Goldfarb A N, Flores J P, Lewandowska K
Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4943, USA.
Mol Immunol. 1996 Aug;33(11-12):947-56. doi: 10.1016/s0161-5890(96)00047-8.
The basic helix-loop-helix (bHLH) transcriptional factor E2A has previously been shown to play a critical role in early B cell development, with E2A knockout mice and Id1 transgenic mice showing an arrest at the pro-B cell stage of development. More recent data suggest that E2A, through an interaction with the immunoglobulin heavy chain 3' enhancer, might also regulate later events in B cell development such as heavy chain class switching. The patterns of E2A protein expression in secondary lymphoid tissues support a role in later stages of B cell maturation. In particular, immunostaining reveals upregulation of E2A protein in cells of the dark zone of the germinal center, the site of immunoglobulin heavy chain class switching. To examine the role of E2A in class switching, the inhibitory HLH protein Id1 was expressed in B cell lines which normally undergo spontaneous and inducible switching from IgM to IgA. The forced expression of Id1 in these cell lines effectively blocked class switching. This Id1 blockade of class switching did not occur via downregulation of immunoglobulin heavy chain germline transcription or through inhibition of cell cycling. Furthermore, Id1 inhibited spontaneous and, to a lesser degree, cytokine inducible class switching. From these data, we conclude that E2A plays an important role in the class switching process.
先前的研究表明，基本螺旋-环-螺旋（bHLH）转录因子E2A在早期B细胞发育中起关键作用，E2A基因敲除小鼠和Id1转基因小鼠在B细胞发育的前B细胞阶段出现发育停滞。最近的数据表明，E2A通过与免疫球蛋白重链3'增强子相互作用，可能还调控B细胞发育后期的事件，如重链类别转换。E2A蛋白在次级淋巴组织中的表达模式支持其在B细胞成熟后期发挥作用。特别是，免疫染色显示生发中心暗区细胞中E2A蛋白上调，而生发中心暗区是免疫球蛋白重链类别转换的部位。为了研究E2A在类别转换中的作用，在通常经历从IgM到IgA自发和诱导性转换的B细胞系中表达抑制性HLH蛋白Id1。在这些细胞系中强制表达Id1有效地阻断了类别转换。Id1对类别转换的这种阻断不是通过下调免疫球蛋白重链种系转录或抑制细胞周期发生的。此外，Id1抑制自发的以及在较小程度上抑制细胞因子诱导的类别转换。从这些数据中，我们得出结论，E2A在类别转换过程中起重要作用。
