Competition for Binding Sites on C3b by CRI, CR2, MCP, Factor B and Factor H

Tc, Farries; Seya, Tsukasa; Ra, Harrison; Jp, Atkinson

doi:10.1159/000463124

Cited by 37 publications

(27 citation statements)

References 21 publications

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“…Thus, they mediate the cleavage of C3b (24,32,36) and accelerate the decay of the C3 convertase C3bBb (26,49). Factor H and FHL-1 compete with factor B in binding to intact C3b (9). These regulatory functions lead to the downregulation or termination of the complement cascade.…”

mentioning

confidence: 99%

The Opportunistic Human Pathogenic FungusAspergillus fumigatusEvades the Host Complement System

Behnsen¹,

Hartmann

Schmaler³

et al. 2008

Infect Immun

105

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The opportunistic human pathogenic fungus Aspergillus fumigatus causes severe systemic infections and is a major cause of fungal infections in immunocompromised patients. A. fumigatus conidia activate the alternative pathway of the complement system. In order to assess the mechanisms by which A. fumigatus evades the activated complement system, we analyzed the binding of host complement regulators to A. fumigatus. The binding of factor H and factor H-like protein 1 (FHL-1) from human sera to A. fumigatus conidia was shown by adsorption assays and immunostaining. In addition, factor H-related protein 1 (FHR-1) bound to conidia. Adsorption assays with recombinant factor H mutants were used to localize the binding domains. One binding region was identified within N-terminal short consensus repeats (SCRs) 1 to 7 and a second one within C-terminal SCR 20. Plasminogen was identified as the fourth host regulatory molecule that binds to A. fumigatus conidia. In contrast to conidia, other developmental stages of A. fumigatus, like swollen conidia or hyphae, did not bind to factor H, FHR-1, FHL-1, and plasminogen, thus indicating the developmentally regulated expression of A. fumigatus surface ligands. Both factor H and plasminogen maintained regulating activity when they were bound to the conidial surface. Bound factor H acted as a cofactor to the factor I-mediated cleavage of C3b. Plasminogen showed proteolytic activity when activated to plasmin by urokinasetype plasminogen activator. These data show that A. fumigatus conidia bind to complement regulators, and these bound host regulators may contribute to evasion of a host complement attack.

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mentioning

confidence: 99%

The Opportunistic Human Pathogenic FungusAspergillus fumigatusEvades the Host Complement System

Behnsen¹,

Hartmann

Schmaler³

et al. 2008

Infect Immun

105

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show abstract

“…Both proteins act as cofactors for the plasma serine protease factor I in the cleavage of C3b (30,33,36) and accelerate the decay of the C3 convertase, C3bBb (32,43). Factor H and FHL-1 can also compete with factor B in binding to intact C3b (11). These regulatory functions lead to downregulation or termination of the complement cascade.…”

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confidence: 99%

The YeastCandida albicansBinds Complement Regulators Factor H and FHL-1

et al. 2002

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The human facultative pathogenic yeast Candida albicans causes mucocutaneous infections and is the major cause of opportunistic fungal infections in immunocompromised patients. C. albicans activates both the alternative and classical pathway of the complement system. The aim of this study was to assay whether C. albicans binds human complement regulators in order to control complement activation at its surface. We observed binding of two central complement regulators, factor H and FHL-1, from normal human serum to C. albicans by adsorption assays, immunostaining, and fluorescence-activated cell sorter (FACS) analyses. Specificity of acquisition was further confirmed in direct binding assays with purified proteins. The surfaceattached regulators maintained their complement regulatory activities and mediated factor I-dependent cleavage of C3b. Adsorption assays with recombinant deletion mutant proteins were used to identify binding domains. Two binding sites were localized. One binding domain common to both factor H and FHL-1 is located in the N-terminal short consensus repeat domains (SCRs) 6 and 7, and the other one located in C-terminal SCRs 19 and 20 is unique to factor H. These data indicate that by surface acquisition of host complement regulators, the human pathogenic yeast C. albicans is able to regulate alternative complement activation at its surface and to inactivate toxic complement activation products.

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“…CR2, in both mouse and man, binds with high affinity to the C3 breakdown fragment C3d (as well as iC3b and C3dg, (Cole et al, 1985;Farries et al, 1990;Iida et al, 1983;Kalli et al, 1991;Molina et al, 1994;Weis et al, 1984) which remains covalently bound to complement activating surfaces or antigen (Law and Dodds, 1997). Consistent with a key role for C3 fragments in amplifying the immune response via the CR2/CD19, C3 −/− mice have weak humoral immune responses and defects in germinal center formation, Wessels et al, 1995).…”

Section: Introductionmentioning

confidence: 94%

Defective B cell ontogeny and immune response in human complement receptor 2 (CR2, CD21) transgenic mice is partially recovered in the absence of C3

Twohig

Kulik

Haluszczak

et al. 2007

Molecular Immunology

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Mice prematurely expressing human CR2 (hCR2) in the B cell lineage have a defective B cell ontogeny and immune response. Our recent analysis of this phenotype suggested that signalling through hCR2 and presumably mouse CD19 on the B cell surface, during bone marrow development, could result in the observed changes in B cell function in these mice. To test this hypothesis, we back crossed hCR2 high transgenic mice onto the CD19 −/− background. CD19 −/− hCR2 high mice were found to possess even fewer mature B cells than their CD19 +/+ hCR2 high littermates, demonstrating that loss of CD19 exascerbated the effects elicited through hCR2. This data suggests that CD19 provides a survival signal during B cell development in this model. Next, we examined if the removal of the main ligand for CR2, namely C3d, through back-crossing onto the C3 −/− background could restore normal B cell development. However, we found only minor recovery in peripheral B cell numbers and no obvious change in function. This was despite a 3-fold increase in the level of hCR2 expression on B cells isolated from the spleen or bone marrow of C3 −/− hCR2 high mice when compared with C3 sufficient littermates. These data demonstrate that hCR2 is integrated in mouse B cell signalling and that the downstream effects of hCR2 expression during early B cell development are partially but not completely due to interaction with C3 fragments and signaling through CD19 in the bone marrow environment.

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Competition for Binding Sites on C3b by CRI, CR2, MCP, Factor B and Factor H

Cited by 37 publications

References 21 publications

The Opportunistic Human Pathogenic FungusAspergillus fumigatusEvades the Host Complement System

The Opportunistic Human Pathogenic FungusAspergillus fumigatusEvades the Host Complement System

The YeastCandida albicansBinds Complement Regulators Factor H and FHL-1

Defective B cell ontogeny and immune response in human complement receptor 2 (CR2, CD21) transgenic mice is partially recovered in the absence of C3

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