Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome
Authors
- 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
Journal
- Blood
Citation
- Blood 127 (18): 2193-2202
Abstract
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.