Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance.
Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance.
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DOI：
10.1016/j.immuni.2015.10.002
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发表时间：
2015-11-17
期刊：
影响因子：
32.4
通讯作者：
Meffre E
中科院分区：
文献类型：
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作者：
Cantaert T;Schickel JN;Bannock JM;Ng YS;Massad C;Oe T;Wu R;Lavoie A;Walter JE;Notarangelo LD;Al-Herz W;Kilic SS;Ochs HD;Nonoyama S;Durandy A;Meffre E
激活诱导型胞苷脱氨酶(AID)是一种介导免疫球蛋白基因的类开关重组(CSR)和体细胞超突变(SHM)的酶，对于清除发育中的自身反应性B细胞是必不可少的。AID是如何调节中枢B细胞耐受的，目前尚不清楚。我们报告说，AID酶是在表达重组激活基因2(RAG2)的未成熟B细胞的离散群体中产生的，这表明它们经历了二次重组以编辑自身反应性抗体。然而，大多数AID+的未成熟B细胞缺乏抗凋亡的MCL-1，并被凋亡所删除。在人源化小鼠的B细胞中使用慢病毒编码的短发夹(Sh)RNA进行辅助抑制，导致未能消除自身反应克隆。因此，B细胞固有的AID表达可能通过其RAG偶联的遗传毒性活性在自身反应性未成熟B细胞中介导中央B细胞耐受。
Activation-induced cytidine deaminase (AID), the enzyme mediating class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin genes, is essential for the removal of developing autoreactive B cells. How AID mediates central B-cell tolerance remains unknown. We report that AID enzymes were produced in a discrete population of immature B cells that expressed recombination-activating gene 2 (RAG2), suggesting that they undergo secondary recombination to edit autoreactive antibodies. However, most AID+ immature B cells lacked anti-apoptotic MCL-1 and were deleted by apoptosis. AID inhibition using lentiviral-encoded short hairpin (sh)RNA in B cells developing in humanized mice resulted in a failure to remove autoreactive clones. Hence, B-cell intrinsic AID expression mediates central B-cell tolerance potentially through its RAG-coupled genotoxic activity in self-reactive immature B cells.