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PubMed1999

Complement depletion does not reduce brain injury in a rabbit model of thromboembolic stroke.

The contribution of the complement system to cerebral ischemic and ischemia/reperfusion injury was examined in a rabbit model of thromboembolic stroke by delivery of an autologous clot embolus to the intracranial circulation via the internal carotid artery. A two-by-two factorial design was employed to study the impact of complement depletion via pretreatment with cobra venom factor (CVF, 100 U/kg i.v.) in the setting of permanent (without tissue plasminogen activator; t-PA) and transient (with t-PA) cerebral ischemia. Thirty-two New Zealand white rabbits were assigned to one of four groups (n=8, each group): control without t-PA, control with t-PA, CVF without t-PA and CVF with t-PA. In the complement intact animals, t-PA administration resulted in an approximate 30% reduction in infarct size when compared to the group not receiving t-PA (20.4+/-6.6% of hemisphere area vs. 30.1+/-7.2%; mean+/-SEM). However, infarct sizes in the complement depleted rabbits, with (30.7+/-8.2%) or without (30.2+/-7.9%) t-PA, were no different from the control group receiving no therapy. Similarly, no difference in regional cerebral blood flow or final intracranial pressure values was noted between any of the four groups. Complement activation does not appear to be a primary contributor to brain injury in acute thromboembolic stroke.

Animals↗
PubMed1976

C3 metabolism in a patient with deficiency of the second component of complement (C2) and discoid lupus erythematosus.

A patient with a hereditary deficiency of the second component of complement and discoid lupus erythematosus with features of systemic lupus erythematosus was studied. The propositus had a 9-year history of rash and arthralgia. Transient renal disease had completely resolved; there was a history of seizures. Examination of his serum disclosed antinuclear antibodies but no total haemolytic complement activity. C2 was absent. Serum concentrations of C1s, C3, C5 and C9 were elevated; other complement components were present in normal concentration, including C3 pro-activator. The patient's C3 pro-activator was electrophoretically converted by inulin and four of five lipopolysaccharides, but was poorly converted by aggregated human IgG. Two separate turnover studies with radiolabelled C3 showed fractional catabolic rates of 3-03 and 2-48% of the remaining plasma pool/hr (range of three normals: 1-62-2-18%/hr); and estimated C3 synthetic rates of 2-74 and 2-31 mg/kg/hr (range of three normals: 0-89-1-40 mg/kg/hr). Serum complement profiles of the patient's family demonstrated that the C2 deficiency was inherited as an autosomal codominant. One sibling, homozygous for C2 deficiency, and three other siblings, both parents and one daughter, all heterozygous for C2 deficiency, are in good health. Immunofluorescent studies of the patient's diseased skin exhibited substantial deposits of IgG, IgM, C1q, and C4 but not of later acting complement components, properdin, or C3 proactivator. These studies do not support the notion that inflammation in C3-deficient individuals with lupus erythematosus is mediated by the alternative complement pathway.

Adult↗
PubMed1984

Evidence for restriction of the ability of complement to lyse homologous erythrocytes.

This research explored the possibility that a mechanism for the inhibition of C exists that is capable of restricting lysis of antibody-sensitized homologous E. The ability of C to lyse E from six species was compared by using a passive lysis system that employed E coated with B. abortus LPS and bovine antibodies specific for B. abortus. A system was developed that permitted comparisons of the hemolytic efficiencies of heterologous and homologous C target cell combinations. C from all of the species tested lysed heterologous E effectively, but homologous E were poorly lysed. Furthermore, a serum factor appeared to be involved with restriction of lysis of homologous E:LPS:Ab by heterologous C, and the restriction was specific for homologous E. Human E:LPS:Ab that were washed after incubation with CH were resistant to subsequent lysis by heterologous C. This restriction did not occur at 0 degrees C or in the absence of antibodies. Incubation of homologous C with EH:LPS:Ab resulted in consumption of C1, C2, C3, and C4, but not C5. The treated CH would lyse sheep EAC1423, but it would not lyse sheep EA, EACI, or EAC142. Late reacting C components (C5 through C9) were not detectable on EH:LPS:Ab after incubation with CH, but C4 and C3 were bound to the cells. Rat late-reacting C components (rat C-EDTA) were capable of detecting C3 convertase sites on EH:LPS:Ab that had been reacted with CH. However, homologous late-reacting components and guinea pig late-reacting components were unable to detect the C3 convertase sites.

