Elimination of Germinal-Center-Derived Self-Reactive B Cells Is Governed by the Location and Concentration of Self-Antigen
Elimination of Germinal-Center-Derived Self-Reactive B Cells Is Governed by the Location and Concentration of Self-Antigen
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DOI：
10.1016/j.immuni.2012.07.017
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发表时间：
2012-11-16
期刊：
影响因子：
32.4
通讯作者：
Brink, Robert
中科院分区：
文献类型：
--
作者：
Chan, Tyani D.;Wood, Katherine;Brink, Robert
在生发中心（GC）通过免疫球蛋白基因体细胞超突变的B细胞库的次级多样化对于提供长期体液免疫所需的高亲和力抗体特异性是必不可少的。虽然由自身反应性GC B细胞的无意产生引起的自身耐受性的风险早已被认识到，但以前不可能鉴定此类细胞并研究它们的命运。在目前的研究中，当自身抗原在GC微环境附近的细胞中广泛表达或特异性表达时，GC中从头产生的自身反应性B细胞无法存活。相比之下，识别罕见或组织特异性自身抗原的GC B细胞没有被消除，而是可以通过交叉反应性外源抗原进行阳性选择，并产生分泌高亲和力自身抗体的浆细胞。这些发现表明GC自身耐受的不完全性，并可能解释交叉反应，器官特异性自身抗体与感染后自身免疫性疾病的频繁关联。
Secondary diversification of the B cell repertoire by immunoglobulin gene somatic hypermutation in the germinal center (GC) is essential for providing the high-affinity antibody specificities required for long-term humoral immunity. While the risk to self-tolerance posed by inadvertent generation of self-reactive GC B cells has long been recognized, it has not previously been possible to identify such cells and study their fate. In the current study, self-reactive B cells generated de novo in the GC failed to survive when their target self-antigen was either expressed ubiquitously or specifically in cells proximal to the GC microenvironment. By contrast, GC B cells that recognized rare or tissue-specific self-antigens were not eliminated, and could instead undergo positive selection by cross-reactive foreign antigen and produce plasma cells secreting high-affinity autoantibodies. These findings demonstrate the incomplete nature of GC self-tolerance and may explain the frequent association of cross-reactive, organ-specific autoantibodies with postinfectious autoimmune disease.