B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice
B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice
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DOI：
10.1182/blood-2010-09-306019
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发表时间：
2011-02-17
期刊：
影响因子：
20.3
通讯作者：
Schmidt-Supprian, Marc
中科院分区：
文献类型：
--
作者：
Chu, Yuanyuan;Vahl, J. Christoph;Schmidt-Supprian, Marc
泛素编辑酶A20/TNFAIP 3对于控制诱导核因子-κ B转录因子活化的信号是必需的。TNFAIP 3基因的多态性和突变与各种人类自身免疫性疾病有关，A20的失活是以组成性核因子-κ B活性为特征的人类B细胞淋巴瘤中的常见事件。通过小鼠中的B细胞特异性消融，我们在这里表明，A20是边缘区B和B1细胞亚群正常分化所必需的。然而，B细胞中A20的缺失降低了它们的活化阈值，并以基因剂量依赖性方式增强了增殖和存活。通过表达促炎细胞因子，最显著的是白细胞介素-6，A20缺陷型B细胞在幼稚小鼠中触发以髓样细胞、效应型T细胞和调节性T细胞扩增为特征的进行性炎症反应。这在老年小鼠中达到高潮，表现为脾肿大、浆细胞增生和存在类别转换的组织特异性自身抗体的自身免疫综合征。（血。2011;117（7）：2227-2236）
The ubiquitin-editing enzyme A20/TNFAIP3 is essential for controlling signals inducing the activation of nuclear factor- kappa B transcription factors. Polymorphisms and mutations in the TNFAIP3 gene are linked to various human autoimmune conditions, and inactivation of A20 is a frequent event in human B-cell lymphomas characterized by constitutive nuclear factor-kappa B activity. Through B cell-specific ablation in the mouse, we show here that A20 is required for the normal differentiation of the marginal zone B and B1 cell subsets. However, loss of A20 in B cells lowers their activation threshold and enhances proliferation and survival in a gene-dose-dependent fashion. Through the expression of proinflammatory cytokines, most notably interleukin- 6, A20-deficient B cells trigger a pro-gressive inflammatory reaction in naive mice characterized by the expansion of myeloid cells, effector-type T cells, and regulatory T cells. This culminates in old mice in an autoimmune syndrome characterized by splenomegaly, plasma cell hyperplasia, and the presence of classswitched, tissue-specific autoantibodies. (Blood. 2011;117(7):2227-2236)