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PubMed1975

Studies on rat complement. II. Complement level in experimental tumor in rats.

In the course of methylcholanthrene induced carcinogenesis in rats, CIA50, C4 and C3 increased as compared with control and correlation of tumor size with increase in CIA50, C4 and C3 was observed. In the course of dimethylaminoazobenzen carcinogenesis of rats, complement level and C3 level decreased but in splenectomized rats fed by dimethylaminoazobenzen showed elevated level of complement system. After Corynebacterium infection, CIA50 and C3 of rats increased. This phenomenon is considered to be one of the essential factors to induce high resistance against tumor inoculation.

Animals↗

PubMed1991

Complement activation and bioincompatibility. The terminal complement complex for evaluation and surface modification with heparin for improvement of biomaterials.

The degree of biocompatibility of biomaterials can be evaluated using various assay systems detecting activation of the blood cascade systems, leukocytes or platelets. Activation of complement is one mechanism associated with adverse effects observed when bioincompatible materials are used. We present data showing that the terminal complement complex, an indicator of terminal pathway activation, is suitable for evaluation of biocompatibility of biomaterials such as cardiopulmonary bypass devices. Furthermore, our results suggest that bioincompatibility is improved when artificial surfaces are modified with end point attached functionally active heparin.

Complement Activation↗

PubMed1988

Opsonin-dependent and independent surface phagocytosis of S. aureus proceeds independently of complement and complement receptors.

We examined the mechanism of surface phagocytosis of Staphylococcus aureus by human polymorphonuclear leucocytes (PMN). Surface phagocytosis of unopsonized bacteria occurred, but was significantly enhanced by the presence of serum. The serum requirement was low, and a maximal effect occurred with serum concentrations of 0.25-0.5%. The opsonic effect of serum was not removed by heat inactivation of complement but was adsorbed, at low serum concentrations, by protein A, indicating that opsonin-dependent surface phagocytosis requires IgG but not C3. The requirement of opsonin-dependent surface phagocytosis for IgG was demonstrated further with purified IgG preparations as the sole opsonin. Activation of PMN by N-formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA) increased opsonin-independent surface phagocytosis by 47% and 66%, respectively, but had no effect on opsonin-dependent surface phagocytosis. Blockade of the PMN iC3b receptor (CR3), which has lectin-like properties, by a panel of monoclonal antibodies against the alpha- and beta-chains of CR3 did not inhibit the surface phagocytosis of opsonized or unopsonized S. aureus, and one antibody (NIMP-R10) enhanced opsonin-independent surface phagocytosis. These results indicate that the mechanism of surface phagocytosis is quite different to that observed in suspension assays. Opsonin-independent surface phagocytosis occurs and is enhanced by PMN activation, opsonin-dependent surface phagocytosis is dependent on IgG and not complement, and neither opsonin-independent nor -dependent surface phagocytosis proceeds through CR3.

Antibodies, Monoclonal↗

PubMedDate not supplied

[Complement activation in patients with chronic polyarthritis, measured by the level of complement fraction C3a in plasma].

Using a new C3a-radioimmunoassay, we could show a significantly increased complement activity in patients with active rheumatoid arthritis. The C3a-plasma level in rheumatoid patients was 529 ng/ml, whereas in patients with psoriatic arthropathy it was 164 ng/ml, in patients with noninflammatory muscular pain syndromes 170 ng/ml and in healthy blood donors we found a mean level of 221 ng/ml. The reproducibility was high, therefore it seems that the possibility to calculate the risks of complement-activating immunological disorders can be increased by using the C3a-radioimmunoassay. On the other hand the C3a-increase in rheumatoid patients may be an expression of the immunological activity of the disease.

Arthritis↗

PubMed1993

Clusterin, the human apolipoprotein and complement inhibitor, binds to complement C7, C8 beta, and the b domain of C9.

Clusterin is a heterodimeric multifunctional protein expressed in a variety of tissues and cells. It forms high density lipid complexes in plasma and participates in the control of the lytic activity of the late complement complex (TCC, C5b-9). Together with vitronectin, clusterin binds to the nascent amphiphilic C5b-9 complex, rendering it water soluble and lytically inactive. To define the interactions that underlie the complement-inhibitory function of clusterin, we have examined the binding interactions between [125I]clusterin and the isolated components of the complex, C5b-6, C7, C8, and C9 and vitronectin. By using ligand blotting in the presence of Tween, specific binding of the labeled clusterin with C7, the beta-subunit of C8 and C9 was detected. Binding to C9 was competed by polymerized C9, but not by C8, C7, C6, and CD59, suggesting that the conformational change occurring during the hydrophilic-amphiphilic transition of C9 exposes the interaction site for clusterin. When thrombin-treated C9 was analyzed, clusterin was found to recognize the C9b fragment containing the hydrophobic membrane interaction segment. Both subunits of clusterin interact with C9 and are similarly potent in inhibiting C5b-9-mediated hemolysis and Zn+(+)-induced C9 polymerization. These results show that clusterin exerts its inhibitory effect by interacting with a structural motif common to C7, C8 alpha, and C9b.

