Bcl-2 obstructs negative selection of autoreactive, hypermutated antibody V regions during memory B cell development
Bcl-2 obstructs negative selection of autoreactive, hypermutated antibody V regions during memory B cell development
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DOI：
10.1016/s1074-7613(00)80471-9
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发表时间：
1998-02-01
期刊：
影响因子：
32.4
通讯作者：
Manser, T
中科院分区：
文献类型：
--
作者：
Hande, S;Notidis, E;Manser, T
我们分析了一个占主导地位的B细胞克隆型在小鼠的抗砷剂免疫反应中的参与，其中Bcl-2表达在B细胞中得到加强。这些小鼠的胂酸盐诱导的记忆区室表达的许多抗体是“双重反应性的”，显示通过V区体细胞超突变获得的对胂酸盐和自身抗原DNA的亲和力增加。由正常小鼠的抗砷化物记忆B细胞区室表达的高度突变的抗体对砷化物具有增加的亲和力，但对DNA缺乏可测量的亲和力。因此，对凋亡途径的干扰允许发育中的记忆B细胞获得自身反应性以绕过外周耐受检查点。这些数据表明，阳性和阴性选择，与V基因体细胞超突变协同工作，导致抗体应答的“特异性成熟”。
We analyzed the participation of a predominant B cell clonotype in the anti-arsonate immune response of mice in which Bcl-2 expression was enforced in B cells. Many of the antibodies expressed by the arsonate-induced memory compartment of these mice were "dual-reactive," displaying increased affinity acquired via V region somatic hypermutation for both arsonate and the autoantigen DNA. The hypermutated antibodies expressed by the anti-arsonate memory B cell compartment of normal mice have increased affinity for arsonate but lack measurable affinity for DNA. Thus, interference with apoptotic pathways allows developing memory B cells that have acquired autoreactivity to bypass a peripheral tolerance checkpoint. These data demonstrate that both positive and negative selection, working in concert with V gene somatic hypermutation, result in the "specificity maturation" of the antibody response.