慕尼黑工业大学医学与健康学院Thomas Korn团队近期取得重要工作进展，他们研究提出，B细胞能够协调对视神经脊髓炎自身抗原AQP4的耐受。相关研究成果2024年2月21日在线发表于《自然》杂志上。

据介绍，视神经脊髓炎是一种典型的中枢神经系统自身免疫性疾病，其中水通道蛋白AQP4是靶抗原。视神经脊髓炎的免疫病理学主要由AQP4自身抗体驱动。然而，产生这些抗AQP4抗体所需的T细胞反应尚不清楚。

研究人员发现，B细胞内源性表达AQP4以响应抗CD40和IL-21的激活，并且能够将其内源性AQP4呈递给具有AQP4特异性T细胞受体（TCR）的T细胞。胸腺B细胞群模拟CD40刺激的B细胞转录组，包括AQP4（在小鼠和人类中），并有效清除AQP4反应性克隆的胸腺TCR库。尽管Aqp4在髓质胸腺上皮细胞中充分表达，但在B细胞中对Aqp4的基因消融挽救了AQP4特异性TCR，并且B细胞条件下的AQP4缺陷小鼠完全有能力在生产性生发中心反应中产生AQP4特异性抗体。

因此，AQP4特异性胸腺细胞的阴性选择取决于胸腺B细胞对AQP4的表达和呈递。由于AQP4在B细胞中以CD40依赖性（但不是AIRE依赖性）的方式表达，研究人员提出胸腺B细胞可能对一组生发中心相关抗原耐受，包括疾病相关的自身抗原，如AQP4。

附：英文原文

Title: B cells orchestrate tolerance to the neuromyelitis optica autoantigen AQP4

Author: Afzali, Ali Maisam, Nirschl, Lucy, Sie, Christopher, Pfaller, Monika, Ulianov, Oleksii, Hassler, Tobias, Federle, Christine, Petrozziello, Elisabetta, Kalluri, Sudhakar Reddy, Chen, Hsin Hsiang, Tyystjrvi, Sofia, Muschaweckh, Andreas, Lammens, Katja, Delbridge, Claire, Bttner, Andreas, Steiger, Katja, Seyhan, Gnl, Ottersen, Ole Petter, llinger, Rupert, Rad, Roland, Jarosch, Sebastian, Straub, Adrian, Mhlbauer, Anton, Grassmann, Simon, Hemmer, Bernhard, Bttcher, Jan P., Wagner, Ingrid, Kreutzfeldt, Mario, Merkler, Doron, Pards, Irene Bonafonte, Schmidt Supprian, Marc, Buchholz, Veit R., Heink, Sylvia, Busch, Dirk H., Klein, Ludger, Korn, Thomas

Issue&Volume: 2024-02-21

Abstract: Neuromyelitis optica is a paradigmatic autoimmune disease of the central nervous system, in which the water-channel protein AQP4 is the target antigen1. The immunopathology in neuromyelitis optica is largely driven by autoantibodies to AQP42. However, the T cell response that is required for the generation of these anti-AQP4 antibodies is not well understood. Here we show that B cells endogenously express AQP4 in response to activation with anti-CD40 and IL-21 and are able to present their endogenous AQP4 to T cells with an AQP4-specific T cell receptor (TCR). A population of thymic B cells emulates a CD40-stimulated B cell transcriptome, including AQP4 (in mice and humans), and efficiently purges the thymic TCR repertoire of AQP4-reactive clones. Genetic ablation of Aqp4 in B cells rescues AQP4-specific TCRs despite sufficient expression of AQP4 in medullary thymic epithelial cells, and B-cell-conditional AQP4-deficient mice are fully competent to raise AQP4-specific antibodies in productive germinal-centre responses. Thus, the negative selection of AQP4-specific thymocytes is dependent on the expression and presentation of AQP4 by thymic B cells. As AQP4 is expressed in B cells in a CD40-dependent (but not AIRE-dependent) manner, we propose that thymic B cells might tolerize against a group of germinal-centre-associated antigens, including disease-relevant autoantigens such as AQP4.

DOI: 10.1038/s41586-024-07079-8

Source: https://www.nature.com/articles/s41586-024-07079-8