Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA.
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
Immunity. 2020 Jun 16;52(6):1022-1038.e7. doi: 10.1016/j.immuni.2020.04.015. Epub 2020 May 25.
Class-switched antibodies to double-stranded DNA (dsDNA) are prevalent and pathogenic in systemic lupus erythematosus (SLE), yet mechanisms of their development remain poorly understood. Humans and mice lacking secreted DNase DNASE1L3 develop rapid anti-dsDNA antibody responses and SLE-like disease. We report that anti-DNA responses in Dnase1l3 mice require CD40L-mediated T cell help, but proceed independently of germinal center formation via short-lived antibody-forming cells (AFCs) localized to extrafollicular regions. Type I interferon (IFN-I) signaling and IFN-I-producing plasmacytoid dendritic cells (pDCs) facilitate the differentiation of DNA-reactive AFCs in vivo and in vitro and are required for downstream manifestations of autoimmunity. Moreover, the endosomal DNA sensor TLR9 promotes anti-dsDNA responses and SLE-like disease in Dnase1l3 mice redundantly with another nucleic acid-sensing receptor, TLR7. These results establish extrafollicular B cell differentiation into short-lived AFCs as a key mechanism of anti-DNA autoreactivity and reveal a major contribution of pDCs, endosomal Toll-like receptors (TLRs), and IFN-I to this pathway.
针对双链 DNA（dsDNA）的类别转换抗体在系统性红斑狼疮（SLE）中普遍存在且具有致病性，但它们的发展机制仍知之甚少。缺乏分泌型 DNASE1L3 的人类和小鼠会迅速产生抗 dsDNA 抗体反应和类似 SLE 的疾病。我们报告称，Dnase1l3 小鼠中的抗 DNA 反应需要 CD40L 介导的 T 细胞帮助，但通过定位于滤泡外区域的短暂存活的抗体形成细胞（AFC）而独立于生发中心形成进行。I 型干扰素（IFN-I）信号和产生 IFN-I 的浆细胞样树突状细胞（pDC）促进了体内和体外 DNA 反应性 AFC 的分化，并且是自身免疫下游表现所必需的。此外，内体 DNA 传感器 TLR9 与另一种核酸感应受体 TLR7 一起在 Dnase1l3 小鼠中促进抗 dsDNA 反应和类似 SLE 的疾病。这些结果确立了滤泡外 B 细胞分化为短暂存活的 AFC 作为抗 DNA 自身反应性的关键机制，并揭示了 pDC、内体 Toll 样受体（TLR）和 IFN-I 在该途径中的主要贡献。
