Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Immunity. 2010 Aug 27;33(2):181-91. doi: 10.1016/j.immuni.2010.07.017. Epub 2010 Aug 12.
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.
A20 是一种泛素修饰酶，可限制 NF-κB 信号，并保护细胞免受肿瘤坏死因子 (TNF) 诱导的程序性细胞死亡。鉴于最近有数据将 A20（TNFAIP3）与人类 B 细胞淋巴瘤和系统性红斑狼疮 (SLE) 联系起来，我们生成了 Tnfaip3 基因敲入小鼠，以探究 A20 在调节 B 细胞功能中的作用。A20 缺陷的 B 细胞对多种刺激过度反应，并表现出对 CD40 诱导信号的过度 NF-κB 反应。在 B 细胞中表达缺失或低功能形式的 A20 的小鼠具有更高数量的生发中心 B 细胞、自身抗体和肾小球免疫球蛋白沉积。A20 缺陷的 B 细胞对 Fas 介导的细胞死亡具有抗性，可能是由于 NF-κB 依赖性抗凋亡蛋白如 Bcl-x 的表达增加所致。这些发现表明 A20 可以限制 B 细胞的存活，而 A20 则保护其他细胞免受 TNF 诱导的细胞死亡。我们的研究表明，A20 表达减少如何导致自身免疫。
