Establishment of animal model for Sjogren's syndrome and genetic analysis of the susceptibility loci

为了阐明自身免疫性涎腺炎的遗传方式和确定干燥综合征的易感基因，制备了除多动脉炎、狼疮性肾炎、类风湿性关节炎外还伴有涎腺炎的重组小鼠基因组，并对个别小鼠的涎腺炎进行了组织病理学分级。对这些小鼠的基因组DNA进行简单序列长度多态性分析，确定与涎腺炎高度相关的微卫星标记为涎腺炎的易感基因。在第10、18、4、1号染色体上分别定位了4个与涎腺炎相关的易感基因。这些基因座在涎腺炎的发生发展过程中表现出相加和等级性。结果表明，MRL/LPR小鼠的涎腺炎受多基因遗传控制，可能涉及等位基因多态性。另一方面，鉴于多基因遗传易受病毒感染等外部因素的影响，本研究还探讨了病毒感染诱导表达的干扰素调节因子-1(IRF-1)对胶原病表现的影响。为此，将IRF-1基因插入到MRL/MPJ-LPR/LPR小鼠的染色体中，建立了新的转基因小鼠品系：MRL/Mn-IRF1-LPR/LPR小鼠。结果，转基因小鼠涎腺炎的组织病理学分级显著提高，而其他病变，如多动脉炎、狼疮性肾炎和类风湿性关节炎的分级则降低。根据这些结果，我们认为MRL株小鼠自身免疫损害的表现受多基因遗传控制，并受IRF-1表达等外部因素的影响。

To clarify the mode of inheritance of autoimmune sialadenitis and identify the susceptibility loci in Sjogren's syndrome, genome-recombinant mice that develop collagen disease involving sialadenitis in addition to polyarteritis, lupus nephritis, rheumatoid arthritis were prepared, and sialadenitis in individual mice was analyzed by histopathologic grading. The genomic DNA of these mice was examined by simple sequence-length polymorphism analysis, and the highly associated polymorphic microsatellite markers with sialadenitis were determined as sialadenitis susceptibility loci. Four susceptible gene loci recessively associated with sialadenitis were mapped on chromosomes 10,18,4, and 1, respectively. These loci manifested additive and hierarchical properties in the development of sialadenitis. The results indicate that sialadenitis in MRL/lpr mice is under the control of polygenic inheritance, possibly involving allelic polymorphism. On the other-hand, since it has been suggested that polygenic inheritance are easily influenced by extrinsic factors such as viral infection, influence on the manifestation of the collagen diseases by interferon regulatory factor-1 (IRF-1) which expression is induced by viral infection was also examined. For this purpose, IRF-1 transgene was inserted into a chromosome of an MRL/MpJ-lpr/lpr mouse, and a novel strain of transgenic mouse, MRL/Mn-IRF1-lpr/lpr mice were established. As a result, histopathological grading of sialadenitis of the transgenic mice was significantly increased while grading of other lesions such as polyarteritis, lupus nephritis, and rheumatoid arthritis was decreased. From these results, we conclude that manifestation of autoimmune lesions in mice of MRL strain are under the control of polygenic inheritance, and influenced by extrinsic factors such as IRF-1 expression.