title: cFLIP overexpression in T cells in thymoma-associated myasthenia gravis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg Mannheim, Germany.
authors.forename: Djeda
authors.initials: D
authors.lastname: Belharazem
authors.affiliation: Department of Neurology, University of Regensburg Regensburg, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Schalke
authors.affiliation: Department of Neurology, University of Bochum Bochum, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.affiliation: Department of Neurology, University of Mainz Mainz, Germany.
authors.forename: Wilfred
authors.initials: W
authors.lastname: Nix
authors.affiliation: Department of Thoracic Surgery, University Medical Centre Mannheim Mannheim, Germany.
authors.forename: Mario
authors.initials: M
authors.lastname: Vitacolonna
authors.affiliation: Department of Thoracic Surgery, University Medical Centre Mannheim Mannheim, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hohenberger
authors.affiliation: Department of Thoracic Surgery, University Medical Centre Mannheim Mannheim, Germany.
authors.forename: Eric
authors.initials: E
authors.lastname: Roessner
authors.affiliation: Institute for Transfusion Medicine and Immunology, German Red Cross Blood Service, University Medical Centre Mannheim Mannheim, Germany.
authors.forename: Torsten J
authors.initials: TJ
authors.lastname: Schulze
authors.affiliation: Department of Physiology, School of Medicine, Istanbul University Istanbul, Turkey.
authors.forename: Güher
authors.initials: G
authors.lastname: Saruhan-Direskeneli
authors.affiliation: Department of Physiology, School of Medicine, Istanbul University Istanbul, Turkey.
authors.forename: Vuslat
authors.initials: V
authors.lastname: Yilmaz
authors.affiliation: Department of Pathology, Robert-Bosch Hospital Stuttgart, Germany.
authors.forename: German
authors.initials: G
authors.lastname: Ott
authors.affiliation: Institute of Pathology, University of Goettingen Goettingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Institute of Pathology, University Medical Centre Mannheim, University of Heidelberg Mannheim, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Marx