions are induced by circulating inflammatory cells or proliferating resident glomerular cells. Understanding of how these cells induce tissue injury has also evolved considerably over the past decade. Neutrophil-induced disease involves leukocyte adhesion molecules in regulating neutrophil localization; proteases, oxidants, and myeloperoxidase in mediating injury; and platelets in augmenting these processes. The activated mesangial cell exhibits altered phenotype and proliferation with the release of oxidants and proteases. Mesangial cell proliferation may be initiated by basic fibroblast growth factor and is maintained by an autocrine mechanism involving platelet-derived growth factor. Transforming growth factor beta is important in the subsequent development of sclerosis.

Animals↗
PubMed1993

Cross-linking of CD59 and of other glycosyl phosphatidylinositol-anchored molecules on neutrophils triggers cell activation via tyrosine kinase.

Many membrane proteins are attached via a glycosyl phosphatidylinositol (GPI) anchor. Proteins anchored in this way make no direct contact with the interior of the cell, therefore a role in signaling or activation would seem unlikely. Nevertheless, cross-linking of GPI-anchored proteins on human and murine T lymphocytes has been shown to cause calcium transients and cell activation. Our studies address the non-lethal events caused by the membrane attack complex of complement, which include release of Ca2+ from intracellular stores, and have suggested that the GPI-anchored complement inhibitor CD59 may be involved in signaling these events. We here report that cross-linking of CD59 on human neutrophils using specific monoclonal antibody and second antibody caused a rapid increase in intracellular free Ca2+ concentration (Ca2+ transient) due to release of Ca2+ from stores and also caused neutrophil oxidase activation. All antibodies against CD59 tested were effective and cross-linking of any other GPI-anchored protein expressed on neutrophils also initiated an increase in intracellular free Ca2+ concentration, whereas cross-linking of transmembrane proteins caused little or no response. A tyrosine kinase-dependent activation pathway was indicated by the demonstration of tyrosine phosphorylation on cross-linking and by blocking of the Ca2+ transient with the tyrosine kinase inhibitor herbimycin.

Animals↗