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PubMed1998

Immunization of rabbits with Amblyomma hebraeum nymphal homogenates and implications for the host amplification system.

Immunochemical mechanisms involved in tick rejection by a host are not well documented. The role of serum globulins, and that played by the amplification system's humoral products (thrombin from the coagulation, plasmin from the fibrinolytic, and kallikrein from the kinin systems) in tick-resistant animal hosts have not yet been demonstrated. It is known, however, that factors C1, C3 and C5 of the complement system play a role in tick rejection, and that factors C3a and C5a are anaphylatoxins capable of degranulating leukocytes, thereby releasing pharmacologically active vasoamines which are involved in tick rejection. In this study, levels of kininogen increased by 56% and those of fibrinogen by 19% in rabbits immunized with nymphal antigens. A highly significant (P < 0.001) number of nymphs that fed on the immunized rabbits failed to moult into adult stages. It is reported for the first time, that increased levels of two glycoproteins, fibrinogen and kininogen occurred in rabbits immunized with homogenates of Amblyomma hebraeum ticks. The role played by the amplification system in tick rejection in resistant animals is clarified.

Animals↗
PubMed2006

Complement in lung disease.

Complement proteins play an integral role in both innate and adaptive immune responses of the host. Complement activation leads to the formation of bioactive molecules including the anaphylatoxins, C3a and C5a, and the lytic membrane attack complex (C5b-9). These molecules trigger a series of events that culminate in the recruitment of phagocytic cells, release of cytokines/chemokines and reactive oxygen species, enhanced expression of adhesion molecules and apoptosis at the site of inflammation. Several animal models provide evidence that this series of events forms the basis for the pathophysiology found in many lung diseases, such as asthma and acute respiratory distress syndrome. Clinical data further confirm these findings. This review briefly discusses recent data from such studies.

Animals↗
PubMed2002

Mucosal type mast cells express complement receptor type 2 (CD21).

Fragments of complement component C3 generated upon activation of the cascade play an important role in the induction and regulation of immune responses. Receptors interacting with various fragments of this versatile complement protein are expressed on a wide variety of cell types, including lymphocytes, macrophages, dendritic cells, follicular dendritic cells, granulocytes, erythrocytes and consequently, C3-products may influence several biological functions at different sites of the body, where complement activation occurs. Regarding the expression of various C3-receptors on mast cells, mainly rodent serosal type mastocytes have been investigated so far. It has been known for a long time that C3a triggers the release of mediators of immediate type hypersensitivity via binding to serosal-type cells. Complement receptor type 1 (CR1/CD35) and type 2 (CR2/CD21) interacting with the larger activation products, such as C3b and C3d, have so far been shown on serosal type mast cells only. In this study, the expression of CR1/2 on mucosal type mast cells is demonstrated. Using mouse CR1/2 specific single chain antibodies and the natural ligand C3d in cytofluorimetric measurements, we show that the rat mucosal mast cell line RBL-2H3 and mouse bone marrow-derived mast cells (BMMC) express CD21. RT-PCR experiments carried out with mouse CR1 and CR2 specific primers show CD21, but not CD35 specific products in BMMC. It is also demonstrated that, in contrast to serosal type mast cells, mucosal mastocytes do not express CD19. In an attempt to reveal the possible function of CR2 on mucosal type mast cells, the effect of receptor-clustering was tested regarding degranulation, Ca-response and IL-6 production, but no CR2-mediated change was detected in any of these processes.

Animals↗
PubMed1992

Assessment of complement activation in clinical samples. Comparison of immunochemical and functional measurements of complement components with quantitation of activation fragments.

