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PubMed2001

Human C-reactive protein: expression, structure, and function.

C-reactive protein (CRP) is an acute-phase protein featuring a homopentameric structure and Ca-binding specificity for phosphocholine (PCh). Expression of CRP is regulated mainly at the transcriptional level with interleukin-6 being the principal inducer of the gene during the acute phase. The crystal structure of CRP has been determined and the topology and chemical composition of its ligand-binding site determined. The wide distribution of PCh in polysaccharides of pathogens and in cellular membranes allows CRP to recognize a range of pathogenic targets as well as membranes of damaged and necrotic host cells. CRP bound to a multivalent ligand can efficiently initiate the assembly of a C3 convertase through the classical pathway and thus decorate the surface of the ligand with opsonic complement fragments. However, the protein does not favor the formation of a C5 convertase and therefore, CRP-initiated complement activation does not mediate acute inflammatory reactions and membrane damage. CRP also interacts with Fc receptors on phagocytic cells and acts as an opsonin. Other CRP-initiated signals through interactions with neutrophil Fc receptors have an overall anti-inflammatory effect. Thus, the main biological function of CRP appears to be host defense against bacterial pathogens and clearance of apoptotic and necrotic cells. Protection from lethal bacterial infection, from complement-induced alveolitis, and from endotoxemia has been confirmed in vivo using transgenic mice. Additional functions, including participation in atherogenesis and pathogenesis of myocardial injury after myocardial infarction have been reported. However, the weight of the evidence is that CRP like other acute-phase proteins is a component first line of innate host defense.

C-Reactive Protein↗
PubMed1999

Decay accelerating activity of complement receptor type 1 (CD35). Two active sites are required for dissociating C5 convertases.

The goal of this study was to identify the site(s) in CR1 that mediate the dissociation of the C3 and C5 convertases. To that end, truncated derivatives of CR1 whose extracellular part is composed of 30 tandem repeating modules, termed complement control protein repeats (CCPs), were generated. Site 1 (CCPs 1-3) alone mediated the decay acceleration of the classical and alternative pathway C3 convertases. Site 2 (CCPs 8-10 or the nearly identical CCPs 15-17) had one-fifth the activity of site 1. In contrast, for the C5 convertase, site 1 had only 0.5% of the decay accelerating activity, while site 2 had no detectable activity. Efficient C5 decay accelerating activity was detected in recombinants that carried both site 1 and site 2. The activity was reduced if the intervening repeats between site 1 and site 2 were deleted. The results indicate that, for the C5 convertases, decay accelerating activity is mediated primarily by site 1. A properly spaced site 2 has an important auxiliary role, which may involve its C3b binding capacity. Moreover, using homologous substitution mutagenesis, residues important in site 1 for dissociating activity were identified. Based on these results, we generated proteins one-fourth the size of CR1 but with enhanced decay accelerating activity for the C3 convertases.

Amino Acid Sequence↗
PubMed1986

Activation of complement by intermediate filaments of glomerular epithelial cells.

Glomerular visceral epithelial cells, podocytes, have been shown by immunofluorescence and immunoperoxidase staining methods to bind serum complement (C) components in vitro. Binding of Clq, C4, and C3 was demonstrated and the C4 and C3 binding could be inhibited by EDTA. Thus complement binding had the capacity to cause antibody-independent activation of the "classical" C pathway. The C-binding structures had the same distribution as intermediate filaments (IMFs) of vimentin but not desmin or keratin types. By ultrastructural immunohistochemical staining C3 was observed in association with cytoskeletal IMFs.

Complement Activation↗
PubMed1975

Complement-mediated release of histamine from human leukocytes.

Activation of either the alternative or classical pathway of complement generated a factor which induced release of histamine from both non-allergic and allergic human basophils. This factor probably is derived from the complement system since 1) its formation was associated with loss of C3 activity in human serum, 2) chemotactic factor, probably also a complement product, was generated simultaneously, 3) heat inactivation blocked its formation, 4) anti-C3 and anti-C5 blocked formation of the factor, and finally 5) anti-C5 inhibited the activity of the factor once it had been formed. It appears that both complement-mediated and allergen-mediated release of histamine from basophils are secretory, non-cytolytic pathways since both were maximal at 37 degrees C, required the presence of divalent cations, and were inhibited by theophylline. One consistent difference between these two mechanisms was noted: complement-initiated release of histamine occurred more quickly.

Animals↗
PubMed1996

Improvements on the purification of mannan-binding lectin and demonstration of its Ca(2+)-independent association with a C1s-like serine protease.

