Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome

• Published in: Blood 2016-05, Vol.127 (18), p.2193-2202
• Main Authors: Janda, Ales, Schwarz, Klaus, van der Burg, Mirjam, Vach, Werner, Ijspeert, Hanna, Lorenz, Myriam Ricarda, Elgizouli, Magdeldin, Pieper, Kathrin, Fisch, Paul, Hagel, Joachim, Lorenzetti, Raquel, Seidl, Maximilian, Roesler, Joachim, Hauck, Fabian, Traggiai, Elisabetta, Speckmann, Carsten, Rensing-Ehl, Anne, Ehl, Stephan, Eibel, Hermann, Rizzi, Marta
• Format: Article
• Language: English
• Subjects: Apoptosis; Autoimmune Lymphoproliferative Syndrome - immunology; Autoimmunity; B-Lymphocyte Subsets - immunology; Cell Line, Transformed; Cell Transformation, Neoplastic; Child; Clonal Selection, Antigen-Mediated; Codon, Nonsense; fas Receptor - deficiency; fas Receptor - genetics; fas Receptor - physiology; Female; Frameshift Mutation; Germ-Line Mutation; Heterozygote; Humans; Immunologic Memory; Loss of Heterozygosity; Male; Mutation; Sequence Analysis, DNA; Somatic Hypermutation, Immunoglobulin; V(D)J Recombination
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2015-04-642488

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. •Fas-mutated B cells accumulate in the memory compartment and are highly mutated and polyreactive.•Fas deficiency leads to an intrinsic defect in B cells selection that predisposes to autoimmunity and identifies B cells as therapeutic targets for autoimmune lymphoproliferative syndrome.