Morel L, Mohan C, Yu Y, Croker B P, Tian N, Deng A, Wakeland E K
Center for Mammalian Genetics and Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville 32610, USA.
J Immunol. 1997 Jun 15;158(12):6019-28.
We describe the in vivo phenotypes associated with three genomic intervals containing systemic lupus erythematosus (SLE)-susceptibility genes derived from the SLE-prone NZM2410 strain on a C57BL/6 genome. These intervals were identified previously via a genome-wide analysis of SLE susceptibility in a (NZM2410 x C57BL/6)F1 x NZM2410 backcross, and transferred independently on a C57BL/6 background to produce three congenic strains: B6.NZMc1 carrying Sle1, B6.NZMc4 carrying Sle2, and B6.NZMc7 carrying Sle3. B6.NZMc1 develops high titers of IgG anti-nuclear autoantibodies in the absence of any severe nephritis. B6.NZMc4 spontaneously develops elevated levels of IgM, but not IgG Abs against several Ags, indicative of polyclonal activation or polyreactivity affecting the B cell lineage. B6.NZMc7 causes the production of IgM and IgG Abs against both nuclear and non-nuclear Ags and the development of severe lupus nephritis. Therefore, our results show that three defined genomic intervals from the NZM2410 SLE-prone strain each contribute specific component phenotypes that have been associated with SLE, which in combination can mediate severe disease.
我们描述了与三个基因组区间相关的体内表型，这些区间包含源自C57BL/6基因组上易患系统性红斑狼疮（SLE）的NZM2410品系的SLE易感基因。这些区间先前是通过对（NZM2410×C57BL/6）F1×NZM2410回交后代进行SLE易感性全基因组分析而确定的，并在C57BL/6背景上独立转移，以产生三个同类系：携带Sle1的B6.NZMc1、携带Sle2的B6.NZMc4和携带Sle3的B6.NZMc7。B6.NZMc1在没有任何严重肾炎的情况下会产生高滴度的IgG抗核自身抗体。B6.NZMc4会自发产生升高水平的IgM，但不会产生针对几种抗原的IgG抗体，这表明多克隆激活或多反应性影响了B细胞谱系。B6.NZMc7会导致产生针对核抗原和非核抗原的IgM和IgG抗体，并引发严重的狼疮性肾炎。因此，我们的结果表明，来自NZM2410 SLE易感品系的三个确定的基因组区间各自贡献了与SLE相关的特定组成表型，这些表型组合起来可介导严重疾病。
