Blood Journal
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B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice

  1. Yuanyuan Chu1,
  2. J. Christoph Vahl1,
  3. Dilip Kumar1,
  4. Klaus Heger1,
  5. Arianna Bertossi1,
  6. Edyta Wójtowicz1,
  7. Valeria Soberon1,
  8. Dominik Schenten2,
  9. Brigitte Mack3,
  10. Miriam Reutelshöfer4,
  11. Rudi Beyaert5,
  12. Kerstin Amann4,
  13. Geert van Loo5, and
  14. Marc Schmidt-Supprian1
  1. 1Max Planck Institute of Biochemistry, Martinsried, Germany;
  2. 2Yale University School of Medicine, New Haven, CT;
  3. 3Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians-University of Munich, Munich, Germany;
  4. 4Universitätsklinikum Erlangen, Pathologisches Institut, Abt Nephropathologie, Erlangen, Germany; and
  5. 5Department for Molecular Biomedical Research, VIB and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium


The ubiquitin-editing enzyme A20/TNFAIP3 is essential for controlling signals inducing the activation of nuclear factor-κB transcription factors. Polymorphisms and mutations in the TNFAIP3 gene are linked to various human autoimmune conditions, and inactivation of A20 is a frequent event in human B-cell lymphomas characterized by constitutive nuclear factor-κB activity. Through B cell-specific ablation in the mouse, we show here that A20 is required for the normal differentiation of the marginal zone B and B1 cell subsets. However, loss of A20 in B cells lowers their activation threshold and enhances proliferation and survival in a gene-dose–dependent fashion. Through the expression of proinflammatory cytokines, most notably interleukin-6, A20-deficient B cells trigger a progressive inflammatory reaction in naive mice characterized by the expansion of myeloid cells, effector-type T cells, and regulatory T cells. This culminates in old mice in an autoimmune syndrome characterized by splenomegaly, plasma cell hyperplasia, and the presence of class-switched, tissue-specific autoantibodies.

  • Submitted September 8, 2010.
  • Accepted October 28, 2010.
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