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

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.

Pubmed ID: 20705491

Authors

  • Tavares RM
  • Turer EE
  • Liu CL
  • Advincula R
  • Scapini P
  • Rhee L
  • Barrera J
  • Lowell CA
  • Utz PJ
  • Malynn BA
  • Ma A

Journal

Immunity

Publication Data

August 27, 2010

Associated Grants

  • Agency: NIAID NIH HHS, Id: P01 AI078869
  • Agency: NIAID NIH HHS, Id: P01 AI078869-010002
  • Agency: NIAID NIH HHS, Id: R01 AI068150
  • Agency: NIDDK NIH HHS, Id: R01 DK071939
  • Agency: NIDDK NIH HHS, Id: R01 DK071939-06

Mesh Terms

  • Animals
  • Antigens, CD40
  • Autoimmunity
  • B-Lymphocytes
  • Cell Lineage
  • Cell Survival
  • Cysteine Endopeptidases
  • Homeostasis
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B
  • Signal Transduction