Deficiency of the oxidative damage-specific DNA glycosylase NEIL1 leads to reduced germinal center B cell expansion.
Deficiency of the oxidative damage-specific DNA glycosylase NEIL1 leads to reduced germinal center B cell expansion.
复制标题
氧化损伤特异性DNA糖基酶NEIL1的缺乏会导致生发中心B细胞膨胀降低。
DOI：
10.1016/j.dnarep.2009.08.007
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发表时间：
2009-11-02
期刊：
影响因子：
3.8
通讯作者：
Wang JY
中科院分区：
文献类型：
--
作者：
Mori H;Ouchida R;Hijikata A;Kitamura H;Ohara O;Li Y;Gao X;Yasui A;Lloyd RS;Wang JY
哺乳动物细胞具有多种DNA糖基酶，包括OGG1、NTH1、NEIL1、NEIL2和NEIL3，用于修复DNA氧化损伤。其中，NEIL1和NEIL2能够去除单链或气泡结构DNA上的氧化碱基，并参与修复与DNA复制或转录相关的氧化损伤。我们发现Neil1在生发中心（GC） B细胞中高度组成表达，这是一种正在经历免疫球蛋白（Ig）基因高突变和同型转换的快速分裂细胞群。虽然Neil1−/−小鼠表现出正常的B细胞和T细胞发育和成熟，但这些小鼠在免疫T依赖抗原后含有的GC B细胞的频率明显低于WT小鼠。与GC B细胞扩增减少一致，Neil1−/−小鼠在一次和二次免疫反应中Ig基因高突变频率降低，产生的抗t依赖性抗原抗体减少。这些结果表明，NEIL1修复内源性氧化DNA损伤对于GC B细胞的快速扩增和有效诱导体液免疫反应是重要的。
Mammalian cells possess multiple DNA glycosylases, including OGG1, NTH1, NEIL1, NEIL2 and NEIL3, for the repair of oxidative DNA damage. Among these, NEIL1 and NEIL2 are able to excise oxidized bases on single stranded or bubble-structured DNA and has been implicated in repair of oxidative damage associated with DNA replication or transcription. We found that Neil1 was highly constitutively expressed in the germinal center (GC) B cells, a rapidly dividing cell population that is undergoing immunoglobulin (Ig) gene hypermutation and isotype switching. While Neil1−/− mice exhibited normal B and T cell development and maturation, these mice contained a significantly lower frequency of GC B cells than did WT mice after immunization with a T-dependent antigen. Consistent with the reduced expansion of GC B cells, Neil1−/− mice had a decreased frequency of Ig gene hypermutation and produced less antibody against a T-dependent antigen during both primary and secondary immune responses. These results suggest that repair of endogenous oxidative DNA damage by NEIL1 is important for the rapid expansion of GC B cells and efficient induction of humoral immune responses.