We have compared functional and immunochemical measurements of complement components with assays measuring the generation of activation fragments, for the assessment of classical pathway activation in vitro and in vivo. The generation of the C3a, C3b/C3bi cleavage fragments of C3, and of the C4d cleavage fragment of C4 measured by ELISA and RIA, was correlated with the decrease in total complement hemolytic activity (CH50) and in functional activity of C3 and C4 in normal human serum in which the classical pathway had been activated with aggregated IgG. The decrease in CH50 in in vitro activated serum was also correlated with the generation of C5a and soluble SC5b-9 complexes. In contrast, no or little increase in the concentration of C3a, C3b/C3bi and C4d was observed in plasma samples from patients with low CH50 and with low levels of immunochemical C3 and C4, indicating that fragment quantitation assays provide no information on the presence and extent of complement activation in vivo. Analysis of samples from patients expressing the four C4 genes and patients having one or two C4 null alleles indicated that a ratio of hemolytic C4 to C2 > or = 1 was indicative of complement activation without C4 deficiency, whereas a ratio below 1 was indicative of C4 deficiency with or without classical pathway consumption. Classical pathway activation and C4 deficiency in clinical samples are best predicted by the concomitant assessment of immunochemical levels of C3 and C4 and hemolytic levels of C4, C2 and C3.

Complement Activation↗
PubMed1998

Compstatin inhibits complement and cellular activation in whole blood in two models of extracorporeal circulation.

Recently, a C3-binding cyclic synthetic peptide (Compstatin) has been identified that binds to complement component C3 and inhibits complement activation. Here we have examined the influence of Compstatin on complement activation and its indirect effects on cellular responses in whole blood in two models for extracorporeal circulation. Compstatin effectively inhibited the generation of C3a and sC5b-9 and the binding of C3/ C3 fragments to the polymer surface. As a result of the inhibition of complement activation, the activation of polymorphonuclear leukocytes (PMNs; as assessed by the expression of CD11b) and the binding of these cells (CD16(+)) to the polymer surface were almost completely lost. In contrast, blood cell counts were not affected. Using surface plasmon resonance technology, we have confirmed that Compstatin exerts its inhibitory effect on complement activation by binding to native C3. These data show that complement activation, leading to activation and binding of PMNs to the biomaterial surface, can be abolished by the addition of Compstatin. The properties of Compstatin make Compstatin a promising drug for use in extracorporeal circuits to avoid bioincompatibility reactions, eg, during cardiopulmonary bypass, but also a favorable precursor peptide for the development of an anticomplement drug for oral use.

Amino Acid Sequence↗
PubMed2003

The inflammatory response to recycled pericardial suction blood and the influence of cell-saving.

OBJECTIVE: To investigate the inflammatory and cellular response attributed to conventional cardiotomy suction vs cell-saver during cardiac surgery. DESIGN: Thirty-three (n = 33) low-risk patients admitted for routine coronary artery bypass grafting were randomly assigned to two groups: cardiotomy suction or cell-saver for salvage of pericardial blood. The groups were compared with reference to proinflammatory cytokines, complement activation, leukocyte pattern, and haemolysis during and after cardiopulmonary bypass. RESULTS: Pericardial suction blood contained significantly increased concentrations of free plasma haemoglobin, C3a, IL-6, IL-8, TNF-alpha, eosinophils and basophils compared with the systemic circulation. No differences were found for the terminal complement complex and lymphocytes, whereas overall concentrations of leukocytes, platelets and haemoglobin were decreased. Recycling of pericardial suction blood gave no systemic effects except from that of free plasma haemoglobin, which increased significantly. The cell-saver eliminated plasma haemoglobin, but no other effects could be demonstrated. CONCLUSION: Cardiotomy suction is a major cause of haemolysis, but contributes insignificantly to the systemic inflammatory response. Treatment of shed mediastinal blood with a cell-saver reduces haemolysis and may lower the dose load of inflammatory components.

Analysis of Variance↗
PubMed1989

Accumulation of hyaluronan (hyaluronic acid) in the lung in adult respiratory distress syndrome.

