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Disturbed B-lymphocytes selection in autoimmune lymphoproliferative syndrome

  • Aleš Janda
  • Klaus Schwarz
  • Mirjam van der Burg
  • Werner Vach
  • Hanna Ijspeert
  • Myriam Ricarda Lorenz
  • Magdeldin Elgizouli
  • Kathrin Pieper
  • Paul Fisch
  • Joachim Hagel
  • Raquel Lorenzetti
  • Maximilian Seidl
  • Joachim Roesler
  • Fabian Hauck
  • Elisabetta Traggiai
  • Carsten Speckmann
  • Anne Rensing-Ehl
  • Stephan Ehl
  • Hermann Eibel
  • Marta Rizzi
Open Access
Meeting abstract
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Keywords

Germinal Center Charge Amino Acid Lymphoid Malignancy Somatic Hypermutation Single Versus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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.

Copyright information

© 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 (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  • Aleš Janda
    • 1
    • 2
  • Klaus Schwarz
    • 3
    • 4
  • Mirjam van der Burg
    • 5
  • Werner Vach
    • 6
  • Hanna Ijspeert
    • 5
  • Myriam Ricarda Lorenz
    • 3
  • Magdeldin Elgizouli
    • 1
  • Kathrin Pieper
    • 1
  • Paul Fisch
    • 7
  • Joachim Hagel
    • 1
  • Raquel Lorenzetti
    • 1
  • Maximilian Seidl
    • 1
    • 7
  • Joachim Roesler
    • 8
  • Fabian Hauck
    • 9
  • Elisabetta Traggiai
    • 10
  • Carsten Speckmann
    • 1
    • 2
  • Anne Rensing-Ehl
    • 1
  • Stephan Ehl
    • 1
    • 2
  • Hermann Eibel
    • 1
  • Marta Rizzi
    • 1
    • 11
  1. 1.Centre for Chronic Immunodeficiency, (CCI)University Medical CentreFreiburgGermany
  2. 2.Centre for Pediatrics and Adolescent MedicineUniversity Medical Centre, University of FreiburgGermany
  3. 3.Institute for Transfusion MedicineUniversity of UlmUlmGermany
  4. 4.Institute for Clinical Transfusion Medicine and Immunogenetics UlmGerman Red Cross Blood Service Baden-Württemberg - HessenUlmGermany
  5. 5.Department of Immunology, Erasmus MCUniversity Medical Center RotterdamRotterdamThe Netherlands
  6. 6.Institute of Medical Biometry and Medical StatisticsUniversity Medical CenterFreiburgGermany
  7. 7.Department of Pathology, Molecular PathologyUniversity Medical Center, University of FreiburgGermany
  8. 8.Department of PediatricsUniversity Clinic Carl Gustav CarusDresdenGermany
  9. 9.Department of Pediatric Hematology, Oncology and Immunology, Dr von Hauner Children's HospitalLudwig-Maximilians-UniversityMunichGermany
  10. 10.Novartis Institute for Biomedical ResearchBaselSwitzerland
  11. 11.Clinic for Rheumatology and Clinical ImmunologyUniversity Medical Centre, University of FreiburgGermany

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