Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, 32610-0275, USA.
Genes Immun. 2010 Oct;11(7):542-53. doi: 10.1038/gene.2010.23. Epub 2010 May 6.
The NZM2410-derived Sle1a lupus susceptibility locus induces activated autoreactive CD4(+) T cells and reduces the number and function of Foxp3(+) regulatory T cells (Tregs). In this study, we first showed that Sle1a contributes to autoimmunity by increasing antinuclear antibody production when expressed on either NZB or NZW heterozygous genomes, and by enhancing the chronic graft versus host disease response indicating an expansion of the autoreactive B-cell pool. Screening two non-overlapping recombinants, the Sle1a.1 and Sle1a.2 intervals that cover the entire Sle1a locus, revealed that both Sle1a.1 and Sle1a.2 were necessary for the full Sle1a phenotype. Sle1a.1, and to a lesser extent Sle1a.2, significantly affected CD4(+) T-cell activation as well as Treg differentiation and function. Sle1a.2 also increased the production of autoreactive B cells. As the Sle1a.1 and Sle1a.2 intervals contain only 1 and 15 known genes, respectively, this study considerably reduces the number of candidate genes responsible for the production of autoreactive T cells. These results also show that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the coexpression of multiple genetic variants with individual weak effects.
NZM2410 衍生的 Sle1a 狼疮易感基因座诱导激活的自身反应性 CD4(+)T 细胞，并减少 Foxp3(+)调节性 T 细胞（Treg）的数量和功能。在这项研究中，我们首先表明 Sle1a 通过在 NZB 或 NZW 杂合基因组上表达来增加抗核抗体的产生而有助于自身免疫，并且通过增强慢性移植物抗宿主病反应表明自身反应性 B 细胞池的扩张。筛选两个非重叠的重组体，即覆盖整个 Sle1a 基因座的 Sle1a.1 和 Sle1a.2 间隔，显示 Sle1a.1 和 Sle1a.2 均对 Sle1a 表型的完全表达是必需的。Sle1a.1 并且在较小程度上 Sle1a.2 显著影响 CD4(+)T 细胞的激活以及 Treg 的分化和功能。Sle1a.2 还增加了自身反应性 B 细胞的产生。由于 Sle1a.1 和 Sle1a.2 间隔仅分别包含 1 和 15 个已知基因，因此这项研究大大减少了负责产生自身反应性 T 细胞的候选基因数量。这些结果还表明 Sle1 基因座是狼疮遗传结构的一个极好模型，其中主要的强制性表型是由多个具有个体弱效应的遗传变异体的共同表达引起的。
