The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

Many autoimmune diseases are characterized by germinal center (GC)-derived, affinity-matured, class-switched autoantibodies, and strategies to block GC formation and progression are currently being explored clinically. However, extrafollicular responses can also play a role. The aim of this study was to investigate the contribution of the extrafollicular pathway to autoimmune disease development. We blocked the GC pathway by knocking out the transcription factor Bcl-6 in GC B cells, leaving the extrafollicular pathway intact. We tested the impact of this intervention in two murine models of systemic lupus erythematosus (SLE): a pharmacological model based on the chronic epicutaneous application of the Toll-like receptor (TLR)-7 agonist Resiquimod (R848), and 564Igi autoreactive B cell receptor knock-in mice. The B cell-intrinsic effects were further investigated in vitro and in autoreactive mixed bone marrow chimeras. GC block failed to curb autoimmune progression in the R848 model base..., Please see the README document (\"README_file extrafollicular response is sufficient paper Voss LF et al 2022\") and the accompanying published article: Voss LF et al. 2022. The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus. Frontiers in Immunology. Accepted. DOI: 10.3389/fimmu.2022.1021370,多种自身免疫性疾病以生发中心（germinal center, GC）来源的、亲和力成熟且发生类别转换的自身抗体为特征，目前临床正探索阻断GC形成与进展的干预策略。然而，滤泡外应答同样可参与疾病的发生发展。本研究旨在探究滤泡外通路在自身免疫性疾病发生发展中的作用贡献。我们通过在GC B细胞中敲除转录因子Bcl-6以阻断GC通路，同时保留滤泡外通路的完整性。我们在两种系统性红斑狼疮（systemic lupus erythematosus, SLE）小鼠模型中验证了该干预手段的效应：其一为基于Toll样受体（Toll-like receptor, TLR）-7激动剂瑞喹莫德（Resiquimod, R848）慢性经皮给药的药理学模型，其二为564Igi自身反应性B细胞受体敲入小鼠模型。我们进一步在体外及自身反应性混合骨髓嵌合体模型中，深入探究了B细胞固有效应的作用机制。在R848模型中，阻断GC通路未能抑制自身免疫性疾病的进展……详情请参阅README文档（"README_file extrafollicular response is sufficient paper Voss LF et al 2022"）及同期发表的研究论文：Voss LF等，2022年。《滤泡外应答足以驱动自身免疫起始及狼疮早期疾病特征》，刊载于《免疫学前沿》（Frontiers in Immunology），已接收。DOI: 10.3389/fimmu.2022.1021370。