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

Yuanyuan Chu, J. Christoph Vahl, Dilip Kumar, Klaus Heger, Arianna Bertossi, Edyta Wójtowicz, Valeria Soberon, Dominik Schenten, Brigitte Mack, Miriam Reutelshófer, Rudi Beyaert, Kerstin Amann, Geert Van Loo, Marc Schmidt-Supprian

Research output: Contribution to journalArticle

128 Scopus citations

Abstract

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 classswitched, tissue-specific autoantibodies.

Original languageEnglish (US)
Pages (from-to)2227-2236
Number of pages10
JournalBlood
Volume117
Issue number7
DOIs
StatePublished - Feb 17 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Chu, Y., Vahl, J. C., Kumar, D., Heger, K., Bertossi, A., Wójtowicz, E., Soberon, V., Schenten, D., Mack, B., Reutelshófer, M., Beyaert, R., Amann, K., Van Loo, G., & Schmidt-Supprian, M. (2011). B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood, 117(7), 2227-2236. https://doi.org/10.1182/blood-2010-09-306019