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模式并鉴定干燥综合征中的易感基因座，制备了发生胶原蛋白疾病的基因组重组小鼠，所述胶原蛋白疾病除了多动脉炎、狼疮性肾炎、类风湿性关节炎之外还涉及涎腺炎，并通过组织病理学分级来分析个体小鼠中的涎腺炎。通过简单序列长度多态性分析检测这些小鼠的基因组DNA，并确定与涎腺炎高度相关的多态性微卫星标记为涎腺炎易感位点。将4个与涎腺炎相关的易感基因位点分别定位在第10、18、4和1号染色体上。这些位点在涎腺炎的发展中表现出加性和层次性。结果表明MRL/lpr小鼠的涎腺炎是多基因遗传的，可能涉及等位基因多态性。另一方面，由于已经提出多基因遗传容易受病毒感染等外在因素的影响，因此还研究了由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。为此目的，将IRF-1转基因插入MRL/MpJ-lpr/lpr小鼠的染色体中，并建立了一种新的转基因小鼠品系，MRL/Mn-IRF 1-lpr/lpr小鼠。结果，转基因小鼠的涎腺炎的组织病理学分级显著增加，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降低。由此可见，MRL系小鼠自身免疫性病变的表现受多基因遗传控制，并受IRF-1表达等外在因素的影响。

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.