| Research Abstract |
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.
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