Clusterin↗

PubMed1977

Complement system in human colostrum: presence of nine complement components and factors of alternative pathway in human colostrum.

Evidence has been obtained for the presence in human colostrum of all nine components of complement (C), C1 through C9, and factors of the alternative pathway. Samples of colostrums collected from five women at 1-4 days after normal parturition were assayed for the haemolytic activities of individual components. As compared with normal human sera, the activities of each component ranged from 0.03 to 7% of those in sera. The activities of C4, C7 and C9 were relatively high, while that of C1 was extremely low. In most of the cases, the activities of individual components gradually increased following delivery, when expressed as the activity per unit weight (g) of protein in the colostrum. When the colostrums were treated with cobra venom factor, most of the colostrums showed 10-20% reduction in the C3 activity. This finding indicates the presence of factors such as B and D which are involved in the activation of C through the alternative pathway. The role as a defense factor of the C system in human colostrum and milk is discussed in connection with the ability of secretory IgA to react with C.

Colostrum↗

PubMed1979

CELISA (complement-enzyme linked immuno sorbent assay) a new method for the estimation of complement fixing antibodies; its use for Chagas' disease.

A description is given of a new method for the estimation of complement fixing antibodies. This is a modification of the Enzyme Linked Immuno Sorbent Assay (ELISA) to a Complement-Enzyme Linked Immuno Sorbent Assay (CILISA) using an anti-C3 conjugate. The method is independent of the haemolytic system. To test the sensitivity of CELISA, comparative studies were carried out with the Haemolytic Complement Fixation Test (CFT), indirect haemagglutination test and ELISA with sera from patients with Chagas' Disease. The results with CELISA showed significant correlations with CFT titers whereas no correlations were observed with the other serological tests.

Antibodies↗

PubMed1989

Regulation of human and murine complement: comparison of 5' structural and functional elements regulating human and murine complement factor B gene expression.

The serine protease complement factor B (Bf), an acute phase plasma protein, is a component of the alternative pathway of complement activation. Previous studies revealed that several cytokines including IFN-gamma and IL-1 are involved in mediating acute phase Bf expression. To determine the molecular details of Bf expression we isolated, sequenced and characterized the 5' flanking regions of the human and murine Bf genes. In both species the Bf transcriptional start site in liver was located less than 400 bp 3' to the polyadenylation site of the upstream C2 gene. This upstream intergenic region contained greater than 65% nucleotide homology between species. Within this region, an IRS and three heat shock consensus elements were found in the murine sequence in an identical position to that of the human. To examine the functional details of Bf expression, a series of mouse and human Bf promoter-chloramphenicol acetyltransferase (CAT) chimeric gene constructs were transfected into mouse L or human HepG2 cells. Analysis of expression of these fusion gene constructs revealed that 1) cis-acting DNA sequences identified, at least in part, in the 3' untranslated region of the C2 gene (within the 400 bp upstream of the Bf cap site) mediate responsiveness to IL-1 and IFN-gamma, 2) the responsiveness to each mediator appears to be conferred by separate upstream regions similar in position and homologous in man and mouse, and 3) the IL-1 responsive region in both species appears to have the characteristics of an enhancer element. The results of this analysis suggest a selective pressure to conserve the intergenic sequence between C2 and Bf genes and that further studies of these sequences will be useful in elucidating mechanisms controlling the acute phase response.

Animals↗

PubMed1994

Complement and neutrophil activation during cardiopulmonary bypass: a study in the complement-deficient dog.

Cardiopulmonary bypass (CPB) is known to cause complement and neutrophil activation, but the relative importance and interaction of these components in CPB-induced inflammation is unknown. In this study, a strain of dogs genetically deficient in the third component of complement (C3) was used to determine the contribution of C3 to neutrophil activation and pulmonary injury after CPB. Eleven dogs (5 C3-deficient and 6 controls) underwent 150 minutes of hypothermic CPB (28 degrees C) followed by 2 hours of observation. Before CPB, C3 levels were normal in controls and less than 1% of normal in C3-deficient dogs. In control dogs, functional activity of C3 decreased to 53.2% of baseline after 1 hour of CPB and there was immunohistochemical evidence of C3 deposition in lung after CPB; C3-deficient dogs had no C3 deposition in lung. Although similar degrees of neutropenia occurred during CPB in the two groups, expression of neutrophil adhesion molecule subunit CD18 was significantly lower in C3-deficient dogs than controls after 1 hour of CPB (45.9 +/- 3.7 versus 82.9 +/- 10.0 mean fluorescence units; p < 0.02). Postbypass lung tissue myeloperoxidase content was also less in C3-deficient dogs (43.8 +/- 4.6 versus 71.1 +/- 8.6 mumol x 10 mg-1 x min-1; p < 0.03). Cardiopulmonary bypass-associated lung injury (assessed by alveolar-arterial oxygen gradient, pulmonary vascular resistance, percent lung water, and light and electron microscopic appearance) was similar between groups. These results demonstrate that (1) C3 is deposited on pulmonary vascular endothelium during CPB and (2) C3 mediates increased expression of neutrophil CD18 and neutrophil sequestration in lung after CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

