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PubMed1983

Hemodialysis leukopenia and complement function with different dialyzers.

The relationship between leukopenia and the complement system during hemodialysis was re-examined by studying not only the in vivo effects of four different dialyzer membranes (cellulose hydrate, cuprophan, cellulose acetate, and polyacrilonitrile) on leukocyte counts and complement levels, but especially by investigating the effects of these membranes on complement function in vitro. Whereas from in vivo studies no definite conclusions could be drawn, in vitro investigations provided clear-cut information. When more sophisticated technical approaches were undertaken, it became evident that hemodialysis leukopenia has to be thought of in terms of chemotactic factor generation. In fact, a strict correlation was demonstrated between the degree of leukopenia induced by the dialyzers tested and the ability of the relative membrane to generate chemotactic activity in vitro. Moreover, the previously observed ability of polyacrilonitrile membrane to induce a decrement in complement function was due to the ability of polyacrilonitrile to adsorb complement activity and did not correspond to effective complement consumption. This finding explained why polyacrilonitrile dialysis is not accompanied by a decrease in circulating granulocytes. Taken together, our data strongly point to a pivotal role of complement system in the pathogenesis of hemodialysis leukopenia.

Acrylic Resins↗
PubMed2005

Immune evasion by a staphylococcal complement inhibitor that acts on C3 convertases.

The complement system is pivotal in host defense but also contributes to tissue injury in several diseases. The assembly of C3 convertases (C4b2a and C3bBb) is a prerequisite for complement activation. The convertases catalyze C3b deposition on activator surfaces. Here we describe the identification of staphylococcal complement inhibitor, an excreted 9.8-kilodalton protein that blocks human complement by specific interaction with C4b2a and C3bBb. Staphylococcal complement inhibitor bound and stabilized C3 convertases, interfering with additional C3b deposition through the classical, lectin and alternative complement pathways. This led to a substantial decrease in phagocytosis and killing of Staphylococcus aureus by human neutrophils. As a highly active and small soluble protein that acts exclusively on surfaces, staphylococcal complement inhibitor may represent a promising anti-inflammatory molecule.

Bacterial Proteins↗
PubMed2001

Complement binding is an early feature of necrotic and a rather late event during apoptotic cell death.

The phagocytosis of dying cells is an integral feature of apoptosis and necrosis. There are many receptors involved in recognition of dying cells, however, the molecular mechanisms of the scavenging process remain elusive. The activation by necrotic cells of complement is well established, however, the importance of complement in the scavenging process of apoptotic cells was just recently described. Here we report that the complement components C3 and C4 immediately bound to necrotic cells. The binding of complement was much higher for lymphocytes compared to granulocytes. In case of apoptotic cell death complement binding was a rather late event, which in lymphocytes was preceded by secondary necrosis. Taken together complement binding is an immediate early feature of necrosis and a rather late event during apoptotic cell death. We conclude that complement may serve as an opsonin for fragments of apoptotic cells that have escaped regular scavenging mechanisms.

Apoptosis↗
PubMed1980

Dimeric, trimeric and tetrameric complexes of immunoglobulin G fix complement.

The binding of pure dimers, trimers and tetramers of randomly cross-linked non-immune rabbit immunoglobulin G to the first component and subcomponent of the complement system, C1 and C1q respectively, was studied. These oligomers possessed open linear structures. All three oligomers fixed complement with decreasing affinity in the order: tetramer, trimer, dimer. Complement fixation by dimeric immunoglobulin exhibited the strongest concentration-dependence. No clear distinction between a non-co-operative and a co-operative binding mechanism could be achieved, although the steepness of the complement-fixation curves for dimers and trimers was better reflected by the co-operative mechanism. Intrinsic binding constants were about 10(6)M-1 for dimers, 10(7)M-1 for trimers and 3 X 10(9)M-1 for tetramers, assuming non-co-operative binding. The data are consistent with a maximum valency of complement component C1 for immunoglobulin G protomers in the range 6-18. The binding of dimers to purified complement subcomponent C1q was demonstrated by sedimentation-velocity ultracentrifugation. Mild reduction of the complexes by dithioerythritol caused the immunoglobulin to revert to the monomeric state (S20,w = 6.2-6.5S) with concomitant loss of complement-fixing ability.

Animals↗
PubMed1982

Complement behavior in infectious mononucleosis: possible mechanisms for the prevention of immune complex injury.