The concentrations of hyaluronan (HA) were measured in bronchoalveolar lavage (BAL) fluid and serum from 12 patients with adult respiratory distress syndrome (ARDS). The median BAL fluid HA concentration was 353 micrograms/L, about six times higher than that seen in control patients (p less than 0.001). The median serum HA value was 619 micrograms/L, which was a 30-fold increase compared with that in the control patients (p less than 0.001). Another connective tissue component, type III procollagen peptide, was not recovered in significant amounts during lavage in patients with ARDS, but it appeared in the bloodstream in increased concentrations (p less than 0.001). Obtained recovery of HA during lavage of patients with ARDS cannot be explained by an enhanced passive leakage from the bloodstream because of increased alveolar-capillary permeability, but rather could reflect a mobilization of HA from lung interstitial tissue because of hydrostatic mechanisms. Alternatively, the appearance of HA in the alveolar space in ARDS might reflect an enhanced lung synthesis of HA. An increased HA production can possibly be mediated, directly or indirectly, by activated complement components, since a significant relationship was seen between increased plasma concentrations of C3a des Arg and BAL fluid HA (r = 0.61; p less than 0.05). The observed accumulation of HA in the small airways in ARDS may be expected to immobilize water and thereby contribute to the interstitial and alveolar edema. The inverse correlation (r = 0.71; p less than 0.01) seen between BAL fluid HA and pulmonary oxygenation index (PaO2/inspired oxygen fraction) supports such a hypothesis.

Adult↗
PubMed2000

A recombinant soluble chimeric complement inhibitor composed of human CD46 and CD55 reduces acute cardiac tissue injury in models of pig-to-human heart transplantation.

BACKGROUND: Inasmuch as complement plays a critical role in many pathological processes and in xenograft rejection, efficient complement inhibitors are of great interest. Because the membrane-associated complement inhibitors are very effective, recombinant soluble molecules have been generated. METHODS: We tested the efficacy of complement activation blocker-2 (CAB-2), a recombinant soluble chimeric protein derived from human decay accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46), in two models of pig-to-human xenotransplantation in which tissue injury is complement mediated. The in vitro model consisted of porcine aortic endothelial cells and human serum, and the ex vivo model consisted of a porcine heart perfused with human blood. RESULTS: In vitro, addition of CAB-2 to serum inhibited cytotoxicity and the deposition of C4b and iC3b on the endothelial cells. Ex vivo, addition of CAB-2 to human blood prolonged organ survival from 17.3 +/- 6.4 min in controls to 108 +/- 55.6 min with 910 nM (100 microg/ml) CAB-2 and 219.8 +/- 62.7 min with 1820 nM (200 microg/ml) CAB-2. CAB-2 also retarded the onset of increased coronary vascular resistance. The complement activity of the perfusate was reduced by CAB-2, as was the generation of C3a and SC5b-9. The myocardial tissues had similar deposition of IgG, IgM, and Clq; however, CAB-2 reduced the deposition of C3, C4, and C9. Hearts surviving >240 min demonstrated trace to no deposition of C9 and normal histologic architecture. CONCLUSION: These results indicate that CAB-2 can function as an inhibitor of complement activation and markedly reduce tissue injury in models of pig-to-human xenotransplantation and thus may represent a useful therapeutic agent for xenotransplantation and other complement-mediated conditions.

Animals↗
PubMed1989

Peptide analogues of the anaphylatoxin C3a; syntheses and properties.

The chemical syntheses of C-terminally shortened analogues of C3a, which is the best investigated anaphylatoxin and derives from the third component of complement system, is reported. The peptide assembly was performed with the solid-phase technique using a polyamide support and an orthogonal protection strategy. The base-labile Fmoc group was chosen for N alpha protection in combination with acid-labile side-chain protection. Excellent acylation yields could be obtained using HBTU (O-benzotriazolyl-N,N,N',N'-tetramethyluronium hexafluorophosphate) as activating reagent. With this methodology we synthesized eighteen different peptides with the following modifications: Varying the peptide length by sequential addition of glycine or arginine residues, prolongating the N-terminus with the Fmoc- or Fmoc-aminohexanoyl residues and exchanging the glycine in position 74 for alanine or D-alanine. We obtained two C3a analogues, Fmoc-YRAAALALAR and Fmoc-Ahx-YRRGRAAALGLAR, which were shown to be substantially more active than native C3a in the guinea-pig-platelet assay.