Animals↗
PubMed1997

C1 esterase inhibitor concentrate for capillary leakage syndrome following bone marrow transplantation.

The prognosis of patients with severe capillary leakage syndrome (CLS) after bone marrow transplantation (BMT) is dismal despite aggressive use of intensive care therapy. Because the activated classical pathway of complement and relatively low levels of C1 esterase inhibitor (C1 INH) activity are known features in these patients, we evaluated the efficacy of a therapy using purified, human C1 INH concentrate. Severe CLS was defined as increase in body weight by more than 3% within 24 h combined with generalized edema, impaired hemodynamic system (tachycardia and/or decreased blood pressure), and non-responsiveness to furosemide. Of 142 patients, 22 developed severe CLS. The first seven patients whom we diagnosed with this complication were assessed as control patients. Fifteen patients with severe CLS were treated with C1 INH concentrate using a cumulative dose of 180 units/kg body wt. (initial dose: 60 units/kg, followed by two doses at 30 units/kg and four doses at 15 units/kg, every 12 h). The survival rate of patients with CLS was 57% at 1 year after BMT in the C1 INH treatment group, compared with 14% in the control group (p = 0.008). Eight of 15 treated patients are alive at a median of 9 months (range: 4-55) after BMT. The plasma levels of the complement activation parameters C4d and C5a were 3 +/- 1.1 mg/dl (mean +/- S.D.) and 0.3 +/- 0.1 microgram/l, respectively, prior to BMT, increasing to 8.2 +/- 2.1 mg/dl and 1.3 +/- 0.4 micrograms/l, respectively, at diagnosis of CLS. After infusion of C1 INH concentrate the plasma levels of C5a and C4d normalized. The activity of C1 INH rose to 139 +/- 10% of normal human plasma NHP pool (mean +/- S.D.) after infusion. The CH50 values were not significantly altered. The fluid status normalized within 11 days in 14 of 15 treated patients. The results of this study suggest that therapy with C1 INH concentrate improves the prognosis of patients with CLS after BMT. This has to be confirmed in a randomized, controlled trial.

Adolescent↗
PubMed2000

Complement-mediated killing of mesangial cells in experimental glomerulonephritis: cell death by a combination of apoptosis and necrosis.

Immune system mediated, particularly antibody- and complement-mediated, glomerular injury triggers glomerulonephritis (GN). To characterize complement-mediated cytotoxicity in GN, we assessed the process of mesangial cell death induced by C5b-9 attack in Thy-1 GN. Cell injury was recognized morphologically, and nuclear DNA breaks were confirmed by the DNA nick end labeling (TUNEL) method as well as DNA gel electrophoresis. Thy-1 GN was induced in rats with anti-Thy-1.1 antibody injection. Mouse IgG (administered antibody) and rat C3 were detected in all glomeruli within 5 min after antibody injection. Damaged mesangial cells with condensed as well as TUNEL-positive nuclei could be observed at 20 min and became prominent at 40-60 min. Ultrastructurally, damaged mesangial cells contained condensed apoptotic nuclei from 40 to 60 min, whereas the cytoplasm showed necrotic degeneration. This was followed by progressive lysis of both nuclei and cytoplasm. The DNA 'ladder' pattern was observed by gel electrophoresis of extracted DNA between 40 and 60 min and correlated with the increased number of TUNEL-positive damaged mesangial cells. To examine the role of complement in this form of cell death, complement depletion was induced in rats by cobra venom factor. Complement-depleted rats showed no rat C3 deposition, rare TUNEL-positive mesangial cells, rare ultrastructural degenerated mesangial cells with apoptotic nuclei and necrotic cytoplasm, and no DNA 'ladder' pattern on gel electrophoresis at 40 min, although prominent mouse IgG was seen in glomeruli. To analyze milder forms of complement injury, a low dose of the antibody was administered to rats with a normal complement level. A few TUNEL-positive mesangial cells were detected in the glomeruli which contained apoptotic nuclei and necrotic cytoplasm. Our results indicate that an apoptotic death mechanism accompanies cell necrosis in complement-mediated mesangial cell destruction in GN and that this unusual form of cell death may represent a combination of apoptosis-necrosis within the same cell. Complement injury activates a 'death program' which in turn leads to irreversible damage of mesangial cells and which may contribute to initiation and development of GN.