The acute-phase complement reaction was examined in patients with uncomplicated infectious mononucleosis (IM). Concentrations of both complement and complement inhibitor protein were significantly elevated during the acute phase, and turnover studies with purified 125I-labeled C3 showed this increase to result from increased C3 synthesis. Nine of 16 patients had evidence of in vivo complement activation during this period. Despite high levels of C1q-binding immune complexes in most acute-phase sera from patients with IM, the capacity of these sera to solubilize immune precipitates in vitro was normal. In contrast, four of five sera from patients with active systemic lupus erythematosus showed reduced solubilization. The level of C3b inactivator in sera from patients with IM and the percentage conversion of C3 after in vitro complement activation by aggregated IgG were inversely correlated (P less than 0.01). It is proposed that an acute-phase complement reaction limits immune complex-mediated injury to tissue by maintaining those complement functions that are required for the effective processing of circulating antigen/antibody material.

Adolescent↗
PubMed1984

Absolute requirement for complement in monoclonal IgM antibody-mediated protection against experimental infection with type III group B streptococci.

The role of complement in the protective and opsonic activity of monoclonal IgM antibody to type III group B streptococci (GBS) was examined in a neonatal rat model of infection and in vitro with human sera as the complement source. C3 levels in uninfected neonatal rats were less than 50% of those in adult rats, similar to the low complement levels observed in human neonates. The monoclonal type III-specific IgM antibody provided protection to neonatal rats (with unaltered complement levels) that were infected intra-peritoneally or intranasally with type III GBS. In contrast, neonatal rats depleted of complement by administration of cobra venom factor were not protected by IgM antibody. In vitro, classical complement pathway activity was adequate in sera from well, term neonates and GBS-infected neonates in the presence of higher concentrations of the monoclonal IgM antibody. At lower IgM levels, however, the alternative complement pathway was less efficient in both neonatal sera and adult sera.

Adult↗
PubMed1989

Complement activation and endotoxin levels in systemic meningococcal disease.

The activation state of the complement system in 39 consecutively admitted patients with systemic meningococcal disease was studied prospectively using two monoclonal antibodies reacting with neoepitopes exposed during complement activation. The fluid-phase C3 activation products and SC5b-9 (terminal complement complex) were strongly correlated to the levels of endotoxin (lipooligosaccharides, LOS) in plasma on admission (r = .79, P less than .0001 and r = .76, P less than .0001, respectively) and to fatality. Maximum complement activation in survivors occurred 7h (median; range 0-44 h) after initiation of antibiotic treatment. The most severely ill patients had the capacity to activate the whole complement cascade. In nonsurvivors, high-grade activation often continued until the patients died. The results suggest that LOS are important activators of complement in systemic meningococcal disease and that complement-activating products, in concert with other mediators, may contribute to the multiple organ failure and death occurring in the most severe cases.

Complement Activation↗
PubMed1992

The role of complement in the host's defense against Haemophilus influenzae.

In vitro studies have shown that Haemophilus influenzae type b (Hib) can activate both the classical and alternative pathways of complement and generate complement-dependent opsonic and bactericidal activities. In vivo studies and observations in complement-deficient patients have established the biologic significance of complement in the host's defense against H. influenzae. The complement system plays a significant role in the host's defense against Hib and against other encapsulated and unencapsulated H. influenzae, mainly by enhancing clearance from the bloodstream through its action as an opsonin in both nonimmune and immune hosts. Patients with genetically determined deficiencies of C3 or of the complement components involved in C3 activation have an increased susceptibility to H. influenzae. More recently, a relatively common deficiency of one isotype of C4 (C4B) has been shown to be associated with invasive Hib disease, suggesting that defects in complement-mediated host defense may be more common in systemic Hib infections than previously appreciated.

Animals↗
PubMed1998

The role of the complement cascade in sepsis.

Complement provides a critical and multifaceted defence system against infection. Following activation, complement can clear invading microorganisms by lysis or by opsonization, which promotes recognition by complement receptors on phagocytes. Complement activation products promote a local inflammatory response and are involved in the modulation of adaptive immune responses that lead to antibody production. The host has developed regulatory mechanisms for controlling complement activation and for protecting its own cells against complement attack. Some microorganisms have also evolved ways to avoid the opsonic and lytic action of complement.

Complement Activation↗
PubMed1990

Complement-mediated enhancement of HIV-1 infection of the monoblastoid cell line U937.

To assess the role of complement and complement receptors in HIV-1 infection of monocytes and macrophages, we studied the infectivity of HIV-1, isolated from the peripheral blood of a patient with subacute AIDS-related encephalopathy, on the human monoblastoid cell line U937. HIV-1 and HIV-1-infected cells were capable of activating the complement system via the classical and the alternative pathways, respectively. Low concentrations of HIV-1 were able to infect U937 cells more easily in the presence than in the absence of complement. At higher virus concentrations, infectivity was no longer facilitated by the presence of complement. Infection of U937 cells was reduced in the presence of any of the monoclonal antibodies (MAbs), OKT4a (anti-CD4), OKM1 (anti-CR3), or M522 (anti-CR3). A combination of all three of these MAbs reduced the infection by an even greater amount. These data indicate that complement receptors may be a port of entry for complement-coated HIV-1.

