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

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 hyper-responsive 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, likely due to increased expression of NF-κB-dependent anti-apoptotic proteins such as Bcl-x. These findings show that A20 can restrict B cell survival, while 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，它限制核因子-κB（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。鉴于近期有数据将A20（TNFAIP3）与人类B细胞淋巴瘤和系统性红斑狼疮（SLE）相关联，我们培育了携带Tnfaip3条件性等位基因的小鼠，以探究A20在调节B细胞功能中的作用。A20缺陷的B细胞对多种刺激反应过度，并对CD40诱导的信号表现出过度的NF -κB反应。在B细胞中A20缺失或表达量低的小鼠，其生发中心B细胞数量增加、自身抗体增多以及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，这可能是由于NF -κB依赖性抗凋亡蛋白（如Bcl - x）表达增加所致。这些发现表明，A20可限制B细胞存活，而A20保护其他细胞免受TNF诱导的细胞死亡。我们的研究证明了A20表达降低如何易引发自身免疫。