2-Chloroadenosine inhibits complement-induced reactive oxygen metabolite production and recovery of human polymorphonuclear leucocytes attacked by complement.

Luminol-enhanced chemiluminescence demonstrated that 2-chloroadenosine inhibited complement-induced reactive oxygen metabolite production in human polymorphonuclear leucocytes. This inhibition was reversed by 8-phenyltheophylline. Binding of a [125I]-labelled monoclonal antibody against C9 to human PMN demonstrated removal of membrane attack complexes from the cell membranes, and in addition indicated inhibition of this process by 2-chloroadenosine. This compound also increased the percentage of complement-induced cell lysis of polymorphonuclear leucocytes.

2-Chloroadenosine↗

PubMed1985

A quantitative method for assessing the third complement factor (C3) attached to the surface of opsonized Pseudomonas aeruginosa: interrelationship between C3 fixation, phagocytosis and complement consumption.

A direct enzyme-linked immunoassay is described for the determination of C3 that becomes attached to the surface of bacteria upon incubation in serum. The assay uses horseradish peroxidase-conjugated rabbit antiserum specific for human C3. In this study various Pseudomonas aeruginosa strains, Escherichia coli and Staphylococcus aureus were opsonized under different conditions and the amount of C3 fixed to the bacterial surface was measured directly. The extent of C3 fixation was compared with the percentage of phagocytosis by human polymorphonuclear leukocytes and with the complement consumption in the fluid phase. It was demonstrated that C3 fixation closely correlated with the percentage of phagocytosis but not with complement consumption. The method can be performed with relatively simple equipment and could be used in routine laboratories in order to determine the extent of opsonization of Pseudomonas aeruginosa and other bacteria and to detect opsonic defects in the sera of patients.

Complement Activation↗

PubMed1993

Organ dysfunction and cardiopulmonary bypass: the role of complement and complement regulatory proteins.

Cardiopulmonary bypass-induced organ dysfunction remains a clinical problem in certain groups of patients. Although the pathogenesis is multifactorial, it is likely that a panendothelial injury consequent upon widespread humoral and cellular activation is a major contributor to this process. The biologically active products of complement activation are certainly capable of inducing many of the features of the post-perfusion syndrome. The complex interactions between complement and many of the other proposed mediators of this response also supports this contention. However, it is equally certain that many of the other proposed mediators have some role to play. Inhibition of one cell type or inflammatory cascade is therefore unlikely to abolish all the adverse effects of CPB but will, at least in experimental systems, permit a more precise determination of the pathogenesis of this problem. The temptation to simply measure elevated circulating levels of newly identified mediators must be resisted and more effort applied to examining the pathophysiological effects of specific inhibitors. This type of investigation should initially be effected in experimental models where reproducible conditions can be ensured. In conjunction with this, far more precise end-points are required in order to assess the effect of any potential therapeutic intervention in a clinical setting. In particular, new techniques of evaluating endothelial injury need to be developed. In clinical studies careful consideration must be given to the patient population studied. Whilst patients undergoing routine coronary artery surgery form a relatively homogeneous group, the magnitude of endothelial injury sustained is probably small and, especially in terms of lung function, the signal will be diluted by other non-bypass-related events. The study of high risk groups would seem more appropriate despite their heterogeneity. An important unanswered question is why certain sub-populations of patients are at increased risk of clinically relevant bypass-induced injury. The endothelium of these patients may be different: the neonatal pulmonary microcirculation is not the same as that of an adult (with increased fluid filtration pressure and a higher microvascular surface area per unit lung mass [5,6]), children with pulmonary hypertension have histological evidence of an altered/damaged endothelium (S.G. Haworth, Personal Communication) whilst pre-existing sepsis could clearly induce a degree of endothelial dysfunction. A further possibility is that the inflammatory response in these patients is already "primed". Some patients with heart failure have been shown to have elevated circulating TNF.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2001

