Activation-induced cytidine deaminase mediates central tolerance in B cells
Activation-induced cytidine deaminase mediates central tolerance in B cells
复制标题
DOI：
10.1073/pnas.1102571108
复制
发表时间：
2011-07-12
影响因子：
11.1
通讯作者：
Kelsoe, Garnett
中科院分区：
文献类型：
--
作者：
Kuraoka, Masayuki;Holl, T. Matt;Kelsoe, Garnett
Aicda基因产物激活诱导的胞苷脱氨酶（AID）通过脱氧胞苷的脱氨基作用启动体细胞超突变、类别转换重组和IG基因的基因转换，随后是易错错配或碱基切除DNA修复。这些过程对于产生遗传多样性、高亲和力抗体和强大的体液免疫至关重要，但会造成显著的遗传损伤并促进细胞死亡。在小鼠中，生理上显著的AID表达被认为仅限于生发中心中抗原活化的成熟B细胞。我们现在证明，在骨髓未成熟和过渡性B细胞中，低水平的AID抑制自身反应性的发展。Aicda（-/-）小鼠表现出显著增加的血清自身抗体和降低的清除自身反应性未成熟和过渡B细胞的能力。在体外，AID缺陷的未成熟/过渡期B细胞对抗IgM诱导的凋亡的抗性显著高于它们的正常对应物。因此，早期AID表达在清除骨髓中成熟过程中的自身反应性未成熟和过渡B细胞中起着根本性的和未预料到的作用。
The Aicda gene product, activation-induced cytidine deaminase (AID), initiates somatic hypermutation, class-switch recombination, and gene conversion of Ig genes by the deamination of deoxycytidine, followed by error-prone mismatch-or base-excision DNA repair. These processes are crucial for the generation of genetically diverse, high affinity antibody and robust humoral immunity, but exact significant genetic damage and promote cell death. In mice, physiologically significant AID expression was thought to be restricted to antigen-activated, mature B cells in germinal centers. We now demonstrate that low levels of AID in bone marrow immature and transitional B cells suppress the development of autoreactivity. Aicda(-/-) mice exhibit significantly increased serum autoantibody and reduced capacity to purge autoreactive immature and transitional B cells. In vitro, AID deficient immature/transitional B cells are significantly more resistant to anti-IgM-induced apoptosis than their normal counterparts. Thus, early AID expression plays a fundamental and unanticipated role in purging self-reactive immature and transitional B cells during their maturation in the bone marrow.