Mannan-binding lectin (MBL), previously called 'mannan-binding protein' or MBP, is a plasma C-type lectin which, upon binding to carbohydrate structures on micro-organisms, activates the classical pathway of complement. Purification of MBL relies on its Ca(2+)-dependent affinity for carbohydrate, but existing methods are susceptible to contamination by anti-carbohydrate antibodies. In the present study a sequential-sugar-elution method has been developed which can achieve a preparation of virtually pure MBL and its associated serine protease (MBL-associated serine protease, MASP) by two steps of affinity chromatography. In further separation of MASP from MBL, it was found that activated MASP was associated with MBL independent of Ca2+. Since MBL was found to bind to underivatized Sepharose 4B, the MBL-MASP complex was purified using Sepharose 4B and protease inhibitors were included to purify the complex with MASP in its proenzyme form. Analysis of thus-purified MBL-MASP complex by gel filtration on a Sephacryl S-300 column at pH 7.8 showed that the proenzyme MASP was also associated with MBL independently of Ca2+, but that the complex could be disrupted at a low pH (5.0). Therefore the mechanism of MBL-MASP-mediated complement activation appears to be significantly different from the C1-mediated classical pathway.

Calcium↗
PubMed1996

Human skeletal myoblasts spontaneously activate allogeneic complement but are resistant to killing.

The complement (C) system has previously been implicated in several diseases of muscle. We here report that human myoblasts or rhabdomyosarcoma cell lines spontaneously activate C through the classical pathway, causing release of anaphylatoxins and coating of myoblasts with opsonic C fragments but without causing cell killing. Survival of myoblasts is a consequence of the abundant expression of the membrane C regulatory molecules MCP and CD59, and neutralization of CD59 renders cells susceptible to C killing. The decay-accelerating factor was expressed at a very low level. Myoblasts and rhabdomyosarcoma lines also abundantly express the fluid-phase regulators C1-inhibitor, factor H, C4 binding protein, S-protein, and clusterin and secrete a soluble form of CD59. Expression of membrane and fluid-phase regulators is enhanced by either IFN-gamma or TNF-alpha. Although myoblasts resist C killing, spontaneous activation of C on these cells may have important consequences in inflammatory diseases of muscle where the generation of anaphylactic and opsonic fragments will recruit and activate inflammatory cells. C activation on myoblasts may also have consequences for the use of these cells as vehicles for gene delivery. Inhibition of C using soluble complement receptor I (sCR1) efficiently protected myoblasts from C attack in vitro, and this agent, already being tested in therapy of several C-mediated diseases, might be of value in inflammatory muscle disease and in improving the efficiency of gene delivery.

Cell Death↗
PubMed2005

Predominant role of IgM-dependent activation of the classical pathway in the clearance of dying cells by murine bone marrow-derived macrophages in vitro.

Soluble molecules including complement components have been shown to facilitate the clearance of dying cells by phagocytes, a process that is important in preventing tissue damage and autoimmunity. However, the extent to which complement is involved in this process and the relative contribution of each of the complement activation pathways is not fully understood. We examined the role of complement in the recognition/uptake of apoptotic thymocytes by murine bone marrow-derived macrophages (BMDM) in vitro using sera from gene-targeted mice. We found this process to be IgM- and complement-dependent, especially when the apoptotic cell-to-BMDM ratio was low, and the level of C3 deposition on apoptotic cells correlated closely with their uptake. The addition of C1q rectified the phagocytic defect seen in the presence of C1q-deficient serum in vitro but had no effect on the phagocytic defect observed with serum deficient in both IgM antibodies and C1q. Similarly, complement activation by IgM antibodies was essential for in vivo C3 deposition on apoptotic cells and their uptake by peritoneal macrophages. Hence, the efficient uptake of dying cells by BMDM requires IgM antibodies and complement.

Animals↗
PubMed2002

Complement-mediated clearance of erythrocytes: mechanism and delineation of the regulatory roles of Crry and DAF. Decay-accelerating factor.

