Control of C3b and C5b deposition by CD46 (membrane cofactor protein) after alternative but not classical complement activation

Devaux, Patricia; Christiansen, Dale; Fontaine, Marc; Gerlier, Denis

doi:10.1002/(sici)1521-4141(199903)29:03<815::aid-immu815>3.0.co;2-8

Cited by 42 publications

(40 citation statements)

References 27 publications

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“…However, in a preceding study with renal tumor cell lines, we did not find an effect on C3 deposition after blocking of CD46 (Blok et al, 1998). This latter finding was in accordance with prior data suggesting that CD46 is mainly involved in regulation of the alternative pathway (Devaux et al, 1999). However, protection of classical pathway activation by CD46 expression on tumor cell lines has been shown previously (Azuma et al, 1995), although mainly CD55 and CD59 have been implicated as being important for classical pathway activation (Bjørge et al, 1997;Brasoveanu et al, 1996;Cheung et al, 1988); Gorter et al, 1996;Venneker et al, 1998).…”

Section: Discussionsupporting

confidence: 90%

A Possible Role of CD46 for the Protection In Vivo of Human Renal Tumor Cells from Complement-Mediated Damage

et al. 2000

Laboratory Investigation

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SUMMARY:It is still unclear which membrane-bound regulatory proteins (mCRP) are important in vivo to protect tumor cells from complement-mediated damage. To address this question, the expression levels of CD46, CD55, and CD59 were measured semi-quantitatively in situ on renal cell carcinomas and compared with the expression level and cellular distribution of these mCRP in proximal tubuli within each patient (n ϭ 31). It was also determined whether the expression of mCRP on tumor cells is associated with deposition of C3d and C5b-9. CD46 expression was decreased on tumor cells; in contrast, CD55 was expressed on tumor cells (12 out of 31 samples), while it was not detected on proximal tubular epithelial cells (PTEC). Also, expression of CD59 on tumor cells was increased as compared with its expression on PTEC. Furthermore, the localization on the cell surface of mCRP as observed on PTEC was altered on tumor cells. Because expression of mCRP may limit a complement-mediated anti-tumor response, we determined whether complement deposition was associated with the expression level of CD46, CD55, and CD59. The presence of C3d on tumor cells was associated with a low expression level of CD46 (p Ͻ 0.02). The expression level of CD46 was also associated with a low tumor stage (p Ͻ 0.04). The results suggest that in vivo CD46 plays a role in the protection of human renal tumor cells from complement-mediated injury. (Lab Invest 2000, 80:335-344).

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Section: Discussionsupporting

confidence: 90%

A Possible Role of CD46 for the Protection In Vivo of Human Renal Tumor Cells from Complement-Mediated Damage

et al. 2000

Laboratory Investigation

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“…Previous studies have examined primarily only one of the four regularly expressed isoforms of MCP (Barilla-LaBarca et al, 2002;Richards et al, 2003).While the MCP isoforms and DAF equivalently and efficiently inhibited the alternative pathway, only DAF inhibited the classical pathway in this experimental system. That MCP preferentially inactivates the alternative pathway agrees with previous findings (Barilla-LaBarca et al, 2002;Devaux et al, 1999;Kojima et al, 1993;Seya and Atkinson, 1989). Interestingly, DAF was also effective in inhibiting the alternative pathway and yet no mutations have thus far linked DAF to aHUS (Esparza-Gordillo et al, 2005) and personal communication, D. Kavanagh).…”

Section: Discussionsupporting

confidence: 86%

“…We have previously shown that MCP minimally inhibits the classical pathway even at low concentrations of Ab (Barilla-LaBarca et al, 2002;Liszewski and Atkinson, 1996). Thus, these findings are consistent with previous studies demonstrating that MCP primarily inhibits the alternative pathway (Devaux et al, 1999;Kojima et al, 1993;Liszewski and Atkinson, 1996). Taken together, these studies indicate that either de novo activation or engagement of the feedback loop is regulated by MCP.…”

Section: Reduced Mcp Expression Decreases Functionalitysupporting

confidence: 93%

“…3A-E). This is consistent with previous data using the MCP-BC1 isoform (Liszewski and Atkinson, 1996) at this as well as lower levels of sensitization (Barilla-LaBarca et al, 2002;Devaux et al, 1999). In contrast, DAF inhibited C3 deposition by 76% ± 6 (mean ± SEM of three experiments) as compared to control.…”

