Nose M, Terada M, Nishihara M, Kamogawa J, Miyazaki T, Qu W, Mori S, Nakatsuru S
Second Department of Pathology, Ehime University School of Medicine, Ehime, Japan.
Int J Cardiol. 2000 Aug 31;75 Suppl 1:S53-61; discussion S63. doi: 10.1016/s0167-5273(00)00191-1.
MRL/MpJ-lpr/lpr (MRL/lpr) mice develop collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjögren's syndrome, respectively. In the previous studies, we observed genetic segregation of these complex pathological manifestations throughout the genome recombination with a C57Bl/6-lpr/lpr or a C3H/HeJ-lpr/lpr (C3H/lpr) strain of mice which rarely develops such lesions, indicating that development of collagen disease is dependent on an MRL host genetic background. To clarify the mode of inheritance and the gene loci affecting four types of the lesions in MRL/lpr mice; vasculitis, glomerulonephritis, arthritis and sialoadenitis, a genetic dissection of the lesions was carried out by using MRL/lpr, C3H/lpr, (MRL/lprxC3H/lpr) F1 intercross, and MRL/lprx(MRL/lprxC3H/lpr) F1 backcross mice. Definition of each lesion was performed by histopathology under light microscopy, and genomic DNA of the backcross mice were subjected to association studies by chi-square analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. We observed that gene loci recessively associated with each lesion were mapped on different chromosomal positions. We conclude that each of four types of the lesions in MRL/lpr mice is under the control of different set of genes, suggesting the complex pathological manifestations of collagen disease result from polygenic inheritance.
MRL/MpJ-lpr/lpr（MRL/lpr）小鼠会患上涉及血管炎、肾小球肾炎、关节炎和涎腺炎的胶原病，其中每种疾病分别被作为结节性多动脉炎、狼疮性肾炎、类风湿性关节炎和干燥综合征的模型进行研究。在之前的研究中，我们通过与很少出现此类病变的C57Bl/6-lpr/lpr或C3H/HeJ-lpr/lpr（C3H/lpr）品系小鼠进行全基因组重组，观察到了这些复杂病理表现的遗传分离，这表明胶原病的发生依赖于MRL宿主的遗传背景。为了阐明MRL/lpr小鼠中影响血管炎、肾小球肾炎、关节炎和涎腺炎这四种病变的遗传方式和基因位点，我们利用MRL/lpr、C3H/lpr、（MRL/lpr×C3H/lpr）F1杂交后代以及MRL/lpr×（MRL/lpr×C3H/lpr）F1回交小鼠对这些病变进行了遗传剖析。通过光学显微镜下的组织病理学对每种病变进行定义，并对回交小鼠的基因组DNA进行卡方分析关联研究，以确定每个病变在患病个体与未患病个体中哪个多态微卫星位点出现的频率更高。我们观察到与每种病变隐性相关的基因位点位于不同的染色体位置。我们得出结论，MRL/lpr小鼠的四种病变类型分别受不同基因集的控制，这表明胶原病复杂的病理表现是由多基因遗传导致的。
