Establishment of a novel recombinant inbred strain of mice MXH/lpr with genetic dissociation of the complex pathological and pathophysiological phenotypes of collagen disease under a polygene network

胶原病是一种与结缔组织疾病、风湿性疾病和自身免疫性或免疫性疾病重叠的综合征。然而，胶原病的遗传基础仍不清楚。小鼠的MRL/MpJ-lpr/lpr（MRL/lpr）品系自发地发展肾小球肾炎、系统性血管炎、多关节炎和涎腺炎，因此分别类似于狼疮肾炎、结节性多动脉炎、类风湿性关节炎和舍格伦综合征，与各种自身抗体的高滴度相关。这些发现表明，这种染色应该被用作胶原蛋白疾病模型。本研究通过MRL/lpr与非胶原病易感小鼠C3 H/HeJ-lpr/lpr杂交，建立了一个由15个品系组成的新型重组近交系MXH/lpr。首先，我们确定了这些品系总染色体上的多态性微卫星标记和SNPs，以建立品系分布模式表。并且，我们准备了s的数据库， 关于我们 肾小球肾炎、血管炎、关节炎和涎腺炎的组织病理学表型的顺序变化，并对病变进行定量评分，重点关注其发病和进展阶段。然后，确定每个病斑的候选数量性状位点。此外，我们基于AlphaScreen方法中所有病变的易感基因座的基因组数据库，检查了针对无细胞系统制备的合成蛋白的自身抗体的表达谱。其中，我们确定了与病变的发展密切相关的自身抗体。最后，为了模拟环境因素对胶原病表型的影响及其基因组多态性，我们将聚I：C注射到RI菌株的每个品系中，并通过TRL 3信号传导分析宿主反应。我们发现RI系间的组织病理学表型有规律的变化，特别是在一个系中引起胰腺炎。此外，我们建立了一个数据库的表达谱的炎症细胞因子在RI株。总之，从这些结果中，通过使用一种新的重组近交系小鼠MXH/lpr，我们了解到，复杂的病理病理生理表型的胶原蛋白疾病可以遗传解剖和修改的特定环境因素下的控制下的多基因网络系统。我们的RI株将是一个重要的工具，以进一步研究基因组和环境因素之间的关系，在胶原蛋白疾病。少

Category of collagen disease has been defined as a syndrome overlapping connective tissue diseases, rheumatic diseases and autoimmune or immunological disorders. However, the genetic basis of collagen disease remains unclear. The MRL/MpJ-lpr/lpr (MRL/lpr) strain of mice spontaneously develop glomerulonephritis, systemic vasculitis, polyarthritis and sialoadenitis, thus resembling lupus nephritis, polyarteritis nodosa, rheumatoid arthritis and Sjogren's syndrome, respectively, associated with the high titers of various autoantibodies. These findings suggest that this stain should be used as a collagen disease model. In this study, we established a novel recombinant inbred strain of mice MXH/lpr composed of 15 lines by intercrosses of MRL/lpr and non-collagen disease-prone strain of mice C3H/HeJ-lpr/lpr. First, we determined polymorphic microsatellite markers and SNPs on total chromosomes of these lines to establish a strain distribution pattern table. And, we prepared the data base of s … More equential changes of histopathological phenotypes of glomerulonephritis, vasculitis, arthritis and sialoadenitis of each line with quantitatively scoring of the lesions, focusing their onset and progression stages. Then, the candidates of quantitative trait loci for each lesion were determined. Moreover, we examined the expression profiles of autoantibodies against the synthetic proteins prepared by cell free system based on the genome data base of susceptibility loci to all lesions in the AlphaScreen method. Among them, we identified the autoantibodies closely associated with the development of the lesions. Finally, to simulate the influence of environmental factors to collagen disease phenotypes in relation with their genomic polymorphism, we injected poly I: C to each line of the RI strain and analyzed the host responses via TRL3 signaling. We found a regular variation of histopathological phenotypes among the RI lines, especially causing pancreatitis in one line. Furthermore, we established a data base of the expression profiles of inflammatory cytokines in the RI strain. In conclusion, from these results by using a novel recombinant inbred strain of mice MXH/lpr, we learned that the complex pathological pathophysiological phenotypes of collagen disease can be genetically dissected and modified by particular environmental factors which are under the control a polygene network system. Our RI strain will be an important tool to further study the relationship between genome and environmental factors in collagen disease. Less