Murine lupus susceptibility locus Sle1a requires the expression of two sub-loci to induce inflammatory T cells.
Murine lupus susceptibility locus Sle1a requires the expression of two sub-loci to induce inflammatory T cells.
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DOI：
10.1038/gene.2010.23
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发表时间：
2010-10
影响因子：
5
通讯作者：
Morel, L.
中科院分区：
文献类型：
--
作者：
Cuda, C. M.;Zeumer, L.;Sobel, E. S.;Croker, B. P.;Morel, L.
NZM2410衍生的Sle1a狼疮易感性基因座诱导活化的自身反应性CD4+ T细胞并减少Foxp3+调节性T细胞的数量和功能。在这项研究中，我们首先表明，Sle1a有助于通过增加抗核抗体的生产时，无论是在NZB或NZW杂合基因组表达，并通过增强慢性移植物抗宿主病的反应，表明自身反应性B细胞池的扩展自身免疫。筛选两个非重叠的重组体，覆盖整个Sle1a基因座的Sle1a.1和Sle1a.2间隔，揭示了Sle1a.1和Sle1a.2对于完整的Sle1a表型都是必需的。Sle1a.1和Sle1a.2在较小程度上显著影响CD4+ T细胞活化以及Treg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间隔分别仅包含1个和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细胞的候选基因的数量。这些结果还表明，Sle1基因座是一个很好的模型的遗传结构的狼疮，其中一个主要的专性表型的结果，从共同表达的多个遗传变异与个人弱的影响。
The NZM2410-derived Sle1a lupus susceptibility locus induces activated autoreactive CD4+ T cells and reduces the number and function of Foxp3+ regulatory T cells. In this study, we first showed that Sle1a contributes to autoimmunity by increasing anti-nuclear antibody production when expressed on either NZB or NZW heterozygous genomes, and by enhancing the chronic graft vs. 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. Since the Sle1a.1 and Sle1a.2 intervals contain only one 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 demonstrate that the Sle1 locus is an excellent model for the genetic architecture of lupus, in which a major obligate phenotype results from the co-expression of multiple genetic variants with individual weak effects.
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