Animals↗
PubMed2001

Gene transfer of the Bcl-2 gene confers cytoprotection to isolated adult porcine pancreatic islets exposed to xenoreactive antibodies and complement.

BACKGROUND: Exposing adult porcine pancreatic islets (PI) to xenoreactive natural antibodies (XNA) induces brisk inflammatory injury that involves activation of the complement system. Gene transfer of Bcl-2 has been shown to protect PI from apoptosis and necrosis in several models. In this study, we investigated the effect of Bcl-2 gene transfer on protection of PI from primate XNA and complement-mediated injury. METHODS: The PI were isolated from adult female sows. Only islet preparations that exhibited >90% viability and purity were used. Fresh rhesus monkey serum served as the XNA source. Gene transfer of Bcl-2 was achieved with an adenoviral vector (AdBcl-2) at 500 particle forming units (pfu)/cell. The Bcl-2 expression was confirmed by Western blot technique. Untransfected and transfected PI were incubated in 50% fresh complete serum (CS) or heat-inactivated (HI) rhesus serum for 24 hours. The PI viability was analyzed with acridine orange and ethidium bromide staining. Antibody and complement-mediated cytotoxicity were tested by intracellular lactate dehydrogenase (LDH) release. The PI function was assessed in vitro by static incubation studies and in vivo after intraportal transplantation in diabetic severe combined immunodeficiency (SCID) mice. RESULTS: The AdBcl-2 gene transfer resulted in Bcl-2 gene expression in >90% of PI cells. Following exposure to XNA, <15% of the untransfected cells were viable. Similar results were obtained in PI transfected with a similar recombinant adenovirus encoding the reporter gene E coli beta-galactosidase (AdLacZ), an irrelevant gene. A significant increase in LDH release was observed in control PI after exposure to CS compared with PI that overexpressed Bcl-2 (82.89% +/- 7.78% vs 34.31% +/- 5.4%, P <.005). Higher insulin release was observed in vitro in PI transfected with Bcl-2 compared with untransfected PI or islets transfected with AdLacZ (stimulation index of 0.9 +/- 0.31, 0.9 +/- 0.3 vs 2.67 +/- 0.4, respectively). Only PI treated with AdBcl-2 were able to achieve euglycemia after exposure to XNA and complement after transplantation. CONCLUSIONS: Transfer of the antiapoptotic and antinecrotic Bcl-2 gene into PI can reduce primate XNA and complement-mediated lysis. Cytoprotection of PI with Bcl-2 has potential to improve survival of PI xenotransplants.

Adenoviridae↗
PubMedDate not supplied

Thermal response to zymosan: the differential role of complement.

OBJECTIVES: This study was designed to determine whether the complement (C) system may be involved in the febrile response to zymosan (Zym), a glycan derived from yeast cell walls. METHODS: Cobra venom factor (CVF) at 100 U/animal or its vehicle, pyrogen-free saline (PFS), was injected intravenously (i.v.) into guinea pigs to deplete serum C. Eighteen hours later, a low or high dose of Zym or its vehicle, PFS, was administered i.v. or intraperitoneally (i.p.) to these animals. The core temperature (T(c)) was measured continuously by thermocouples. Serum C levels were determined by sheep erythrocyte hemolytic assay. RESULTS: Zym at 1 mg/kg caused a 1 degrees C T(c) rise that was not significantly affected by CVF pretreatment. However, CVF-induced hypocomplementation converted the T(c) fall ( approximately 1.2 degrees C) produced by 100 mg/kg of Zym i.p. into a 1 degrees C T(c) rise. Similarly, CVF pretreatment did not affect the T(c) rise caused by 0.5 mg/kg of Zym i.v., but converted the T(c) fall induced by 25 mg/kg i.v. into a 1 degrees C T(c) rise. A separate experiment showed that 25, but not 0.5 mg/kg of Zym i.v., decreased serum C by 34% in 15 min; C did not recover over the next 6 h. A second i.v. injection of 25 mg Zym/kg 210 min later, when the T(c) had recovered but the serum C had not, yielded a smaller and briefer T(c) fall. CONCLUSION: These results suggest that Zym is inherently pyrogenic, but this effect is manifested only when the dose of zymosan is too small to activate C or when C has been reduced by prior activation.

