通过研究原发性人类淋巴瘤并开发新的小鼠模型，研究人员发现影响BTG1的突变破坏了一个关键的免疫看门人机制，该机制在抗体亲和成熟过程中严格限制了B细胞的适应度。这种机制将生发中心B细胞转变为超级竞争者，迅速超过正常的B细胞。这种效应是由MYC蛋白诱导动力学的微小变化所赋予的，但会导致侵袭性淋巴瘤，这在人类中与可怕的临床结果有关。这项发现揭示了B细胞提供免疫的自然选择和潜在危险之间微妙的演化权衡，这些特征让人想起单细胞生物更具竞争性的本质。
研究人员表示，多细胞生命需要细胞间无私的合作。适应性免疫系统是一个显著的例外，其中生发中心B细胞激烈竞争限制正向选择信号。
附：英文原文
Title: BTG1 mutation yields supercompetitive B cells primed for malignant transformation
Author: Coraline Mlynarczyk, Matt Teater, Juhee Pae, Christopher R. Chin, Ling Wang, Theinmozhi Arulraj, Darko Barisic, Antonin Papin, Kenneth B. Hoehn, Ekaterina Kots, Jonatan Ersching, Arnab Bandyopadhyay, Ersilia Barin, Hui Xian Poh, Chiara M. Evans, Amy Chadburn, Zhengming Chen, Hao Shen, Hannah M. Isles, Benedikt Pelzer, Ioanna Tsialta, Ashley S. Doane, Huimin Geng, Muhammad Hassan Rehman, Jonah Melnick, Wyatt Morgan, Diu T. T. Nguyen, Olivier Elemento, Michael G. Kharas, Samie R. Jaffrey, David W. Scott, George Khelashvili, Michael Meyer-Hermann, Gabriel D. Victora, Ari Melnick
Issue&Volume: 2023-01-20
Abstract: Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.
DOI: abj7412
Source: https://www.science.org/doi/10.1126/science.abj7412