Amino Acids↗
PubMedDate not supplied

Comparison of porcine hepatocytes with human hepatoma (C3A) cells for use in a bioartificial liver support system.

Cells from primary porcine hepatocytes (PPH) and the immortalized human hepatoma cell line C3A are both used in bioartificial liver support systems (BALSS). In this work the viability and metabolic capacity of PPH and C3A cells cultured in different media were compared. Also, because the cells come into direct or indirect contact with human blood components in BALSS, the effects of human complement on survival and functions of the cells was evaluated. For short-term culture, maintenance of PPH viability was essential for retention of P450IA1 activity (r = 0.882, p < 0.01) and effective ammonia clearance (r = -0.791, p < 0.01). When cell viability was below 60% P450IA1 activity could not be recorded and nitrogen elimination activity significantly diminished. In contrast to PPH, ammonia levels were markedly increased for C3A cells in all culture media tested (p < 0.01). Ammonia increase correlated with C3A viability (r = 0.896, p < 0.05). PPH metabolic function was superior to that of the C3A cell line when evaluated by P450IA1 activity, ammonia removal, and amino acid metabolism. When PPH were incubated in human plasma (HP) or human serum (HS) there was rapid and irreversible deterioration of viability occurring within 9 h. This toxic effect could be prevented by the inactivation of complement. When sodium citrate dissolved in dextrose was added to medium, there was considerable damage to both PPH and the C3A cell line. However, there was no demonstrable toxic effect when hepatic cells of either type were exposed to heparin. We conclude that PPH cultivated in complement-inactivated HP or HS are to be preferred to C3A for clinical application of BALSS, and that heparin should be preferred for anticoagulation in BALSS.

Amino Acids↗
PubMed2006

Complement component C3 mediates inflammatory injury following focal cerebral ischemia.

The complement cascade has been implicated in ischemia/reperfusion injury, and recent studies have shown that complement inhibition is a promising treatment option for acute stroke. The development of clinically useful therapies has been hindered, however, by insufficient understanding of which complement subcomponents contribute to post-ischemic injury. To address this issue, we subjected mice deficient in selected complement proteins (C1q, C3, C5) to transient focal cerebral ischemia. Of the strains investigated, only C3-/- mice were protected, as demonstrated by 34% reductions in both infarct volume (P<0.01) and neurological deficit score (P<0.05). C3-deficient mice also manifested decreased granulocyte infiltration (P<0.02) and reduced oxidative stress (P<0.05). Finally, administration of a C3a-receptor antagonist resulted in commensurate neurological improvement and stroke volume reduction (P<0.05). Together, these results establish C3 activation as the key constituent in complement-related inflammatory tissue injury following stroke and suggest a C3a anaphylatoxin-mediated mechanism.

Animals↗
PubMed1997

In vitro and in vivo biocompatibility of substituted cellulose and synthetic membranes.