Animals↗
PubMed1975

The complement system in cryoglobulinaemia. Interaction with immunoglobulins and lipoproteins.

Serum from a patient with an IgM-lipoprotein cryoglobulin, both before and after removal of the cryoprecipitate at 0 degrees C, had extremely low levels of whole complement (C), C1, C4 and C2, while amounts of the remaining components were normal or only slightly reduced. The cryopredipitate, when added to fresh normal human serum, reproduced this pattern of C fixation. Separation of the patients's serum at 37 degrees C into its lipoprotein, IgG and IgM fractions revealed that the IgM alone would precipitate at 0 degrees C. This precipitation was unaffected by the patients's IgG, but was markedly enhanced by extremely small amounts of the patient's d less than 1-075 lipoprotein fraction or of homologous very low density lipoprotein (VLDL). Aggregation occurred even at 37 degrees C in the presence of VLDL. Fixation of semi-purified human C1 paralleled these results closely: it occurred with the patient's IgM alone at 0 degrees but not at 37 degrees C, while IgM in the presence of the patient's lipoprotein, or of VLDL from normal serum, fixed C1 strongly at 37 degrees as well as at 0 degrees C. Fab dimers and monomers prepared from the patient's IgM did not aggregate in the cold, even in the presence of lipoprotein, and did not inhibit the aggregation of intact IgM in the presence of VLDL, at any temperature. All three highly purified IgM cryoglobulins, and three of four IgG cryoglobulins, fixed C1 strongly. The IgG preparation which failed to fix C1 was the only one which had lost its cryoprecipitability during purification. Measurement of C3 or whole C levels may be an insensitive method for detecting C fixation in cryoglobulinaemia. It is suggested that analysis for C1, C4 or C2 should be employed instead.

Aged↗
PubMed2003

Ischaemia-reperfusion is an event triggered by immune complexes and complement.

BACKGROUND: Reperfusion injury is a common clinical problem that lacks effective therapy. Two decades of research implicating oxygen free radicals and neutrophils has not led to a single successful clinical trial. METHODS: The aim was to review new clinical and preclinical data pertaining to the alleviation of reperfusion injury. A review of the literature was undertaken by searching the MEDLINE database for the period 1966-2003 without language restrictions. RESULTS AND CONCLUSION: Evidence now points to complement and immune complexes as critical players in mediating reperfusion injury. Ischaemia is postulated to induce a phenotypical cellular change through the surface expression of a neoantigen. Preformed circulating natural IgM antibodies are then trapped and complement is activated. Final events leading to reperfusion injury include formation of the membrane attack complex and mast cell degranulation.

Antigen-Antibody Complex↗
PubMed1976

A plaque assay for all cells secreting Ig of a given type or class.

A modification of the hemolytic plaque assay using protein A-coated red cells is described which makes use of the fact that the Fc portion of IgG binds to protein A. A number of murine plasmacytomas secreting different classes of Ig have been tested for plaque formation with these indicator red cells. In the presence of complement-binding antibodies specific for the corresponding class of secreted Ig, between 10 and 70% of all plated myeloma cells formed plaques. The assay shows a prozone effect in excess of antibody, suggesting that complexes of antibody and secreted Ig effect lysis of the target cells. This assay can be used to enumerate cells secreting any molecules for which complement-binding antibodies are available.

