Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome


  • A. Janda
  • K. Schwarz
  • M. van der Burg
  • W. Vach
  • H. Ijspeert
  • M.R. Lorenz
  • M. Elgizouli
  • K. Pieper
  • P. Fisch
  • J. Hagel
  • R. Lorenzetti
  • M. Seidl
  • J. Roesler
  • F. Hauck
  • E. Traggiai
  • C. Speckmann
  • A. Rensing-Ehl
  • S. Ehl
  • H. Eibel
  • M. Rizzi


  • Blood


  • Blood 127 (18): 2193-2202


  • Fas is a transmembrane receptor involved in the maintenance of tolerance and immune homeostasis. In murine models, it has been shown to be essential for deletion of autoreactive B cells in the germinal center. The role of Fas in human B-cell selection and in development of autoimmunity in patients carrying FAS mutations is unclear. We analyzed patients with either a somatic FAS mutation or a germline FAS mutation and somatic loss-of-heterozygosity, which allows comparing the fate of B cells with impaired vs normal Fas signaling within the same individual. Class-switched memory B cells showed: accumulation of FAS-mutated B cells; failure to enrich single V, D, J genes and single V-D, D-J gene combinations of the B-cell receptor variable region; increased frequency of variable regions with higher content of positively charged amino acids; and longer CDR3 and maintenance of polyreactive specificities. Importantly, Fas-deficient switched memory B cells showed increased rates of somatic hypermutation. Our data uncover a defect in B-cell selection in patients with FAS mutations, which has implications for the understanding of the pathogenesis of autoimmunity and lymphomagenesis of autoimmune lymphoproliferative syndrome.