cFLIP overexpression in T cells in thymoma‐associated myasthenia gravis
| Autor: | Vuslat Yilmaz, German Ott, Eric Dominic Roessner, Mario Vitacolonna, Djeda Belharazem, Güher Saruhan-Direskeneli, Peter Hohenberger, Wilfred Nix, Torsten J. Schulze, Ralf Gold, Philipp Ströbel, Alexander Marx, Berthold Schalke |
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| Rok vydání: | 2015 |
| Předmět: |
0303 health sciences
Thymoma medicine.diagnostic_test Apoptosis Inhibitor business.industry General Neuroscience medicine.disease Peripheral blood mononuclear cell Myasthenia gravis Flow cytometry Blot 03 medical and health sciences 0302 clinical medicine Apoptosis hemic and lymphatic diseases Immunology medicine Cancer research MTT assay Neurology (clinical) business Research Articles 030304 developmental biology 030215 immunology |
| Zdroj: | Annals of Clinical and Translational Neurology |
| ISSN: | 2328-9503 |
| DOI: | 10.1002/acn3.210 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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