Relative Contributions of Decay Accelerating Factor (DAF), Membrane Cofactor Protein (MCP) and CD59 in the Protection of Melanocytes from Homologous Complement

Venneker, G.T.; Vodegel, R.M.; Okada, N; Westerhof, W.; Bos, Jan D.; Asghar, Syed S.

doi:10.1016/s0171-2985(98)80054-5

Cited by 17 publications

(6 citation statements)

References 27 publications

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“…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). We propose, in view of our present results, that CD46 is able to regulate the amplification loop of the classical pathway when the expression of CD55 is low or absent.…”

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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“…In addition, we have measured whether relevant cytokines did not downregulate the renal tumour‐associated target antigen G250/MN/CAIX. CD55 and CD59 are presumed to be the most important regulators of classical pathway‐induced complement activation [42, 43]. Therefore, the functional effects of alterations in CD55 or CD59 expression on the resistance of renal tumour cells to complement‐mediated injury induced by MoAb were also studied.…”

Section: Discussionmentioning

confidence: 99%

Cytokines Affect Resistance of Human Renal Tumour Cells to Complement‐Mediated Injury

et al. 2003

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Overexpression of membrane-bound complement regulatory proteins (mCRPs) on tumour cells may hamper the effect of immunotherapy with complementactivating monoclonal antibody (MoAb). Therefore, it is important to investigate whether cytokines can downregulate the expression of mCRP on tumour cells. In this study, the effect of 10 cytokines on the expression of the mCRP CD46, CD55 and CD59 and the renal tumour-associated antigen G250/MN/ CAIX on four human renal tumour cell lines and proximal tubular epithelial cells was determined by flow cytometry. In addition, it was measured whether changes in the expression of the classical pathway regulatory proteins CD55 and CD59 had an effect on C3 deposition and lysis. Interleukin-1b (IL-1b) consistently downregulated the expression of CD46 and CD59; IL-4 consistently downregulated the expression of CD46 and transforming growth factor-b 1 , consistently downregulated the expression of both CD46 and CD55. However, treatment with IL-1b and IL-4 also decreased the expression of G250/MN/ CAIX. Changes in the expression of CD55 and CD59 were associated with changes in the amount of C3 deposited and the extent of complement-mediated lysis, respectively. This suggests that clinical immunotherapy, consisting of treatment with cytokines and MoAb, may induce either up-or downregulation of CD55 or CD59 and thus affect the effectiveness of immunotherapy with MoAb.

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“…In vitro studies were used to demonstrate that melanocytes are vulnerable to complement-mediated killing and ADCC (Norris et al, 1988). Complement-activated killing may occur speci¢cally in vitiligo patients where aberrant expression of complement regulatory proteins, membrane cofactor protein (MCP), and decay-accelerating factor (DAF) leaves melanocytes sensitive to complement-mediated lysis (Venneker et al, 1998;van den Wijngaard et al, 2002a). In vivo, vitiligo serum is capable of reducing melanocyte numbers in xenotransplanted human skin (Gilhar et al, 1995).…”

Section: Depigmentation and Serum Autoantibodiesmentioning

confidence: 99%

Autoimmune Aspects of Depigmentation in Vitiligo

Poole

Wańkowicz-Kalińska

Wijngaard

et al. 2004

Journal of Investigative Dermatology Symposium Proceedings

115

102

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Autoimmune depigmentation of the skin, vitiligo, afflicts a considerable number of people, yet no effective therapeutic modalities have been developed to treat it. In part, this can be attributed to the obscure etiology of the disease, which has begun to reveal itself only recently. It is known that pigment is lost as a function of reduced melanocyte numbers in the epidermis, and that depigmentation is accompanied by T cell influx to the skin in the vast majority of patients. Characterizing such infiltrating T cells as type 1 proinflammatory cytokine-secreting cells reactive with melanocyte-specific antigen is a major step toward effective therapy. Melanoma research has shown that differentiation antigens, also expressed by normal melanocytes, can be immunogenic when expressed in the melanosomal compartment of the cell. Similar reactivity to melanosomal antigens is apparent for T cells infiltrating vitiligo skin. It may eventually be possible to treat patients with decoy antigens that anergize such Tcells, or to prevent recruitment of the T cells to the skin altogether. In this respect, it is important that T cells are recruited to the skin as a function of dendritic cell activation and that dendritic cells are likely activated at sites of epidermal trauma as a consequence of stress proteins that spill over into the microenvironment. Stress proteins chaperoning antigens representative of the cells from which they were derived are then processed by dendritic cells and contribute to their activation. Activated dendritic cells not only migrate to draining lymph nodes to recruit T cells but may execute cytotoxic effector functions as well. The contribution of the effector functions to actual depigmentation of the skin remains to be investigated.

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Relative Contributions of Decay Accelerating Factor (DAF), Membrane Cofactor Protein (MCP) and CD59 in the Protection of Melanocytes from Homologous Complement

Cited by 17 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

Cytokines Affect Resistance of Human Renal Tumour Cells to Complement‐Mediated Injury

Autoimmune Aspects of Depigmentation in Vitiligo

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