Mohan C, Morel L, Yang P, Wakeland E K
Center for Mammalian Genetics and Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville 32610, USA.
J Immunol. 1997 Jul 1;159(1):454-65.
Susceptibility to systemic lupus erythematosus in the NZM2410 murine model maps to Sle1, Sle2, Sle3, and the H2 loci. To unravel how these loci contribute to the pathogenesis of lupus, individual NZM2410-derived genomic intervals bearing these loci have been successfully backcrossed onto the resistant C57BL/6 (B6) background. The focus of this study was to understand how Sle2 on murine chromosome 4 impacts the immune system. Compared with C57BL/6 (B6) mice, B6 mice congenic for Sle2 exhibit a variety of immunophenotypes affecting their B cells. They have an early, but transient, expansion of splenic, CD23(low) B cells. Thereafter, their B cells appear activated by surface phenotype and functional criteria, paralleled by elevated serum levels of polyreactive/polyclonal IgM. Importantly, Sle2 leads to a heightened B cell responsiveness to in vitro stimuli and to in vivo antigenic challenge. Finally, they exhibit increased levels of peritoneal and splenic B1 cells. Thus, Sle2 harbors a gene that leads to B cell hyperactivity and elevated B1 cell formation. However, Sle2 by itself on the normal B6 background is insufficient to generate IgG antinuclear Abs (ANA) or nephritis. By reducing the B cell signaling threshold, Sle2 might serve to amplify an ongoing autoimmune response.
在 NZM2410 小鼠模型中，系统性红斑狼疮的易感性定位于 Sle1、Sle2、Sle3 和 H2 基因座。为了阐明这些基因座如何导致狼疮的发病机制，携带这些基因座的单个 NZM2410 衍生基因组区间已成功回交到抗性 C57BL/6（B6）背景上。本研究的重点是了解小鼠 4 号染色体上的 Sle2 如何影响免疫系统。与 C57BL/6（B6）小鼠相比，携带 Sle2 的 B6 同源基因小鼠表现出多种影响其 B 细胞的免疫表型。它们的脾脏 CD23（低表达）B 细胞有早期但短暂的扩增。此后，它们的 B 细胞根据表面表型和功能标准似乎被激活，同时血清中多反应性/多克隆 IgM 水平升高。重要的是，Sle2 导致 B 细胞对体外刺激和体内抗原攻击的反应性增强。最后，它们的腹膜和脾脏 B1 细胞水平升高。因此，Sle2 含有一个导致 B 细胞过度活跃和 B1 细胞形成增加的基因。然而，在正常 B6 背景下，单独的 Sle2 不足以产生 IgG 抗核抗体（ANA）或肾炎。通过降低 B 细胞信号阈值，Sle2 可能有助于放大正在进行的自身免疫反应。