Regenerated cellulosic membranes are held as bioincompatible due to their high complement - and leukopenia - inducing properties. Adherence of polymorphonuclear neutrophils and monocyte purified from normal human blood to the three membranes were evaluated in an in vitro recirculation circuit in the presence or absence of fresh, autologous plasma after recirculation in an in vitro circuit using minimodules with each of the three membranes. In in vivo studies, 9 patients were treated with conventional haemodialysis for 2 weeks with each membrane and 1 week for wash-out using haemodialysers with the following surface: 1.95 m2 for benzyl-cellulose, 1.8 m2 for acetate-cellulose and low-flux polysulfone. Measurement of leukopenia, plasma C3a des Arg and elastase-alpha1 proteinase inhibitor complex levels as well as urea, creatinine, phosphate and uric acid clearances was performed. Plasma-free neutrophils adhered maximally to acetate-cellulose (65% remaining in the circulation), while there was no significant difference between low-flux polysulfone and benzyl-cellulose (80% circulating neutrophils, at 15 min, p<0.001 vs acetate cellulose). In the presence of fresh plasma, as source of complement, the differences between acetate cellulose vs polysulfone and benzyl-cellulose were even more evident, suggesting the role of complement-activated products in neutrophil adherence. A similar trend was observed for monocyte adherence with the three membranes in the absence or presence of plasma. In vivo studies showed that the nadir of leukopenia was at 15 and 30 min with acetate-cellulose (79%) and benzyl-cellulose (50%) (p<0.05 acetate- vs benzyl-cellulose) and at 15 min with polysulfone (24%) (p<0.01 vs acetate- and benzyl-cellulose). Plasma C3a des Arg levels arose to 2037 +/- 120 ng/ml, 1216 + 434 ng/ml and 46 +/- 55 ng/ml with acetate-, benzyl-cellulose and polysulfone, respectively. No pre- vs post-dialysis increase in the intracellular content of TNF-alpha was detected with any of three membranes. Clearance values of urea, creatinine and uric acid were superimposable for all the three membranes. However, benzyl cellulose had a significantly higher clearance for phosphorus (normalized for surface area) (p<0.01 vs acetate-cellulose, 0.001 vs polysulfone). These results implicate that synthetic modification of the cellulose polymer as for the benzyl-cellulose significantly reduces the in vitro adherence, delays the in vivo activation of "classic" biocompatibility parameters and notably improves the removal of inorganic phosphorus.

Aged↗
PubMed1987

Sepsis score and acute-phase protein response as predictors of outcome in septic surgical patients.

In a series of 135 patients with severe surgical infections, we determined the sepsis score and the plasma level of the acute-phase proteins alpha-1-acid glycoprotein, alpha 1-antitrypsin, complement factor B, and C3. The initial sepsis score was a strong determinant of survival: in survivors it was significantly lower than in nonsurvivors. Only 8% of patients with a sepsis score above 20 survived. At the onset of severe sepsis, the plasma levels of all four acute-phase proteins were significantly lower in nonsurvivors. A significant elevation of C3a levels in the plasma of both surviving and nonsurviving patients indicated marked consumption of complement components in all patients with severe sepsis. A linear equation was developed to predict survival: sepsis index of survival (SIS) % = 121 + 0.26 (complement factor B) + 0.36 (alpha-1-acid glycoprotein)-6 (sepsis score). Based on our analysis, at the onset of severe sepsis, an SIS of 50% or more can correctly predict 88% of survivors and an SIS less than 50% can correctly predict 86% of nonsurvivors several days in advance of clinical outcome.

Adult↗
PubMed1992

The apolipoprotein(a) moiety of lipoprotein(a) interacts with the complement activation fragment iC3b but does not functionally affect C3 activation or degradation.

A previous study has shown that complement component C3 binds to recombinant apolipoprotein(a) (r-apo(a)). In the present report we have investigated the interactions between lipoprotein(a) (Lp(a)), r-apo(a) and C3 in relation to complement activation and degradation. Neither Lp(a) nor r-apo(a) affected complement activation as indicated by sheep and rabbit red blood cell hemolytic assays, and by assessment of the amount of C3a generated in zymosan-activated human serum in the presence or absence of Lp(a). Crossed immunoelectrophoretic analyses indicated that Lp(a) retarded the migration of iC3b in complement-activated serum but had no effects on C3, C3b, C3c or C3dg. Recombinant apo(a) exhibited the same properties as intact Lp(a) indicating that it is the apo(a) portion of Lp(a) that mediates this effect and not the lipid moiety. Low density lipoprotein had no effect on the migration of C3 cleavage fragments. Treatment of Lp(a) or apo(a) with neuraminidase abolished their capacity to alter iC3b migration. SDS-PAGE immunoblotting analysis of C3 activation fragments generated in the presence of Lp(a) demonstrated the usual physiologic C3 cleavage fragments. Rocket intermediate gel immunoelectrophoresis of complement-activated serum demonstrated that Lp(a) did not hinder or accelerate the generation of C3c and C3dg breakdown fragments of iC3b. The results indicate that the apo(a) moiety of Lp(a) alters the migration of iC3b in an electric field but does not affect complement activation or degradation of activated C3. The sialic acid residues on apo(a) are necessary for the apo(a)-iC3b interaction.

