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PubMed1983

The human C3b receptor.

The cellular receptor for the C3b fragment of the third component of complement is a 205,000 molecular weight glycoprotein expressed by erythrocytes, polymorphonuclear leukocytes, monocytes, B lymphocytes, a subset of T lymphocytes and glomerular podocytes. The receptor molecule is a potent inhibitor of complement activation by both the alternative and classical pathways. It serves as a cofactor in the proteolytic degradation of C3b bound to immune complexes. On neutrophils and monocytes, the receptor enhances immunoglobulin-dependent phagocytosis of opsonized particles and triggers internalization of soluble ligands bearing C3b. The number of C3b receptor molecules expressed on erythrocytes is genetically determined and was found to be low in patients with systemic lupus erythematosus: these abnormalities when associated with a low number of receptors in the kidney of patients with non-systemic lupus erythematosus nephritis may predispose to immune complex diseases.

Animals↗
PubMedDate not supplied

Studies on the immunopathology of the nephrotic syndrome associated with Plasmodium malariae. 1. Serum levels of an immune adherence inhibitor.

A comparative study of the serum levels of an immune-adherence inhibiting factor was carried out on serum samples from eighty-seven nephrotic syndrome children, twenty-eight nephrotic adults, 202 normal school children, 116 blood donors, twenty-five falciparum malaria children and 172 patients with miscellaneous diseases. Low titres (1/32 and below) of the factor were present in sera from 63.2% of the nephrotic children 60.7% of nephrotic adults and 60.0% of children malaria, as compared with 30.7% of the normal children, 25.5% of the patients with miscellaneous diseases and 41.4% of the blood donors. There is a significant difference between nephrotic children and normal children with low titres (P less than 0.05). Furthermore, 36.8% of the nephrotic children had serum titres of 1/4 or less, as compared with 6.4% of normal children. The serum factor is tentatively referred to as 'C3b-inase'. Its similarity to conglutinogen-activating factor (KAF) and its possible role in the pathogenesis of the immune-complex nephropathy of childhood nephrotic syndrome associated with malaria are discussed.

Adolescent↗
PubMedDate not supplied

[Substances contained in the coelomic fluid of Lumbricus terristris having functions in common with those of some human complement components].

In the present work, it was demonstrated for the first time that the coelomic fluid of Lumbricus terrestris contained a substance recognized by human classical convertase. This substance permitted an immune, complement-dependent agglutination response of sheep erythrocytes carrying C3-convertase (EAC142). In addition, substances secreted by coelomic leukocytes possessed an inhibitory activity against human complement: the component C3 was cleaved into a C3b fragment. This result suggests the presence of a system the function of which is C3-convertase-like. We have thus shown that some complement functions, with their natural inhibitors, appear early in evolution. Certain of these functions and structures might be preserved throughout evolution.

Animals↗
PubMedDate not supplied

Inhibition of complement by gold sodium thiomalate.

The effect of gold sodium thiomalate on C3 and factor B activation by monosodium urate monohydrate (MSUM) and zymosan was studied using a quantitative immunoelectrophoretic assay for complement activation. C3 and factor B conversion by the classical pathway activator MSUM, was inhibited 50% and 100% by 3.2 x 10(-4)M and 10(-3)M gold sodium thiomalate, respectively. C3 and factor B conversion by the alternative pathway activator, zymosan, was much less susceptible to inhibition by gold. Gold at 10(-3)M, inhibited alternative pathway activation by only 30%. A 50% inhibition would have required 10(-2)M gold. There was no significant inhibition of complement activation through either pathway by less than 10(-4)M gold. Sodium thiomalate alone showed no inhibition. Studies using other crystals and immune complexes were confirmatory. Thus, there was no appreciable inhibition of the complement system at concentrations of gold attainable in the serum of patients receiving chrysotherapy. The in vivo significance of these findings is unknown.

Complement C3↗
PubMed1978

Effect of C3b inactivator on monocyte-bound C3-coated human erythrocytes.

