Metabolic Gatekeepers of Pathological B Cell Activation.
Metabolic Gatekeepers of Pathological B Cell Activation.
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DOI：
10.1146/annurev-pathol-061020-050135
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发表时间：
2020-12
期刊：
影响因子：
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通讯作者：
Teresa Sadras;L. Chan;G. Xiao;M. Müschen
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文献类型：
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作者：
Teresa Sadras;L. Chan;G. Xiao;M. Müschen
与其他细胞类型不同，B细胞会经历多轮V（D）J重组和超突变，以进化出高亲和力抗体。这反映出DNA双链断裂的高频率，B细胞提供的适应性免疫保护伴随着恶性转化风险的增加。此外，绝大多数新生成的B细胞表达自身反应性B细胞受体（BCR）。因此，B细胞面临着强大的选择压力，需要清除自身反应性和癌前克隆。尽管存在严格的阴性选择，B细胞仍经常引发自身免疫性疾病和B细胞恶性肿瘤。在这篇综述中，我们讨论了我们称之为代谢守门人的机制，该机制基于能量耗竭来清除致病性B细胞克隆。来自自身反应性BCR或致癌基因的慢性激活信号会增加自身反应性和癌前B细胞的能量需求。因此，代谢守门人将能量供应限制在不足以驱动致癌基因或自身反应性BCR过度活跃信号传导的水平。《病理学年度评论：疾病机制》第16卷的预计最终在线发布日期为2021年2月。如需修订后的预估日期，请访问http://www.annualreviews.org/page/journal/pubdates 。
Unlike other cell types, B cells undergo multiple rounds of V(D)J recombination and hypermutation to evolve high-affinity antibodies. Reflecting high frequencies of DNA double-strand breaks, adaptive immune protection by B cells comes with an increased risk of malignant transformation. In addition, the vast majority of newly generated B cells express an autoreactive B cell receptor (BCR). Thus, B cells are under intense selective pressure to remove autoreactive and premalignant clones. Despite stringent negative selection, B cells frequently give rise to autoimmune disease and B cell malignancies. In this review, we discuss mechanisms that we term metabolic gatekeepers to eliminate pathogenic B cell clones on the basis of energy depletion. Chronic activation signals from autoreactive BCRs or transforming oncogenes increase energy demands in autoreactive and premalignant B cells. Thus, metabolic gatekeepers limit energy supply to levels that are insufficient to fuel either a transforming oncogene or hyperactive signaling from an autoreactive BCR. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 16 is February 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.