title: Disturbed B-lymphocyte selection in autoimmune lymphoproliferative syndrome.
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.
authors.affiliation: Center for Chronic Immunodeficiency and Center for Pediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Freiburg, Germany;
authors.forename: Ales
authors.initials: A
authors.lastname: Janda
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, Ulm, Germany; Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Württemberg-Hessen, Ulm, Germany;
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.affiliation: Institute of Medical Biometry and Medical Statistics, and.
authors.forename: Werner
authors.initials: W
authors.lastname: Vach
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands;
authors.forename: Hanna
authors.initials: H
authors.lastname: Ijspeert
authors.affiliation: Institute for Transfusion Medicine, University of Ulm, Ulm, Germany;
authors.forename: Myriam Ricarda
authors.initials: MR
authors.lastname: Lorenz
authors.affiliation: Center for Chronic Immunodeficiency and.
authors.forename: Magdeldin
authors.initials: M
authors.lastname: Elgizouli
authors.affiliation: Center for Chronic Immunodeficiency and.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Pieper
authors.affiliation: Molecular Pathology, Department of Pathology, University Medical Center, University of Freiburg, Freiburg, Germany;
authors.forename: Paul
authors.initials: P
authors.lastname: Fisch
authors.affiliation: Center for Chronic Immunodeficiency and.
authors.forename: Joachim
authors.initials: J
authors.lastname: Hagel
authors.affiliation: Center for Chronic Immunodeficiency and.
authors.forename: Raquel
authors.initials: R
authors.lastname: Lorenzetti
authors.affiliation: Center for Chronic Immunodeficiency and Molecular Pathology, Department of Pathology, University Medical Center, University of Freiburg, Freiburg, Germany;
authors.forename: Maximilian
authors.initials: M
authors.lastname: Seidl
authors.affiliation: Department of Pediatrics, University Clinic Carl Gustav Carus, Dresden, Germany;
authors.forename: Joachim
authors.initials: J
authors.lastname: Roesler
authors.affiliation: Department of Pediatric Hematology, Oncology and Immunology, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany;
authors.forename: Fabian
authors.initials: F
authors.lastname: Hauck
authors.affiliation: Novartis Institute for Biomedical Research, Basel, Switzerland; and.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.affiliation: Center for Chronic Immunodeficiency and Center for Pediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Freiburg, Germany;
authors.forename: Carsten
authors.initials: C
authors.lastname: Speckmann
authors.affiliation: Center for Chronic Immunodeficiency and.
authors.forename: Anne
authors.initials: A
authors.lastname: Rensing-Ehl
authors.affiliation: Center for Chronic Immunodeficiency and Center for Pediatrics and Adolescent Medicine, University Medical Center, University of Freiburg, Freiburg, Germany;
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
authors.affiliation: Center for Chronic Immunodeficiency and.
authors.forename: Hermann
authors.initials: H
authors.lastname: Eibel
authors.affiliation: Center for Chronic Immunodeficiency and Clinic for Rheumatology and Clinical Immunology, University Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Marta
authors.initials: M
authors.lastname: Rizzi
mesh_terms: D017209:Apoptosis; D056735:Autoimmune Lymphoproliferative Syndrome / Q000276:immunology*; D015551:Autoimmunity; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic; D002648:Child; D060966:Clonal Selection, Antigen-Mediated; D018389:Codon, Nonsense; D005260:Female; D016368:Frameshift Mutation; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007156:Immunologic Memory; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin; D060152:V(D)J Recombination; D019014:fas Receptor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018389:Codon, Nonsense; C491901:FAS protein, human; D019014:fas Receptor
keywords: ALPS and B cells; ALPS and B-lymphocytes; ALPS and Rizzi; autoimmune lymphoproliferative syndrome and B cells