Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome.
نویسندگان
چکیده
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.
منابع مشابه
Disturbed B-lymphocytes selection in autoimmune lymphoproliferative syndrome
lymphoproliferative syndrome Aleš Janda, Aff1 Aff2 Corresponding Affiliation: Aff1 Klaus Schwarz, Aff3 Aff4 Mirjam van der Burg, Aff5 Werner Vach, Aff6 Hanna Ijspeert, Aff5 Myriam Ricarda Lorenz, Aff3 Magdeldin Elgizouli, Aff1 Kathrin Pieper, Aff1 Paul Fisch, Aff7 Joachim Hagel, Aff1 Raquel Lorenzetti, Aff1 Maximilian Seidl, Aff1 Aff7 Joachim Roesler, Aff8 Fabian Hauck, Aff9 Elisabetta Traggiai...
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ورودعنوان ژورنال:
- Blood
دوره 127 18 شماره
صفحات -
تاریخ انتشار 2016