The role of complement in the pathogenesis of autoimmune hemolytic anemia (AIHA) has been controversial and may depend on a number of factors, including the affinity and isotype of the pathogenic antibodies involved. We have recently shown that mouse erythrocytes deficient in the membrane C3 regulatory protein, complement receptor 1-related gene/protein y (Crry), but not decay-accelerating factor (DAF), were spontaneously eliminated in vivo by complement. Here, by generating a mouse deficient in both DAF and Crry, we further delineated the roles of Crry and DAF in regulating alternative and classical pathway C3 activation. By using immunoglobulin-, Fcgamma receptor (FcgammaR)-, C3-, C4-, and C5-deficient mice, we also determined the mechanism by which membrane C3 regulator-deficient erythrocytes are cleared from the circulation. Finally, we evaluated the relative importance of the Fc receptor versus the complement pathway in disposing antibody-opsonized DAF/Crry-deficient erythrocytes. We conclude that (1) Crry plays a more dominant role than DAF in regulating the alternative pathway of complement, whereas DAF and Crry are equally effective in preventing antibody-induced runaway complement activation on mouse erythrocytes; (2) DAF/Crry-deficient erythrocytes are eliminated by the alternative pathway of complement via complement receptor-mediated erythrophagocytosis in the spleen; and (3) when opsonized with an immunoglobulin G2a (IgG2a) autoantibody, Crry/DAF-deficient erythrocytes are eliminated more rapidly by complement than by the Fc receptor pathway. These results shed new light on the relative activities of Crry and DAF and underscore the critical roles of membrane C3 regulators in preventing spontaneous and antibody-induced erythrocyte damage in vivo.

Agammaglobulinemia↗
PubMed2000

Interaction between human complement and a pectin type polysaccharide fraction, PMII, from the leaves of Plantago major L.

The interaction between a pectin type polysaccharide fraction, PMII, isolated from the leaves of Plantago major, and human complement was tested in two different hemolytic complement-fixation tests and in addition by two ELISA methods detecting complement-activation products. Sera were used as a complement source of 10 arbitrary human volunteers, individually and as a pool. The complement-fixation tests were designed to measure the concentration of the pectin necessary to inhibit 50% of the hemolysis (ICH(50)). The ELISA tests for complement-activation products were measured in AU/mg using a fully activated serum as a standard. We observed a more than 200-fold difference in ICH(50) activity of the PMII pectin in one of the hemolytic tests by varying the individual sera used as complement-source. On the other hand, the ELISA complement-activation tests showed no significant variation in activity of the PMII depending on the complement-serum used. The level of antibodies against PMII detected in the complement-sera did not correlate with the ICH(50) activity of PMII. The results show that PMII is a potent complement activator with an activity of the same order of magnitude on a weight basis as that of aggregated human immunoglobulin (Ig)G. This activation leads to a complement consumption probably explaining the PMII's effect in the complement-fixation tests. PMII seems to be an activator both on the classical and the alternative pathway of activation. The results might be related to the reported wound-healing effect of the leaves of Plantago major.

Adult↗
PubMed1997

Beta-amyloid peptides initiate the complement cascade without producing a comparable effect on the terminal pathway in vitro.

Activation of the classical complement cascade by beta-amyloid peptides has been hypothesized to underlie the neurodegeneration observed in Alzheimer's diseased brains. In this study, various lots of synthetic beta-amyloid peptides, A beta(1-40), A beta(1-42), and A beta(25-35), were tested for their ability to activate both early complement cascade events and formation of the membrane attack complex through terminal pathway activation. Unlike recent reports which did not assess activation of complement terminal pathway, we found that concentrations of beta-amyloid which activated early cascade events, to an extent comparable to aggregated IgG, failed to elicit formation of comparable levels of membrane attack complex.

Amyloid beta-Peptides↗
PubMedDate not supplied

Anticomplement activity of lysine complexes of propolis phenolic constituents and their synthetic analogs.

Several phenolic constituents of propolis and their synthetic analogs were derivatized with L-lysine. The ability of these complexes to alter complement activity was estimated in vitro in human serum. The influence of selected complexes on C3 hemolytic activity via classical pathway (CP) and alternative pathway (AP) and on zymosan-induced AP activation was determined. The results suppose that the anticomplement effect of the complexes might be related to the interaction with C3 complement component.

Complement Inactivator Proteins↗
PubMed1984

MHC Class III products: an electron microscopic study of the C3 convertases of human complement.

We have reported a transmission electron microscopic study of the two C3 convertases of human complement and their precursors. The corresponding proteins and complexes of the classical and alternative pathway appear very similar. Cofactors C3b and C4b are nearly indistinguishable and display a characteristic but highly irregular substructure. C2 and Factor B are globular with diameters of 85 +/- 8 A and 80 +/- 8 A and both consist of three discrete globular domains each approximately 40 A in diameter. Bb and C2a each contain two domains connected by a short linker segment. Both domains of Bb and one domain of C2a are 42 A in diameter (28 kd), while the second domain of C2 is 47 A in diameter (39 kd). Attachment of the enzymatic subunits to cofactors occurs through one domain only.

