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    block this user Werner Muller

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    Faculty of Life Science, University of Manchester, Manchester

    Constitutive CD40 signaling in B cells selectively activates the noncanonical NF- B pathway and promotes lymphomagenesis

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    CD40, a member of the tumor necrosis factor (TNF) receptor family, plays an essential role in T celldependent immune responses. Because CD40 is widely expressed on the surface of tumor cells in various B cell malignancies, deregulated CD40 signaling has been suggested to contribute to lymphomagenesis. In this study, we show that B cell-specific expression of a constitutively active CD40 receptor, in the form of a latent membrane protein 1 (LMP1)/CD40 chimeric protein, promoted an increase in the number of follicular and marginal zone B cells in secondary lymphoid organs in transgenic mice. The B cells displayed an activated phenotype, prolonged survival and increased proliferation, but were significantly impaired in T cell-dependent immune responses. Constitutive CD40 signaling in B cells induced selective and constitutive activation of the noncanonical NF-κB pathway and the mitogen-activated protein kinases Jnk and extracellular signalregulated kinase. LMP1/CD40-expressing mice older than 12 mo developed B cell lymphomas of mono- or oligoclonal origin at high incidence, thus showing that the interplay of the signaling pathways induced by constitutive CD40 signaling is sufficient to initiate a tumorigenic process, ultimately leading to the development of B cell lymphomas.

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    Description

    Title : Constitutive CD40 signaling in B cells selectively activates the noncanonical NF- B pathway and promotes lymphomagenesis
    Author(s) : C. Homig-Holzel, C. Hojer, J. Rastelli, S. Casola, L. J. Strobl, W. Muller, L. Quintanilla-Martinez, A. Gewies, J. Ruland, K. Rajewsky, U. Zimber-Strobl
    Abstract : CD40, a member of the tumor necrosis factor (TNF) receptor family, plays an essential role in T celldependent immune responses. Because CD40 is widely expressed on the surface of tumor cells in various B cell malignancies, deregulated CD40 signaling has been suggested to contribute to lymphomagenesis. In this study, we show that B cell-specific expression of a constitutively active CD40 receptor, in the form of a latent membrane protein 1 (LMP1)/CD40 chimeric protein, promoted an increase in the number of follicular and marginal zone B cells in secondary lymphoid organs in transgenic mice. The B cells displayed an activated phenotype, prolonged survival and increased proliferation, but were significantly impaired in T cell-dependent immune responses. Constitutive CD40 signaling in B cells induced selective and constitutive activation of the noncanonical NF-κB pathway and the mitogen-activated protein kinases Jnk and extracellular signalregulated kinase. LMP1/CD40-expressing mice older than 12 mo developed B cell lymphomas of mono- or oligoclonal origin at high incidence, thus showing that the interplay of the signaling pathways induced by constitutive CD40 signaling is sufficient to initiate a tumorigenic process, ultimately leading to the development of B cell lymphomas.
    Keywords : animals, antigens, cd40, cd40 deficiency, cd40 genetics, cd40 immunology, b lymphocytes, b lymphocytes immunology, crosses, genetic, germinal center, germinal center immunology, lymphocyte activation, lymphocyte count, lymphoma, b cell, b cell immunology,

    Subject : unspecified
    Area : Other
    Language : English
    Year : 2008

    Affiliations Faculty of Life Science, University of Manchester, Manchester
    Journal : Journal of Experimental Medicine
    Volume : 205
    Issue : 6
    Publisher : The Rockefeller University Press
    Pages : 1317 - 1329
    Url : http://www.jem.org/cgi/doi/10.1084/jem.20080238
    Doi : 10.1084/jem.20080238

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    Werner's Peer Evaluation activity

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    • Mahendra Kumar Trivedi, Independent researcher, Las Vegas Naveda, Trivedi Global Inc., Trivedi Science Research Laboratory Pvt. Ltd.
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