Section: Daf But Not Mcp Inhibits C3b Deposition By the Classical Psupporting

confidence: 93%

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Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

Liszewski

Leung

Schraml

et al. 2007

Molecular Immunology

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Mutations in complement regulatory proteins predispose to the development of aHUS. Approximately 50% of patients bear a mutation in one of three complement control proteins, factor H, factor I, or membrane cofactor protein (MCP; CD46). Another membrane regulator that is closely related to MCP, decay accelerating factor (DAF; CD55) thus far has shown no association with aHUS and continues to be investigated. The goal of this study was to compare the regulatory profile of MCP and DAF and to assess how alterations in MCP predispose to complement dysregulation. We employed a model system of complement activation on Chinese hamster ovary (CHO) cell transfectants. The four regularly expressed isoforms of MCP and DAF inhibited C3b deposition by the alternative pathway. DAF, but not MCP, inhibited the classical pathway. Most patients with MCPaHUS are heterozygous and express only 25-50 % of the wild-type protein. We, therefore, analyzed the effect of reduced levels of wild-type MCP and found that cells with lowered expression levels were less efficient in inhibiting alternative pathway activation. Further, a dysfunctional MCP mutant, expressed at normal levels and identified in five patients with aHUS (S206P), failed to protect against C3b amplification on CHO cells, even if expression levels were increased 10-fold. Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS.

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“…The cells were washed with PBS and fixed with 4% paraformaldehyde in PBS for 10 min; the cells were permeabilized with 1% Tween 20 in PBS for 10 min. After three washes in PBS, the cells were incubated for 45 min at room temperature with the mouse anti-human C3 ␤-chain Ab WMI (dilution 1/20 in PBS-1% BSA) (28). Following washes, the cells were incubated with goat anti-mouse Ab conjugated with Alexafluor 488 (Invitrogen; dilution 1/100) for 45 min.…”

Section: Immunofluorescence Analysis Of Intracellular C3mentioning

confidence: 99%

Human C3 Deficiency Associated with Impairments in Dendritic Cell Differentiation, Memory B Cells, and Regulatory T Cells

Ghannam

Pernollet

Fauquert

et al. 2008

The Journal of Immunology

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Primary C3 deficiency, a rare autosomal inherited disease (OMIM 120700), was identified in a 2-year-old male suffering from recurrent pyogenic infections from early infancy with undetectable total complement hemolytic activity (CH50) and C3 values. The nonconsanguineous parents and the two patients’ two siblings had 50% normal serum C3 concentration. The molecular abnormality associated a paternal allele coding C3 with the missense mutation p.Ser550Pro and an apparently null maternal allele, with production of a defective protein that could no longer be secreted. Vaccination of the child did not induce a long-term Ab response. Accordingly, switched memory IgD−CD27+ B cells were barely detected, amounting to only 2.3% of peripheral blood CD19+ cells. Cells were significantly defective in stimulating alloreactive responses. The in vitro development of immature dendritic cells and their maturation capacity were greatly impaired, with decreased CD1a expression and IL-12p70 secretion ability. These cells were unable to induce autologous B cell proliferation and Ig secretion in the presence of CD40L and C3. Finally, the regulatory T cell development ability of CD4+ T cells after CD3 and CD46 activation in the presence of IL-2 was significantly impaired. Thus, the association of important functional defects of dendritic cells, acquisition of B cell memory, and regulatory T cells with human C3 deficiency strongly supports a major role for C3 in bridging innate and adaptive immunity in humans.

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Control of C3b and C5b deposition by CD46 (membrane cofactor protein) after alternative but not classical complement activation

Cited by 42 publications

References 27 publications

A Possible Role of CD46 for the Protection In Vivo of Human Renal Tumor Cells from Complement-Mediated Damage

A Possible Role of CD46 for the Protection In Vivo of Human Renal Tumor Cells from Complement-Mediated Damage

Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome

Human C3 Deficiency Associated with Impairments in Dendritic Cell Differentiation, Memory B Cells, and Regulatory T Cells

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