cFLIP overexpression in T cells in thymoma-associated myasthenia gravis

• Verfasst von: Belharazem, Djeda [VerfasserIn]
• Verfasst von: Schalke, Berthold [VerfasserIn]
• Verfasst von: Gold, Ralf [VerfasserIn]
• Verfasst von: Nix, Wilfred [VerfasserIn]
• Verfasst von: Vitacolonna, Mario [VerfasserIn]
• Verfasst von: Hohenberger, Peter [VerfasserIn]
• Verfasst von: Rößner, Eric [VerfasserIn]
• Verfasst von: Schulze, Torsten [VerfasserIn]
• Verfasst von: Saruhan-Direskeneli, Güher [VerfasserIn]
• Verfasst von: Yilmaz, Vuslat [VerfasserIn]
• Verfasst von: Ott, German [VerfasserIn]
• Verfasst von: Ströbel, Philipp [VerfasserIn]
• Verfasst von: Marx, Alexander [VerfasserIn]
• Titel: cFLIP overexpression in T cells in thymoma-associated myasthenia gravis
• Verf.angabe: 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
• E-Jahr: 2015
• Jahr: 22 July 2015
• Umfang: 12 S.
• Fussnoten: Gesehen am 08.06.2020
• Titel Quelle: Enthalten in: Annals of Clinical and Translational Neurology
• Ort Quelle: Chichester [u.a.] : Wiley, 2013
• Jahr Quelle: 2015
• Band/Heft Quelle: 2(2015), 9, Seite 894-905
• ISSN Quelle: 2328-9503
• DOI: doi:10.1002/acn3.210
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1700175831

Abstract

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.