Bacterial Proteins↗
PubMed1989

Absence of homologous restriction factor does not affect CTL-mediated cytolysis.

Homologous restriction factor (HRF) is a membrane protein of erythrocytes and leukocytes that inhibits the complement (C5b-9)-mediated lysis in a species-restricting manner. HRF has also been reported to inhibit perforin-mediated cytolysis and postulated to play a role in cytotoxic T lymphocyte (CTL) self-protection. We show that paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes, lacking HRF, are no more sensitive to Ca2+-dependent human CTL-mediated lysis than normal erythrocytes. Furthermore, mouse and normal human erythrocytes, as well as PNH erythrocytes, are similarly lysed by isolated murine perforin-containing granules. We conclude that HRF does not inhibit perforin-mediated lysis and therefore is not likely to play a role in CTL self-protection.

Blood Proteins↗
PubMed1992

Relative roles of decay-accelerating factor, membrane cofactor protein, and CD59 in the protection of human endothelial cells against complement-mediated lysis.

Human umbilical vein endothelial cells (HUVEC) were found by Western blot analysis to express three membrane-bound C regulatory proteins, decay-accelerating factor (DAF), membrane cofactor protein (MCP) and CD59. DAF was detected on sodium dodecyl sulfate-polyacrylamide gel electrophoresis as a 70-kDa molecule under nonreducing conditions in 2% deoxycholate extracts of HUVEC, MCP as a 63-kDa protein and CD59 as a 20-kDa molecule. Northern blot analysis revealed the presence of two species of mRNA expressed in HUVEC, which hybridized to a cDNA probe specific for DAF, with sizes of about 2.0 kb and 2.7 kb. MCP mRNA was detected at 4.2 kb and a CD59 cDNA probe hybridized with three mRNA species with sizes of about 800, 1400 and 2000 bp. DAF and CD59 were released from the surface of HUVEC by phosphatidylinositol-phospholipase C, demonstrating that both are attached to the cell membrane by means of a glycolipid anchor. The relative contribution of DAF, MCP and CD59 in regulating the sensitivity to lysis of HUVEC by autologous complement was determined by incubation of sensitized endothelial cells with F(ab')2 fragments of polyclonal antibodies raised against these proteins. The susceptibility of sensitized cells to lysis by homologous complement was markedly increased in the presence of F(ab')2 anti-CD59 and to a lesser, but significant, extent in the presence of F(ab')2 anti-DAF. F(ab')2 anti-MCP did not significantly alter the susceptibility of HUVEC to complement-mediated lysis.

Antigens, CD↗
PubMed1995

Decay-accelerating factor (CD55) protects human immunodeficiency virus type 1 from inactivation by human complement.

HIV-1, in contrast to animal retroviruses, is not lysed by human complement, but is readily inactivated by the sera from different animal species. To identify a possible species-specific protection mechanism. HIV-1 was expressed in cells of non-human origin. Recombinant HIV-1 virions that could encode the chloramphenicol acetyltransferase (CAT) protein were produced in African green monkey COS-1 cells, mink cells and, as a control, in human HEp-2 cells and were then used to infect CD4-positive target cells. Analysis of the CAT activity of the target cells revealed that fresh HIV-1-negative human serum reduced the infectivity of HIV-1 derived from monkey and mink cells five- to tenfold, but had no effect on HIV-1 produced in human cells. In addition, human serum efficiently lysed HIV-1 produced in non-human cells in contrast to HIV-1 originating from human cells, suggesting lysis as an important mechanism of virus inactivation. Mammalian cells are protected against lysis by homologous complement by membrane-bound regulatory molecules. Two of these complement inhibitors, namely decay-accelerating factor (DAF) and, to a lesser extent, CD59 were found on the surface of HIV-1 virions by means of a virus capture assay. Antibodies against DAF, but not against other host cell molecules found on the viral surface, efficiently blocked the resistance of HIV-1 produced in human cells to human complement. These results suggest that the acquisition of DAF during the budding process from human cells protects HIV-1 in a species-specific way against the attack of human complement.

Animals↗