| Research Abstract |
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
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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
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