Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland.
Turku Doctoral Programme of Biomedical Sciences and Turku Doctoral Programme of Molecular Medicine, University of Turku, Turku, Finland.
Eur J Immunol. 2017 Jun;47(6):993-1001. doi: 10.1002/eji.201646895. Epub 2017 Apr 11.
The transcription factor Bach2 is required for germinal center formation, somatic hypermutation (SHM), and class-switch recombination (CSR) of immunoglobulins. SHM and CSR are initiated by activation-induced cytidine deaminase (AID) which has potential to induce human B cell lymphoma. To understand the role of Bach2 in AID-mediated immunoglobulin gene diversification processes, we established a BACH2-deficient DT40 B cell line. We show that in addition to allowing SHM, Bach2 drives immunoglobulin gene conversion (GCV), another AID-dependent antibody gene diversification process. We demonstrate that Bach2 promotes GCV by increasing the expression of AID. Importantly, we found that the regulation of AID is independent of Blimp-1 and that BACH2-deficient cells have altered expression of several genes regulating AID expression, stability and function. Furthermore, re-expression of BACH2 or AID in Bach2KO cells restored the SHM and GCV defects. These results demonstrate that Bach2 has a previously unappreciated role in the production of high-affinity antibodies.
转录因子 Bach2 对于生发中心的形成、免疫球蛋白的体细胞高频突变（SHM）和类别转换重组（CSR）是必需的。SHM 和 CSR 是由激活诱导胞苷脱氨酶（AID）引发的，AID 有可能诱导人类 B 细胞淋巴瘤。为了了解 Bach2 在 AID 介导的免疫球蛋白基因多样化过程中的作用，我们建立了 Bach2 缺陷型 DT40 B 细胞系。我们表明，Bach2 除了允许 SHM 外，还驱动免疫球蛋白基因转换（GCV），这是另一种依赖 AID 的抗体基因多样化过程。我们证明 Bach2 通过增加 AID 的表达来促进 GCV。重要的是，我们发现 AID 的调节独立于 Blimp-1，并且 Bach2 缺陷型细胞中调节 AID 表达、稳定性和功能的几个基因的表达发生了改变。此外，在 Bach2KO 细胞中重新表达 Bach2 或 AID 恢复了 SHM 和 GCV 缺陷。这些结果表明 Bach2 在产生高亲和力抗体方面具有以前未被认识到的作用。
