Positive selection of B cells expressing low densities of self-reactive BCRs
Positive selection of B cells expressing low densities of self-reactive BCRs
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DOI：
10.1084/jem.20030955
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发表时间：
2004-03-15
影响因子：
15.3
通讯作者：
Freitas, AA
中科院分区：
文献类型：
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作者：
Gaudin, E;Hao, Y;Freitas, AA
B细胞耐受性或自身免疫是由选择性事件决定的。自反应性B细胞的阴性选择是有充分记录和证明的。相比之下，传统B细胞的阳性选择尚未牢固建立。在这里，我们证明了发育中的自反应性B细胞并不总是对膜结合的自身抗原所施加的缺失机制高度敏感。在低剂量下，膜结合抗原允许携带单一高亲和力自反应性B细胞受体（BCR）的B细胞存活。更重要的是，我们发现强制等位基因包涵改变了B细胞的命运；低量的自身抗原诱导增加自身反应性B细胞的选择和积累，同时降低抗原特异性bcr的表达。通过直接测量完整B细胞的抗原结合，我们发现低量的自身抗原选择具有较低关联常数的自身反应性B细胞。这些B细胞中的一小部分被激活并分泌自身抗体，与自身抗原形成循环免疫复合物。这些发现表明，传统的B细胞可以进行正向选择，而自身反应性B细胞的命运取决于自身抗原的数量、参与的bcr的数量以及其整体抗原结合的亲和力，而不是单个bcr的亲和力。
B cell tolerance or autoimmunity is determined by selective events. Negative selection of self-reactive B cells is well documented and proven. In contrast, positive selection of conventional B cells is yet to be firmly established. Here, we demonstrate that developing self-reactive B cells are not always highly sensitive to the deletion mechanisms imposed by membrane-bound self-antigens. At low amounts, membrane-bound antigens allow survival of B cells bearing a single high affinity self-reactive B cell receptor (BCR). More importantly, we show that forced allelic inclusion modifies B cell fate; low quantities of self-antigen induce the selection and accumulation of increased numbers of self-reactive B cells with decreased expression of antigen-specific BCRs. By directly measuring antigen binding by intact B cells, we show that the low amounts of self-antigen select self-reactive B cells with a lower association constant. A fraction,of these B cells is activated and secretes autoantibodies that form circulating immune complexes with self-antigen. These findings demonstrate that conventional B cells can undergo positive selection and that the fate of a self reactive B cell depends on the quantity of self-antigen, the number of BCRs engaged, and on its overall antigen-binding avidity, rather than on the affinity of individual BCRs.