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

胶原蛋白疾病已被定义为结缔组织疾病、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，胶原蛋白疾病的遗传基础仍不清楚。MRL/MpJ-lpr/lpr （MRL/lpr）株小鼠可自发发生肾小球肾炎、全身性血管炎、多发性关节炎和涎腺炎，与狼疮性肾炎、结节性多动脉炎、类风湿关节炎和干燥综合征相似，并伴有多种自身抗体的高滴度。这些发现表明该染色剂可作为胶原蛋白疾病模型。本研究通过MRL/lpr与小鼠非胶原易发菌株C3H/HeJ-lpr/lpr杂交，建立了由15个系组成的重组小鼠自交系MXH/lpr。首先，我们测定了这些品系的多态性微卫星标记和总染色体上的snp，建立了品系分布格局表。对各系肾小球肾炎、血管炎、关节炎和涎腺炎的组织病理表型变化进行了比较，并对病变进行了定量评分，重点关注其发病和进展阶段。然后，确定每个病变的候选数量性状位点。此外，基于所有病变易感位点的基因组数据库，我们用alphasgreen方法检测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，我们发现了与病变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poly I: C注射到RI菌株的每株中，并通过TRL3信号分析宿主的反应。我们发现在RI系中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，我们还建立了RI菌株中炎症因子表达谱的数据库。综上所述，通过重组小鼠MXH/lpr自交系，我们了解到胶原蛋白疾病复杂的病理生理表型可以在多基因网络系统的控制下，通过特定的环境因素进行遗传解剖和修饰。我们的RI菌株将成为进一步研究胶原蛋白疾病中基因组与环境因素关系的重要工具。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