As a model of IgM-induced hemolytic anemia in man, human erythrocytes were sensitized with IgM antibody and coated with complement components, including C3 and C4, using human serum as a source of complement. These coated red cells were then interacted with monolayers of human mononuclear phagocytic cells (monocytes). Complement-coated red cells so bound could be displaced from their monocyte attachment site in a dose- and time-dependent manner by serum factors, including C3b inactivator (C3bINA). These factors were more efficient in inactivating red cell-bound complement components prior to interaction of the coated cells with monocytes. With large amounts of complement per erythrocyte, measured as membrane-bound C3, the ability of the serum inactivating factor(s) to remove the complement-coated red cells from the monocyte surface was compromised and persistently bound red cells were progressively phagocytosed. These studies implicate C3bINA in the displacement of complement-coated erythrocytes, formed from the interaction of IgM antibody and serum complement, from the hepatic macrophage in IgM-induced immune hemolysis. They suggest that both the concentration of complement components, especially on the erythrocyte surface, and the level of C3bINA and perhaps other inactivators may be important features regulating hemolysis in this disorder.

Complement C3b Inactivator Proteins↗
PubMed1977

Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein beta1H for cleavage of C3b and C4b in solution.

The complement regulatory enzyme, C3b inactivator (C3bINA), has been purified from human serum by affinity chromatography on an anti-C3bINA Sepharose column. Subsequent chromatography on DEAE-cellulose and removal of IgG with anti-IgG Sepharose resulted in a product which was found to be homogeneous by polyacrylamide gel electrophoresis at pH 8.9 and by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The molecule is composed of two disulfide bonded polypeptide chains with mol wt of 50,000 and 38,000 daltons. Human CobINA was found to be a glycoprotein containing at least 10.7% carbohydrate and to have a normal serum concentration of 34 +/- 7 mug/ml (mean +/- 1 SD). Highly purified C3bINA cleaved neither free C3b nor free C4b if trace amounts of contaminating beta1H were removed from these proteins with anti-beta1H Sepharose. However, in the presence of highly purified beta1H and C3bINA, both C3bIna, both C3b and C4b were cleaved. Incubation of native C3 or C4 with C3bINA and beta1H had no effect on their cleaved. Incubation of native C3 or C4 with C3bINA and beta1H had no effect on their structure. The action of C3bINA and beta1H on C3b produced two fragments of the alpha1-chain which did not dissociate without reduction of the molecule. These fragments have mol wt of 67,000 and 40,000 daltons. The action of C3bINA and beta1H on C4b resulted in cleavage of the alpha'-chain giving rise to the 150,000-dalton C4c and the 49,000-dalton C4d fragments which dissociated without reduction. To produce from C3b the immunochemically defined C3c and C3d, fragments, the action of an additional serum enzyme appears to be required, the effect of which can be mimicked by trypsin.

Amino Acids↗
PubMed2004

Kinetic analysis of the interactions between vaccinia virus complement control protein and human complement proteins C3b and C4b.

The vaccinia virus complement control protein (VCP) is an immune evasion protein of vaccinia virus. Previously, VCP has been shown to bind and support inactivation of host complement proteins C3b and C4b and to protect the vaccinia virions from antibody-dependent complement-enhanced neutralization. However, the molecular mechanisms involved in the interaction of VCP with its target proteins C3b and C4b have not yet been elucidated. We have utilized surface plasmon resonance technology to study the interaction of VCP with C3b and C4b. We measured the kinetics of binding of the viral protein to its target proteins and compared it with human complement regulators factor H and sCR1, assessed the influence of immobilization of ligand on the binding kinetics, examined the effect of ionic contacts on these interactions, and sublocalized the binding site on C3b and C4b. Our results indicate that (i) the orientation of the ligand is important for accurate determination of the binding constants, as well as the mechanism of binding; (ii) in contrast to factor H and sCR1, the binding of VCP to C3b and C4b follows a simple 1:1 binding model and does not involve multiple-site interactions as predicted earlier; (iii) VCP has a 4.6-fold higher affinity for C4b than that for C3b, which is also reflected in its factor I cofactor activity; (iv) ionic interactions are important for VCP-C3b and VCP-C4b complex formation; (v) VCP does not bind simultaneously to C3b and C4b; and (vi) the binding site of VCP on C3b and C4b is located in the C3dg and C4c regions, respectively.

Binding Sites↗
PubMed1992

Expression of genes encoding receptors for IgG (FcRIII) and for C3b/C4b (Crry) in rat sciatic nerve during development and Wallerian degeneration.

