Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome

A Janda, K Schwarz, Mirjam van der Burg, W Vach, Hanna Ijspeert, MR 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

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21 Citations (Scopus)


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.
Original languageUndefined/Unknown
Pages (from-to)2193-2202
Number of pages10
Issue number18
Publication statusPublished - 2016

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