Complement Activating Enzymes↗
PubMed2003

Anti-complementary activity of protostane-type triterpenes from Alismatis rhizoma.

Four protostane-type triterpenes, alisol B 23-acetate (1a), alisol C 23-acetate (2a), alisol B (3a), and alisol A 24-acetate (4a), were isolated from the rhizome of Alismatis plantago-aquatice L. var. orientale Samuelson (Alismataceae) and eleven protostane derivatives (compounds 1-11) were obtained by selective modification from alisol B 23-acetate (1a). These compounds were investigated for their anti-complement activity against the classical pathway of the complement system. Alisol B (3a) and alisol A 24-acetate (4a) exhibited anti-complement activity with IC50 values of 150 and 130 microM. Among the synthetic derivatives, the tetrahydroxylated protostane triterpene (9) showed moderate inhibitory activity with IC50 value of 97.1 microM. Introduction of an aldehyde group at C-23 (10; IC50 value, 47.7 microM) showed the most potent inhibitory effect on the complement system in vitro.

Alismataceae↗
PubMed2002

Interactions of CD55 with non-complement ligands.

Decay Accelerating Factor (or CD55) is a major regulator of the alternative and classical pathways of complement activation and is expressed on all serum-exposed cells. It is commonly hijacked by invading pathogens, including many enteroviruses and uropathogenic Escherichia coli, to promote cellular attachment prior to infection. This review will attempt to summarize our knowledge about these interactions between CD55 and various pathogens and also what is known about the non-complement interaction between CD55 and CD97.

Animals↗
PubMed2006

The complement system in central nervous system diseases.

The activation of complement system is important factor in inflammatory, neurodegenerative and cerebrovascular diseases. CNS cells are able to synthesize complement components, and myelin and oligodendrocytes (OLG) are known to activate the classical pathway of complement in vitro in the absence of antibodies. Although activation of the complement system is known to promote tissue injury, recent evidence has also indicated that this process can have neuroprotective effects. In particular, terminal C5b-9 complexes enhance OLG survival both in vitro and in vivo. Complement activation may also reduce the accumulation of amyloid and degenerating neurons by promoting their clearance and suggest that certain inflammatory defense mechanisms in the brain may be beneficial in neurodegenerative disease. Complement system activation plays also an important role in brain damage after ischemic injury or head trauma. These findings strongly suggest that complement activation and membrane assembly of C5b-9 can play a role in injury but can also provide neuroprotection depending on the pathophysiological context.

Animals↗
PubMed1998

C1q knock-out mice for the study of complement deficiency in autoimmune disease.

In humans, homozygous deficiency of the first component of the classical pathway of complement, C1q, is a powerful disease susceptibility factor for the development of systemic lupus erythematosus (SLE). This strong association indicates that a functional activity of C1q protects from the development of SLE. Studies in vitro have shown that C1q can bind apoptotic keratinocytes suggesting that it may have an important role in the clearance of apoptotic cells. C1q-deficient mice, generated by gene targeting, showed an increased mortality and 25% of the mice had histological evidence of glomerulonephritis characterised by multiple apoptotic cell bodies and immune deposits, assessed by immunofluorescence and electron microscopy. These observations are compatible with the hypothesis that C1q deficiency causes autoimmunity by an impaired clearance of apoptotic cells.

Animals↗
PubMed2006

Anti-complementary activity of ursane-type triterpenoids from Weigela subsessilis.

A new ursane-type triterpenoid, weigelic acid (1), and seven known compounds, ursolic acid (2), ilekudinol A (3), corosolic acid (4), ilekudinol B (5), esculentic acid (6), pomolic acid (7), and asiatic acid (8) were isolated from the leaf and stem of Weigela subsessilis. The structure of the new triterpenoid was established as 1beta,2alpha,3alpha,23-tetrahydroxyurs-12-en-28-oic acid on the basis of spectroscopic analyses. In addition, the isolated compounds were evaluated for their anti-complement activity against the classical pathway of the complement system. Of these, compounds 1-2 and 4-8 exhibited anti-complement activity with IC50 values of 152, 90, 130, 51, 56, 4, and 163 microM, respectively, whereas 3 was inactive. This shows that a carboxylic group of ursane-type triterpenoids seems to play an important role in inhibiting the hemolytic activity of human serum against erythrocytes.

Animals↗