Northern blots were used to examine the expression of genes encoding receptors for IgG (FcRIII) and for C3b/C4b (Crry) in rat sciatic nerve during development and Wallerian degeneration. Steady state levels of FcRIII (1.4 kb) and Crry (1.9 and 2.1 kb) mRNAs were higher in adult rat nerves than in 6 day and 21 day postnatal rat nerves, indicating that the expression of these receptors is developmentally regulated. The FcRIII and Crry cDNA probes also hybridized with total RNA from 3 day old rat Schwann cells and from adult rat peritoneal macrophages. The size of the FcRIII mRNA expressed by cultured Schwann cells (1.6 kb) differed from that expressed by peritoneal macrophages (1.4 kb); the two may be splice variants of one transcript or products of related genes. Peritoneal macrophages contained approximately 100 times higher FcRIII mRNA levels than Schwann cells. In contrast, steady state levels of both 1.9 and 2.1 kb Crry mRNAs were similar in cultured Schwann cells and macrophages. Nerve transection induced a generalized increase in the level of sciatic FcRIII mRNA (1.4 kb) 3 days post-surgery, whereas the level of Crry mRNA was increased only in the nerve segment immediately to the cut. The increase of FcRIII mRNA that occurred in Wallerian degeneration was most likely due to infiltration of macrophages, as FcRIII mRNA-positive macrophages were demonstrated in the degenerating nerves by in situ hybridization. FcRIII mRNA-positive macrophages were not found in normal nerve. The functions of FcRIII and Crry in peripheral nerves are uncertain, but they may be of significance in phagocytosis, antibody-dependent cellular cytotoxicity, and in local immune regulation.

Aging↗
PubMed1990

C4b-binding protein and a 60,000-Dalton plasma protein share antigenic determinants with membrane cofactor protein of complement.

Membrane cofactor protein (MCP) of the C system is a widely distributed regulatory molecule with C3b/C4b binding and factor I-dependent cofactor activity. A rabbit polyclonal antibody was raised against purified human MCP, and it was found to also immunoprecipitate C4b-binding protein (C4bp). Other related complement regulatory proteins, factor H, C3b/C4b receptor, and decay-accelerating factor, were not recognized by this polyclonal antibody to MCP. The cross-reactive epitope was sensitive to reduction with 2-ME and about 3% of the anti-MCP antibody reacted with C4bp. The amino-terminal 48,000-Da, chymotryptic fragment of C4bp was recognized by the antibody to MCP. This fragment of C4bp contains a seven-amino acid peptide that is identical, in its sequence and its location in the third short consensus repeat, to one found in MCP. Two polyclonal antibodies to C4bp, one raised to native and the other to reduced C4bp, did not cross-react with MCP. In addition to this one-way cross-reaction with C4bp, a protein with a m.w. of approximately 60,000 (p60) was found in two of three C4bp preparations that also cross-reacted with antiserum to MCP. p60 was present in trace quantities in the C4bp preparation and was successfully isolated from plasma by C3b affinity chromatography. Its Mr was distinct from that of MCP and other known C3b/C4b binding proteins. Furthermore, p60 was isolated by two different procedures and such material possessed no detectable cofactor activity. Based on these results, p60 is a plasma C3b-binding protein that shares epitopes with C4bp and MCP, and is probably not a soluble form of MCP.

Antigens, CD↗
PubMed2000

Functional modulation of human macrophages through CD46 (measles virus receptor): production of IL-12 p40 and nitric oxide in association with recruitment of protein-tyrosine phosphatase SHP-1 to CD46.

Human CD46, formerly membrane cofactor protein, binds and inactivates complement C3b and serves as a receptor for measles virus (MV), thereby protecting cells from homologous complement and sustaining systemic measles infection. Suppression of cell-mediated immunity, including down-regulation of IL-12 production, has been reported on macrophages (Mphi) by cross-linking their CD46. The intracellular events responsible for these immune responses, however, remain unknown. In this study, we found that 6- to 8-day GM-CSF-treated peripheral blood monocytes acquired the capacity to recruit protein-tyrosine phosphatase SHP-1 to their CD46 and concomitantly were able to produce IL-12 p40 and NO. These responses were induced by stimulation with mAbs F(ab')(2) against CD46 that block MV binding or by a wild-type MV strain Kohno MV strain (KO; UV treated or untreated) that was reported to induce early phase CD46 down-regulation. Direct ligation of CD46 by these reagents, but not intracellular MV replication, was required for these cellular responses. Interestingly, the KO strain failed to replicate in the 6- to 8-day GM-CSF-cultured Mphi, while other MV strains replicated to form syncytia under the same conditions. When stimulated with the KO strain, rapid and transient dissociation of SHP-1 from CD46 was observed. These and previous results provide strong evidence that CD46 serves as a signal modulatory molecule and that the properties of ligands determine suppression or activation of an innate immune system at a specific maturation stage of human Mphi.