Apolipoproteins↗
PubMed1975

Complement deposition in glomerular diseases.

Biopsies from 400 patients affected by glomerular diseases, both "primary" and secondary to systemic diseases, have been studied by immunofluorescence. Staining was performed for immunoglobulins fibrogen and C1q, C4, C3 and C3A. C1q, C4 and C3 were positive in a high percentage of cases in focal glomerulosclerosis, membranoproliferative glomerulonephritis, lupus nephritis and essential cryoglobulinaemia glomerulonephritis. C1q and C4 were very rarely present in focal proliferative glomerulonephritis and rheumatoid purpura glomerulonephritis. C3A was found frequently only in acute glomerulonephritis. Results are discussed with reference to their diagnostic value and to information about mechanisms of complement activation.

Complement C1↗
PubMed1997

Complement and neutrophil activation during cardiopulmonary bypass: a randomized comparison of hypothermic and normothermic circulation.

OBJECTIVE: Activation of both complement and neutrophils has been demonstrated to be involved in many pathological reactions following cardiopulmonary bypass (CPB). The aim of the present study is to evaluate the effect of normothermic and hypothermic CPB on both complement and neutrophil activation. METHODS: Two groups of patients (n = 20 each) scheduled for elective coronary artery bypass grafting, underwent CPB with intermittent warm or cold blood cardioplegia. Plasma concentration of C3a, C5a and C5b-9, as well as nitro-blu tetrazolium (NBT) scores of circulating neutrophils were measured before anesthesia, 10 and 30 min after the beginning of CPB, and 8, 16 and 24 h, postoperatively. RESULTS: In both groups, CPB determined a significant complement activation, evidenced as a significant increase in plasma concentration of C3a, C5a and C5b-9. This in turn triggered the neutrophil activation, documented as a significant increase of NTB scores in circulating neutrophils at the end of CPB and in the early postoperative period. Interestingly, in the warm group the extent of both complement and neutrophil activation was significantly higher compared with the cold group during the whole sampling period. CONCLUSION: In conclusion, our study clearly demonstrates that warm CPB is associated with an increased ability to activate complement and neutrophils in patients undergoing coronary surgery.

Adult↗
PubMed1987

[Components of the classical complement pathway in systemic lupus erythematosus].

Measurements of complement components in sera from patients with systemic lupus erythematosus (SLE) and some of their relatives indicated that decreased levels of CH50, C4 and C2 were mostly related to a genetic deficiency at one or both of the loci coding for C4, at least in those patients in whom decreased C4 levels were associated with normal C1 hemolytic activity. C4 deficiency is either isolated or associated with complement activation. In some patients with C4 deficiency, complement activation could only be demonstrated by measuring plasma level of the C3 cleavage fragment, C3a des Arg. Decreased concentration and/or hemolytic activity of C4 and C2 in SLE cannot be used to assess the activity of the disease.

Complement Activation↗
PubMed1980

Analysis of the different types of leukocyte membrane complement receptors and their interaction with the complement system.

The specificity, distribution, and structure of 8 different types of leukocytes membrane complement (C) receptors (CR1, CR2, CR3, and receptors for C1q, beta 1H, C3e, C3a, and C5a) are discussed. Recent data are reviewed on the synthesis of C components by macrophages and B lymphocytes, and how these components may function in the activation of these two cell type by the C system. Commonly used C receptor assay procedures are evaluated in terms of both specificity and sensitivity. Specific assay procedures are recommended for measuring CR1 (C4b-C3b receptor), CR2 (C3d receptor), CR3 (C3bi receptor), and the beta 1H receptor. Assays include both rosette and fluorescence procedures for detection of C receptors on either mouse or human leukocytes. Primary systems have been selected for optimal sensitivity and specificity, and where possible, acceptable alternative systems that are less sensitive or specific are suggested for laboratories lacking facilities for C purification.

Animals↗