Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, U.S.A.
Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT 06520, U.S.A.
Biochem Soc Trans. 2021 Jun 30;49(3):1467-1478. doi: 10.1042/BST20201316.
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.
B 细胞是适应性免疫系统中产生抗体的细胞。骨髓中约 75%的新生成的 B 细胞是自身反应性的，并表达潜在的有害自身抗体。为了防止自身免疫性疾病，免疫系统已经进化出一种强大的机制来消除自身反应性 B 细胞，称为负 B 细胞选择。虽然负 B 细胞选择旨在在早期 B 细胞发育过程中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 细胞也受到负选择的影响。事实上，除了患自身免疫性疾病的风险外，B 细胞天生就容易恶性转化：为了产生高亲和力的抗体，B 细胞经历多次体细胞免疫球蛋白基因重组和超突变。反映出 DNA 断裂的高频率，B 细胞的适应性免疫保护伴随着白血病和淋巴瘤发展的风险显著增加。值得注意的是，B 细胞在能量代谢受到慢性限制的情况下存在。在这里，我们讨论 B 细胞发育过程中的这些代谢守门员功能如何为清除自身反应性和前恶性 B 细胞提供共同的机制，以预防自身免疫性疾病和 B 细胞恶性肿瘤。
