Metabolic determinants of B-cell selection.
Metabolic determinants of B-cell selection.
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DOI：
10.1042/bst20201316
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发表时间：
2021-07
影响因子：
3.9
通讯作者：
L. Chan;Eamon Aghania;Etienne Leveille;M. Müschen
中科院分区：
文献类型：
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作者：
L. Chan;Eamon Aghania;Etienne Leveille;M. Müschen
B细胞是适应性免疫系统中产生抗体的细胞。在骨髓中新生成的所有B细胞中，约75%具有自身反应性，且表达可能有害的自身抗体。为预防自身免疫性疾病，免疫系统进化出一种强大的机制来清除自身反应性B细胞，这一过程被称为B细胞阴性选择。尽管该机制旨在在B细胞早期发育阶段清除自身反应性克隆，但我们实验室最近发现，白血病和淋巴瘤中的转化B细胞同样会经历阴性选择。实际上，除了有患自身免疫性疾病的风险，B细胞本身就易于发生恶性转化：为产生高亲和力抗体，B细胞要经历多轮体细胞免疫球蛋白基因重排和超突变。这反映出DNA断裂的高频率，B细胞提供的适应性免疫保护伴随着白血病和淋巴瘤发病风险的大幅增加。值得注意的是，B细胞处于能量代谢长期受限的条件下。在此，我们将探讨B细胞发育过程中的这些代谢调控功能，如何为清除自身反应性和癌前B细胞提供一种通用机制，以防范自身免疫性疾病和B细胞恶性肿瘤。
B-cells are antibody-producing cells of the adaptive immune system. Approximately 75% of all newly generated B-cells in the bone marrow are autoreactive and express potentially harmful autoantibodies. To prevent autoimmune disease, the immune system has evolved a powerful mechanism to eliminate autoreactive B-cells, termed negative B-cell selection. While designed to remove autoreactive clones during early B-cell development, our laboratory recently discovered that transformed B-cells in leukemia and lymphoma are also subject to negative selection. Indeed, besides the risk of developing autoimmune disease, B-cells are inherently prone to malignant transformation: to produce high-affinity antibodies, B-cells undergo multiple rounds of somatic immunoglobulin gene recombination and hypermutation. Reflecting high frequencies of DNA-breaks, adaptive immune protection by B-cells comes with a dramatically increased risk of development of leukemia and lymphoma. Of note, B-cells exist under conditions of chronic restriction of energy metabolism. Here we discuss how these metabolic gatekeeper functions during B-cell development provide a common mechanism for the removal of autoreactive and premalignant B-cells to safeguard against both autoimmune diseases and B-cell malignancies.