德国慕尼黑工业大学Marc Schmidt-Supprian研究团队发现，过度反应的B细胞通过T细胞指示其清除来遏制自体炎症和淋巴瘤生成。相关论文于2024年12月26日在线发表在《免疫》杂志上。

研究人员探讨了以典型的负免疫调节因子TNFAIP3/A20为中心的，自体免疫和淋巴瘤风险因子在小鼠中的相互作用。出乎意料的是，B细胞对刺激的敏感性适度升高时，会导致致命的自体免疫病理，而高敏感性B细胞则没有。

研究人员通过识别类似调节器的细胞毒性T细胞检查点，解决了这一明显的悖论。细胞毒性由高内在过度反应性的B细胞指示并作用于其上，而低反应性的B细胞则未受影响。去除T细胞控制后，内在B细胞反应性与致命性淋巴增生、淋巴瘤发生和自体炎症之间恢复了线性关系。

因此，研究人员确定了T细胞介导的强大负反馈控制作用，限制了遗传性和后天性B细胞致病性的发生，并定义了自体免疫发生的许可窗口。

据了解，B细胞免疫具有偏离正常免疫反应的固有风险，可能导致自体免疫和恶性肿瘤的发生，这两者都与增加免疫信号的基因变异或改变密切相关。

附：英文原文

Title: Hyperreactive B cells instruct their elimination by T cells to curb autoinflammation and lymphomagenesis

Author: Carina Diehl, Valeria Soberón, Seren Baygün, Yuanyan Chu, Jonathan Mandelbaum, Laura Kraus, Thomas Engleitner, Martina Rudelius, Marco Fangazio, Christoph Daniel, Sabrina Bortoluzzi, Sabine Helmrath, Pankaj Singroul, Vanessa Glling, Francisco Osorio Barrios, Gnül Seyhan, Lena Owald, Maike Kober-Hasslacher, Theodor Zeng, Rupert llinger, Ali M. Afzali, Thomas Korn, Mohsen Honarpisheh, Maciej Lech, Qurrat Ul Ain, Joachim Pircher, Vanna Imirovi, Vedrana Jeleni, Felix M. Wensveen, Verena Passerini, Stefanie Brthel, Govind Bhagat, David Dominguez-Sola, Dieter Saur, Katja Steiger, Roland Rad, Laura Pasqualucci, Oliver Weigert, Marc Schmidt-Supprian

Issue&Volume: 2024-12-26

Abstract: B cell immunity carries the inherent risk of deviating into autoimmunity and malignancy, which are both strongly associated with genetic variants or alterations that increase immune signaling. Here, we investigated the interplay of autoimmunity and lymphoma risk factors centered around the archetypal negative immune regulator TNFAIP3/A20 in mice. Counterintuitively, B cells with moderately elevated sensitivity to stimulation caused fatal autoimmune pathology, while those with high sensitivity did not. We resolved this apparent paradox by identifying a rheostat-like cytotoxic T cell checkpoint. Cytotoxicity was instructed by and directed against B cells with high intrinsic hyperresponsiveness, while less reactive cells were spared. Removing T cell control restored a linear relationship between intrinsic B cell reactivity and lethal lymphoproliferation, lymphomagenesis, and autoinflammation. We thus identify powerful T cell-mediated negative feedback control of inherited and acquired B cell pathogenicity and define a permissive window for autoimmunity to emerge.

DOI: 10.1016/j.immuni.2024.11.023

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00538-7