AIDS Dementia Complex↗
PubMedDate not supplied

Mechanism of complement activation during extracorporeal blood-biomaterial interaction: effects of heparin coated and uncoated surfaces.

In vitro studies with miniaturized rotating circuits and heparinized human blood, as well as long-term extracorporeal membrane oxygenation with either heparin coated (HBS) or uncoated surfaces connected to adult sheep, were performed comparing the impact on complement activation in blood and on surfaces. Analysis of surface bound complement proteins revealed significantly reduced binding of activated C3 and C5b-9 to HBS in vitro, compared with uncoated surfaces, which was probably due to more HBS bound complement inhibitors (C1-Inhibitor, factor H) being present. This was reflected by significantly reduced activation of the alternative pathway (C3bBbP) and terminal complex (SC5b-9) by HBS but slightly increased levels of classic pathway complex (C1rs-C1-inhibitor). These results were confirmed during in vivo study by analysis of hemolytic complement function, activation specific C3 derived split products, and surface bound complement proteins. Increased binding of complement regulators to HBS appears to effectively reduce complement activation by biomaterials, leading to improved long-term biocompatibility.

Animals↗
PubMed1982

Antibody-independent binding of Clq and activation of serum complement by human skin in vitro.

By exposing frozen sections of human skin to fresh normal human serum, binding and activation of complement was observed. Attached complement components Clq, C4, and C3 were detected by immunofluorescence microscopy using anticomplement conjugates. Isolated Clq bound to the same structures as serum Clq, C4, and C3 and binding of C4 and C3 was dependent on binding of Clq. The complement components bound to capillary endothelial cells and to fibrillar structures in the dermis and reacted with the epidermis. Complement binding dermal fibrillar structures in adult skin were scant but abundant in fetal skin. They had similar distribution as "microfibrils" demonstrable by human autoantibodies. Antibody independence of the Clq binding was shown using isolated Clq and by the observed constant and reproducible binding of complement of normal sera lacking antibodies to the described target structures. The observations suggest that antibody independent binding of complement should be considered as a possible mechanism leading to dermal complement deposition in vivo.

Adult↗
PubMed1983

Role of the capsule and the O antigen in resistance of O18:K1 Escherichia coli to complement-mediated killing.

Epidemiological data show that O18:K1 Escherichia coli is a common cause of neonatal bacteremia and meningitis. These bacteria were capable of multiplying in the bloodstream of newborn rats and were resistant to the bactericidal effects of complement in the absence of specific antibodies. The roles played by the O antigen and the K antigen in complement resistance were analyzed by comparing the bactericidal effects of normal sera and of sera deficient in various complement components or in immunoglobulins. These sera were tested on O18:K1 bacteria and on mutants lacking either the lipopolysaccharide O antigen or the K1 capsular polysaccharide. In addition, O1:K1 cells, which can cause pyelonephritis but which are rare in newborn meningitis and which do not multiply in the bloodstream of newborn rats, were also examined. Different mechanisms of protection against the alternative and classical pathways were recognized: K1-positive cells were resistant to the bactericidal activity of sera deficient in classical complement pathway components, whereas K1-negative cells were sensitive to these sera. Based on these results and on those from complement fixation assays, the K1 sialic acid polysaccharide impedes the activation of, and thus protects the bacteria against, the alternative complement pathway. Not only the K1-negative mutant cells but also O1:K1 bacteria and mutants lacking the O18 oligosaccharide repeating units of the lipopolysaccharide were sensitive to the classical complement pathway. These bactericidal effects were observed even in the absence of specific antibodies. It is proposed that both the K1 capsule and the O18 oligosaccharide restrict antibody-independent classical pathway activation by shielding deeper structures on the cell membrane that are capable of activating this pathway.

Animals↗
PubMed2002

Deficiency of complement-dependent prevention of immune precipitation in systemic sclerosis.

BACKGROUND: Previous studies have indicated that complement may be activated or inherently abnormal in systemic sclerosis (SSc), and it has been suggested that immune complex deposition plays a part in the microvascular damage of this disease. OBJECTIVE: To study several aspects of the complement system in 24 patients with SSc. METHODS: Complement dependent prevention of immune precipitation (PIP) was measured by a sensitive enzyme immunoassay, levels of C1q, C4, and C3 by rocket immunoelectrophoresis, C4 allotypes by high voltage agarose electrophoresis, and C4A, C4B, and C3d by an enzyme linked immunosorbent assay (ELISA). RESULTS: PIP was markedly decreased in the patients with SSc (p<0.001). Abnormal complement activation was detected in nine patients as raised levels of the complement split product C3d. However, a relation between low PIP and complement activation was not seen. PIP was significantly lower in patients who carried the C4A*Q0 allotype (p=0.03), and a strong correlation was found between PIP and C4A concentration (p<0.00001). The PIP defect may, at least in some patients, be associated with the initial phase of the disease. CONCLUSIONS: The results show a previously unrecognised functional defect of complement in SSc; the defect correlates with low levels of classical pathway components and, in particular, C4A.

