Class-switched IgG autoantibodies but not unswitched IgM autoantibodies play a crucial role in the development of systemic lupus erythematosus (SLE). Bach2 is known to be essential for class switch recombination of Ig genes, but recent genomic and clinical studies have suggested an association of Bach2 deficiency with SLE. This study was undertaken to examine the mechanism by which Bach2 regulates the development of SLE. Despite defects in Ig class switch recombination and germinal center formation when actively immunized, Bach2-/- mice spontaneously accumulated IgG autoantibody-secreting cells without germinal center reactions in a regulatory T cell-independent manner, and this phenomenon was accompanied by manifestations akin to SLE. Transcriptome analyses revealed that Bach2 regulated the expression of genes related to germinal center formation and SLE pathogenesis in B cells. B cell-specific deletion of Bach2 was sufficient to impair the development of germinal center B cells but insufficient to promote the production of IgG autoantibodies. Bach2 deficiency caused CD4+ T cells to overexpress Icos and differentiate into extrafollicular helper T cells in a cell-autonomous manner. These findings suggest that Bach2-deficient autoreactive B cells preferentially react at extrafollicular sites to give rise to IgG class-switched pathogenic plasma cells and that this effect requires the help of Bach2-Icoshi helper T cells. Thus, the cell-autonomous roles of Bach2 in B cells and in their cognate CD4+ T cells are required to maintain self-tolerance against SLE.

中文翻译：

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Bach2 缺乏导致自身反应性 B 细胞产生 IgG 自身抗体并通过 T 细胞依赖性滤泡外途径诱导狼疮。

类别转换的 IgG 自身抗体而非未转换的 IgM 自身抗体在系统性红斑狼疮 (SLE) 的发展中起关键作用。已知 Bach2 对 Ig 基因的类别转换重组至关重要，但最近的基因组和临床研究表明 Bach2 缺乏与 SLE 相关。本研究旨在检查 Bach2 调节 SLE 发展的机制。尽管主动免疫时 Ig 类转换重组和生发中心形成存在缺陷，但 Bach2-/- 小鼠以非调节性 T 细胞的方式自发积累 IgG 自身抗体分泌细胞而没有生发中心反应，并且这种现象伴随着类似于 SLE 的表现. 转录组分析显示，Bach2 调节 B 细胞中与生发中心形成和 SLE 发病机制相关的基因的表达。Bach2 的 B 细胞特异性缺失足以损害生发中心 B 细胞的发育，但不足以促进 IgG 自身抗体的产生。Bach2 缺乏导致 CD4+ T 细胞过度表达 Icos 并以细胞自主方式分化为滤泡外辅助 T 细胞。这些发现表明，缺乏 Bach2 的自身反应性 B 细胞优先在滤泡外部位发生反应，从而产生 IgG 类别转换的致病浆细胞，并且这种效应需要 Bach2-Icoshi 辅助 T 细胞的帮助。因此，Bach2 在 B 细胞及其同源 CD4+ T 细胞中的细胞自主作用是维持对 SLE 的自我耐受所必需的。