The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity

Immunity. 2010 Aug 27;33(2):181-91. doi: 10.1016/j.immuni.2010.07.017. Epub 2010 Aug 12.

Abstract

A20 is a ubiquitin modifying enzyme that restricts NF-kappaB signals and protects cells against tumor necrosis factor (TNF)-induced programmed cell death. Given recent data linking A20 (TNFAIP3) with human B cell lymphomas and systemic lupus erythematosus (SLE), we have generated mice bearing a floxed allele of Tnfaip3 to interrogate A20's roles in regulating B cell functions. A20-deficient B cells are hyperresponsive to multiple stimuli and display exaggerated NF-kappaB responses to CD40-induced signals. Mice expressing absent or hypomorphic amounts of A20 in B cells possess elevated numbers of germinal center B cells, autoantibodies, and glomerular immunoglobulin deposits. A20-deficient B cells are resistant to Fas-mediated cell death, probably due to increased expression of NF-kappaB-dependent antiapoptotic proteins such as Bcl-x. These findings show that A20 can restrict B cell survival, whereas A20 protects other cells from TNF-induced cell death. Our studies demonstrate how reduced A20 expression predisposes to autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity*
  • B-Lymphocytes / cytology*
  • B-Lymphocytes / enzymology
  • B-Lymphocytes / immunology*
  • CD40 Antigens / immunology
  • CD40 Antigens / metabolism
  • Cell Lineage
  • Cell Survival
  • Cysteine Endopeptidases / deficiency
  • Cysteine Endopeptidases / immunology*
  • Cysteine Endopeptidases / metabolism*
  • Homeostasis
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / immunology*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • CD40 Antigens
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • Tumor Necrosis Factor alpha-Induced Protein 3
  • Cysteine Endopeptidases
  • Tnfaip3 protein, mouse