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cFLIP overexpression in T cells in thymoma-associated myasthenia gravis

Objective The capacity of thymomas to generate mature CD4+ effector T cells from immature precursors inside the tumor and export them to the blood is associated with thymoma-associated myasthenia gravis (TAMG). Why TAMG(+) thymomas generate and export more mature CD4+ T cells than MG(−) thymomas is...

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Main Authors: Belharazem, Djeda (Author) , Schalke, Berthold (Author) , Gold, Ralf (Author) , Nix, Wilfred (Author) , Vitacolonna, Mario (Author) , Hohenberger, Peter (Author) , Rößner, Eric (Author) , Schulze, Torsten (Author) , Saruhan-Direskeneli, Güher (Author) , Yilmaz, Vuslat (Author) , Ott, German (Author) , Ströbel, Philipp (Author) , Marx, Alexander (Author)
Format: Article (Journal)
Language:English
Published: 22 July 2015
In: Annals of Clinical and Translational Neurology
Year: 2015, Volume: 2, Issue: 9, Pages: 894-905
ISSN:2328-9503
DOI:10.1002/acn3.210
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/acn3.210
Verlag, lizenzpflichtig, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1002/acn3.210
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Author Notes:Djeda Belharazem, Berthold Schalke, Ralf Gold, Wilfred Nix, Mario Vitacolonna, Peter Hohenberger, Eric Roessner, Torsten J. Schulze, Güher Saruhan‐Direskeneli, Vuslat Yilmaz, German Ott, Philipp Ströbel, Alexander Marx
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Summary:Objective The capacity of thymomas to generate mature CD4+ effector T cells from immature precursors inside the tumor and export them to the blood is associated with thymoma-associated myasthenia gravis (TAMG). Why TAMG(+) thymomas generate and export more mature CD4+ T cells than MG(−) thymomas is unknown. Methods Unfixed thymoma tissue, thymocytes derived thereof, peripheral blood mononuclear cells (PBMCs), T-cell subsets and B cells were analysed using qRT-PCR and western blotting. Survival of PBMCs was measured by MTT assay. FAS-mediated apoptosis in PBMCs was quantified by flow cytometry. NF-κB in PBMCs was inhibited by the NF-κB-Inhibitor, EF24 prior to FAS-Ligand (FASLG) treatment for apoptosis induction. Results Expression levels of the apoptosis inhibitor cellular FLICE-like inhibitory protein (c-FLIP) in blood T cells and intratumorous thymocytes were higher in TAMG(+) than in MG(−) thymomas and non-neoplastic thymic remnants. Thymocytes and PBMCs of TAMG patients showed nuclear NF-κB accumulation and apoptosis resistance to FASLG stimulation that was sensitive to NF-κB blockade. Thymoma removal reduced cFLIP expression in PBMCs. Interpretation We conclude that thymomas induce cFLIP overexpression in thymocytes and their progeny, blood T cells. We suggest that the stronger cFLIP overexpression in TAMG(+) compared to MG(−) thymomas allows for the more efficient generation of mature CD4+ T cells in TAMG(+) thymomas. cFLIP overexpression in thymocytes and exported CD4+ T cells of patients with TAMG might contribute to the pathogenesis of TAMG by impairing central and peripheral T-cell tolerance.
Item Description:Gesehen am 08.06.2020
Physical Description:Online Resource
ISSN:2328-9503
DOI:10.1002/acn3.210

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