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  • Meeting abstract
  • Open Access

Disturbed B-lymphocytes selection in autoimmune lymphoproliferative syndrome

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Molecular and Cellular Pediatrics20152 (Suppl 1) :A23

  • Published:


  • Germinal Center
  • Charge Amino Acid
  • Lymphoid Malignancy
  • Somatic Hypermutation
  • Single Versus

Meeting abstract

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphoproliferative disease, autoimmune cytopenias and increased susceptibility to lymphoid malignancies. Central to the pathophysiology of the disease are defects in the FAS signaling leading to impaired lymphocyte homeostasis. Most of the patients harbor heterozygous germline or somatic mutations in FAS. The hallmark of the disease is the impaired FAS-mediated apoptosis of activated T cells and presence of atypical "double-negative" T cells (CD3+TCRalpha/beta+CD4-CD8-). While FAS is essential for deletion of autoreactive B cells in the germinal center in murine models, the role of FAS in human B cell selection and development of autoimmunity in patients carrying FAS mutation is unclear.

We analyzed patients with somatic FAS mutation or germline FAS mutation plus somatic loss-of-heterozygosity allowing to compare the fate of B cells with impaired versus normal FAS signaling within the same individual. We found in the class-switched memory B cells: 1) accumulation of FAS- mutated B cells, 2) a failure to enrich single V genes and in single V-D, D-J gene combinations of the B cell receptor variable region, 3) increased frequency of variable regions with higher content of positively charged amino acids and longer CDR3 and 4) 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 ALPS patients and indicate a role for B cell dysregulation in the pathogenesis of autoimmunity and B-cell lymphoma in ALPS patients.

Authors’ Affiliations

Centre for Chronic Immunodeficiency, (CCI), University Medical Centre, Freiburg, Germany
Centre for Pediatrics and Adolescent Medicine, University Medical Centre, University of Freiburg, Germany
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
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
Institute of Medical Biometry and Medical Statistics, University Medical Center, Freiburg, Germany
Department of Pathology, Molecular Pathology, University Medical Center, University of Freiburg, Germany
Department of Pediatrics, University Clinic Carl Gustav Carus, Dresden, Germany
Department of Pediatric Hematology, Oncology and Immunology, Dr von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany
Novartis Institute for Biomedical Research, Basel, Switzerland
Clinic for Rheumatology and Clinical Immunology, University Medical Centre, University of Freiburg, Germany


© Janda et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.