Animals↗
PubMed1998

Molecular cloning of a murine homologue of membrane cofactor protein (CD46): preferential expression in testicular germ cells.

Human membrane cofactor protein (MCP, CD46) has been suggested, although no convincing evidence has been proposed, to be a fertilization-associated protein, in addition to its primary functions as a complement regulator and a measles virus receptor. We have cloned a cDNA encoding the murine homologue of MCP. This cDNA showed 45% identity in deduced protein sequence and 62% identity in nucleotide sequence with human MCP. Its ectodomains were four short consensus repeats and a serine/threonine-rich domain, and it appeared to be a type 1 membrane protein with a 23-amino acid transmembrane domain and a short cytoplasmic tail. The protein expressed on Chinese hamster ovary cell transfectants was 47 kDa on SDS/PAGE immunoblotting, approximately 6 kDa larger than the murine testis MCP. It served as a cofactor for factor I-mediated inactivation of the complement protein C3b in a homologous system and, to a lesser extent, in a human system. Strikingly, the major message of murine MCP was 1.5 kb and was expressed predominantly in the testis. It was not detected in mice defective in spermatogenesis or with immature germ cells (until 23 days old). Thus, murine MCP may be a sperm-dominant protein the message of which is expressed selectively in spermatids during germ-cell differentiation.

Amino Acid Sequence↗
PubMed1992

Role of fibrinogen in complement inhibition by streptococcal M protein.

M protein, the major virulence factor of group A streptococci, has antiopsonic activity in that it inhibits activation of the alternative complement pathway on the streptococcal surface. Two properties of M protein have been claimed to account for the inhibitory activity, namely, (i) its binding affinity for complement factor H, which is an inhibitor of alternative pathway activation, and (ii) its high binding affinity for fibrinogen. We have recently shown that fibrinogen, like M protein, inhibits alternative pathway activation by possessing binding affinity for factor H. Here we report that fibrinogen effectively competes with factor H for binding to M protein but retains its own binding affinity for factor H. The presence of fibrinogen did not significantly affect alternative pathway inhibition on the streptococcal surface.

Antigens, Bacterial↗
PubMed1986

Mechanism of resistance to lysis by the alternative complement pathway in Trypanosoma cruzi trypomastigotes: effect of specific monoclonal antibody.

Trypanosoma cruzi G strain epimastigotes were lysed by normal human serum (NHS) through activation of the alternative complement pathway (ACP), whereas metacyclic trypomastigotes were resistant to lysis. Epimastigotes and metacyclics with equivalent amounts of C3b deposited on their surface bound factor B with similar affinities. In contrast, factor H bound with higher affinity to metacyclics than to epimastigotes. Both T. cruzi forms with bound C3b were extensively (60 to 80%) lysed after formation of surface C3-convertase and the addition of a C3-C9 complement source. In the presence of factors H and I, or incubation with NHS with EDTA, the percentage of lysis of metacyclics decreased faster than that of epimastigotes with increasing incubation times. These data suggest, as a possible mechanism of resistance to lysis in metacyclic trypomastigotes, the higher binding affinity of factor H to C3b and the inactivation of the latter by serum regulatory proteins. Metacyclics were lysed by NHS, through ACP, in the presence of human immune serum to T. cruzi or anti-T. cruzi monoclonal antibody, but not with the Fab fragment of the latter, which recognizes a 90,000 m.w. antigen from T. cruzi metacyclics. Protection of parasite-bound C3b from serum control proteins was observed when parasites were incubated, before C3 deposition, with the lytic monoclonal antibody but not with its Fab fragment or a nonrelated IgG control. When C3b was deposited on metacyclics before antibody binding, C3b inactivation occurred. In the lysis of metacyclics, through ACP activation, binding of antibody apparently creates new acceptor sites which prevent the activity of serum regulatory proteins.

Animals↗