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The roles of E2A and Id2 in class switch recombination

E2A和Id2在类别转换重组中的作用

基本信息

批准号：
14570104
负责人：
SUGAI Manabu
金额：
$ 1.86万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570104/
关键词：
Id2 E2A Pax5 B cell IgE class switch TGF-β class switch recombination germline transcript TGF-beta1 B cell activation

项目摘要

1.Immunoglobulin E (IgE) plays a central,role in the pathogenesis of allergic disorders but its serum level is kept much lower than other immunoglobulin classes in normal. In B cells lacking Id2, the highly augmented activity of E2A enhances ε germline transcription, and thus class switch recombination (CSR) to IgE. In wild-type B cells, in contrast, Id2 is induced by TGF-β1 and suppresses IgE CSR. This suppression does not occur in Id2 deficient B cells. Our results provide evidence for the inhibitory and selective role of Id2 in IgE CSR, especially in response to TGF-β1. indicating Id2 is a safeguard molecule.2.Pax5 activity is enhanced in activated B cells and is essential for class switch recombination (CSR). We show that Id2 suppresses CSR by repressing the gene expression of activation-induced cytidine deaminase (AID), which has been shown to be indispensable for CSR. Furthermore, a putative regulatory region of AID contains E2A-and Pax5-binding sites and the latter site is indispensable for AID gene expression. Moreover, the DNA binding activity of Pax5 is decreased in Id2-overexpressing B cells, and enhanced in Id2^<-/-> B cells. The kinetics of Pax5-occupancy, but not E2A, to AID locus is the same as AID expression in primary B cells. Finally, enforced-expression of Pax5 induces AID transcription in pro-B cell lines. Our results provide evidence that the balance between E2A, Pax5 and Id2 activities has a key role in AID gene expression.Thus, Id2 acts as a negative regulator to prevent potentially harmful effects brought about by excessive immunological reactions: one of its special roles is to maintain low serum concentrations of immunoglobulin E (IgE).

1.免疫球蛋白E(IgE)在变态反应性疾病的发病机制中起中心作用，但其血清水平远低于正常人群中的其他免疫球蛋白。在缺乏Id2的B细胞中，E2a的活性高度增强，促进了ε胚系转录，从而将类重组转换为Ig E。相反，在野生型B细胞中，Id2由转化生长因子-β1诱导，并抑制IgECSR。这种抑制不会发生在Id2缺陷的B细胞中。我们的结果为Id2在IgECSR中的抑制和选择性作用提供了证据，特别是在对转化生长因子-β的反应中。1.Id2是一个保护分子。我们发现Id2通过抑制激活诱导型胞苷脱氨酶(AID)的基因表达来抑制CSR，AID已被证明是CSR所必需的。此外，AID的一个可能的调节区包含E2A和Pax5结合位点，后者是AID基因表达所必需的。此外，在Id2过度表达的B细胞中，Pax5的DNA结合活性降低，而在Id2^&lt；-/-&Gt；B细胞中增强。在原代B细胞中，Pax5占据AID位点的动力学与AID表达相同，而不是E2a。最后，Pax5的强制表达可诱导Pro-B细胞中的AID转录。我们的结果表明，E2a、Pax5和Id2活性之间的平衡在AID基因的表达中起着关键作用。因此，Id2作为负调控因子来防止过度免疫反应带来的潜在有害影响：其特殊作用之一是维持较低的血清免疫球蛋白E(IgE)浓度。