RETRACTED: Crystal structure of a complement control protein that regulates both pathways of complement activation and binds heparan sulfate proteoglycans.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of request of the editors. Cell is retracting this paper reporting structures of a poxvirus protein, VCP, that inhibits the complement system. The paper presents a structural model derived from two crystal forms of the protein (PDB: 1G40 and 1G44) that defines an interaction surface implicated in inhibition of complement C3 proteins and visualizes heparin binding sites. We were contacted by the University of Alabama, Birmingham (UAB), the corresponding author's institution, with a report detailing concerns about the veracity of the structures and recommending that the structures be retracted from the Protein Data Bank. We then conducted an assessment with input from experts in the field who found that the structures as presented in the paper were not consistent with available data, including spatial packing and structure (B) factors. These findings were consistent with issues contained in the UAB report. A subsequent investigation by the Department of Health and Human Services Office of Research Integrity (https://www.federalregister.gov/documents/2018/04/16/2018-07782/findings-of-research-misconduct) has concluded that the corresponding author, Krishna H.M. Murthy, engaged in research misconduct and that the structures were falsified and/or fabricated. Given the results of our own assessment and the institutional investigations, the most appropriate course of action is to retract the paper. Co-authors Nick Mullin, Paul N. Barlow, and Craig M. Ogata support this retraction.

Amino Acid Motifs↗

PubMed1983

Complement, the immune-complex lattice, and the pathophysiology of complement-deficiency syndromes.

The role of the components of the complement classical pathway in maintaining antigen-antibody complexes in solution has implications for the understanding of the pathophysiology of complement-deficiency syndromes. It is proposed that this mechanism may normally keep immune complexes soluble for a sufficient time for their safe elimination by the mononuclear phagocyte system. When an early component of the classical pathway is deficient or depleted antigen-antibody complexes would be more likely to precipitate at or near their site of formation and lead to immunologically mediated inflammation. This hypothesis is supported by the predisposition to immune-complex diseases of patients with genetically determined deficiencies of components of the classical pathway.

Antigen-Antibody Complex↗

PubMed2002

Association of factor H of the alternative pathway of complement with agrin and complement receptor 3 in the Alzheimer's disease brain.

Factor H, a regulatory protein of the alternative pathway of complement (APC), is present in amyloid-beta (Abeta) plaques in Alzheimer's disease (AD). Abeta plaques also contain significant amounts of heparan sulfate proteoglycans (HSPGs), such as agrin, as well as numerous activated microglia expressing increased levels complement receptor 3 (CR3). Here, we show the colocalization of each of these molecules in the AD brain and the functional capacity for these molecules to bind to one another in vitro. We propose that CR3 receptors expressed by microglia are used for ligand binding to factor H bound to HSPGs and Abeta in plaques in the AD brain.

Aged↗

PubMed1996

Complement expression on astrocytes and astrocytoma cell lines: failure of complement regulation at the C3 level correlates with very low CD55 expression.

Primary fetal human astrocytes and an astrocytoma cell line, U373-MG, expressed membrane cofactor protein (CD46), CD59, and low levels of decay-accelerating factor (CD55). Astrocyte CD55 was capable of regulating C3 deposition on the cell surface; albeit at a lower level than primary human fibroblasts. Negligible complement-mediated lysis of primary astrocytes and the U373-MG cell line was observed, even when large amount of astrocyte-specific, complement-activating antibodies were bound to the cells. Blocking the function of CD59 on astrocytes resulted in a > 90% cell lysis, while equivalent lysis of fibroblasts could only be achieved with additional blocking of CD55.

Antigens, CD↗

PubMed1997

Complement coating of erythrocytes is reduced following their interaction with neutrophils in vitro without loss of complement receptor 1 (CR1).

We have investigated the interaction of complement-coated erythrocytes (E) with neutrophils, in vitro, to determine the effects of erythrocyte CR1. Complement-coating in vitro, to mimic immune complex uptake, caused a reduction in E-CR1, but subsequent interaction with neutrophils effected a removal of E-C3b and a return of E-CR1 to levels approximating that of uncoated erythrocytes. These data indicate that C3b, associated with immune complexes, may bind to E-CR1 in a reversible manner and that subsequent interaction with phagocytes need not necessarily result in cleavage (and loss of) E-CR1. Further, we conclude that E-CRI can apparently be reduced by epitope masking.

Antigen-Antibody Complex↗

PubMed1981

[Normal values of IgA, IgG, IgM, a1-antitrypsin, C2-complement, C4-complement, ceruloplasmin, haptoglobin and transferrin in serum of healthy, matured newborns and comparison with adults. Method: kinetic nephelometry. (author's transl)].

Concentrations of IgA, IgG, IgM, a1-antitrypsin, C3-complement, C4-complement, ceruloplasmin, haptoglobin and transferrin were determined by the kinetic nephelometric method in fasting blood serum of 88 healthy, matured newborns (male=46, female=42) and of 50 healthy adults (male=12, female=38). The age specific comparison showed that all the nine examined proteins had significantly lower levels in the group of newborns. Sex specific differences were not detected in the group of newborns.

Adult↗