Adolescent↗
PubMed2003

Inhibition of complement activation decreases airway inflammation and hyperresponsiveness.

Studies in murine models have suggested the involvement of the complement anaphylatoxins (C3a and C5a) in the development of allergic asthma. We investigated the effects of inhibiting complement activation after sensitization but before allergen challenge on the development of allergic airway inflammation and airway hyperresponsiveness. To prevent complement activation, we used a recombinant soluble form of the mouse membrane complement inhibitor complement receptor-related gene y (Crry) fused to the IgG1 hinge, CH2 and CH3 domains (Crry-Ig), which has decay-accelerating activity for both the classic and alternative pathways of complement as well as cofactor activity for factor I-mediated cleavage of C3b and C4b. C57BL/6 mice were sensitized (Days 1 and 14) and challenged (Days 24-26) with ovalbumin. Crry-Ig was administered after allergen sensitization either as an intraperitoneal injection or by nebulization before allergen challenge. Crry-Ig significantly prevented the development of airway hyperresponsiveness, decreased airway and lung eosinophilia as well as the numbers of lung lymphocytes, decreased levels of interleukin (IL)-4, IL-5, and IL-13 in bronchoalveolar lavage fluid and decreased serum ovalbumin-specific IgE and IgG1. These results suggest that prevention of complement activation may have a therapeutic role in the treatment of allergic airway inflammation and asthma in sensitized individuals.

Animals↗
PubMed2005

Opportunities for new therapies based on the natural regulators of complement activation.

While the complement system is an essential component of immunity, shutting down all or part of it could be beneficial in a wide range of clinical situations. Designer, small-molecule, protease inhibitors and antagonists of protein-protein interactions are under development, while an approach based on a humanized monoclonal antibody to the C5 component works effectively against the later stages of complement activation and is close to completing clinical trials. The cobra venom factor depletes plasma of essential complement components, and a humanized (nonimmunogenic) version is being sought. Perhaps the most promising approach to comprehensive complement downregulation, however, is the exploitation of innate regulators of complement activation, with two products in clinical trials. The potential for more efficacious complement blockers of this kind is growing because of better targeting, but a deeper knowledge at the atomic level of mechanisms of action of these regulators is needed to underpin a rational approach to design of still more potent complement inhibitors.

Complement Activation↗
PubMed1983

Serial changes of complement titers in the acute phase of myocardial infarction.

Although some studies suggest the involvement of a complement activation in the development of acute myocardial infarction, there has been little convincing evidence of the change of the complement in patients suffering from myocardial infarction. In 11 patients with acute myocardial infarction the serial changes of the total hemolytic complement titer (CH50), C3, C4, total serum protein and C3 conversion were investigated up to 120 hours after its attack. The level of CH50 and C4 increased consistently in the acute phase of myocardial infarction, but C3 did not show any change and total serum protein declined after 96 hours. Beta 1 A globulin, the split product of C3, could not be detected in the blood stream. These results suggest that the infarcted or ischemic myocardium would activate complements, and C3 might be consumed continuously by the infarcted or ischemic myocardium. Such consumption of complements should stimulate the production of complement and would give rise of an increase in C4 and CH50. It is suggested that activated complement might play a significant role in the development of myocardial infarction.

Adult↗
PubMed1987

Biological effects of short-term, high-concentration exposure to methyl isocyanate. VI. In vitro and in vivo complement activation studies.

The ability of MIC to induce complement activation in vitro and in vivo was investigated. For the in vitro studies, both human and guinea pig serum or EDTA-plasma samples were exposed to 1167 to 1260 ppm MIC vapor for 15 min at room temperature. The human serum samples exposed to MIC showed significant reductions in Factor B, C2, C4, C3, C5, and total hemolytic complement CH50 activity levels. C6 functional activity was unaffected. The C3, C5, and CH50 functional activities in guinea pig serum (the only functional tests conducted on these samples) were more sensitive to MIC-mediated reduction than the corresponding activity reductions observed in the human serum samples. The human and single guinea pig EDTA-plasma samples exposed to MIC vapor showed no evidence of C3 consumption but did show significant reductions in CH50 levels. Thus, MIC vapor was able to activate, and thereby reduce serum complement C3 activity in vitro by a complement-dependent process. However, the data suggest at least one complement component other than C3 was inactivated in EDTA-plasma by a complement-independent mechanism. For the in vivo studies, five pairs of guinea pigs were exposed to 644 to 702 ppm MIC vapor until one of the pair died (11-15 min). MIC exposure was then discontinued, the surviving guinea pig was sacrificed, and EDTA-plasma was obtained from both animals and analyzed for complement consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