@article{115ac2da38914e988370e44c40e4da3c,
title = "The Ubiquitin Modifying Enzyme A20 Restricts B Cell Survival and Prevents Autoimmunity",
abstract = "A20 is a ubiquitin modifying enzyme that restricts NF-κB 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-κB 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-κB-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.",
keywords = "Cellimmuno, Molimmuno, Signaling",
author = "Tavares, {Rita M.} and Turer, {Emre E.} and Liu, {Chih L.} and Rommel Advincula and Patrizia Scapini and Lesley Rhee and Julio Barrera and Lowell, {Clifford A.} and Utz, {Paul J.} and Malynn, {Barbara A.} and Averil Ma",
note = "Funding Information: This work was supported by the National Institutes of Health, the Alliance for Lupus Research (A.M.), the Funda{\c c}{\~a}o para a Ci{\^e}ncia e Tecnologia (to R. T.), UCSF-VAMC Pathology Core, the Cancer Center Pathology Core, UCSF Liver Center Immunology and Pathology Cores, the UCSF Transgenic and Targeted Mutagenesis Core Facility, and the Rainin Foundation. We thank the skillful technical assistance of I. Hsieh (UCSF-VAMC Pathology) and J. Publicover (UCSF Liver Center), and helpful advice from J.P. Pereira and L. Reinhardt. We thank T. DeFranco and J. Cyster for critically reading the manuscript. R.M.T. planned and performed the experiments, analyzed the data, and assisted in writing the manuscript. E.E.T. made the conditional gene targeting construct, performed gene targeting in ESCs, and characterized the original Tnfaip3 fl germline mice. R.A. performed mice breeding and genotyping, and assisted with mouse injections and bleeding. C.L.L. performed the antibody array experiments and statistical analyses, under the supervision of P.J.U. C.A.L., and P.J.U. edited the manuscript. P.S. assisted in the analysis of the autoantibody data and mouse histology and immunohistochemistry, under the supervision of C.A.L. L.R. performed some of the initial experiments with R.M.T. J.B. provided excellent technical assistance. B.A.M. and A.M. helped plan and supervise the experiments and data analysis and wrote the manuscript. ",
year = "2010",
month = aug,
doi = "10.1016/j.immuni.2010.07.017",
language = "English (US)",
volume = "33",
pages = "181--191",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "2",
}