| Research Abstract |
Systemic vasculitis is a major complication of autoimmune diseases such as SLE and RA.However, it is still unclear whether this complication is a manifestation of advanced disease or represents distinct entities possibly restricted by genetic factors. An MRL/lpr strain of mice is one of the few animal models for systemic vasculitis, conicidentally developing lupus-like nephritis and artheritis. Using this strain, we clarified several responsible proteins and genes for the development and progression of systemic vasculitis as follows. 1. Taking advantage that the hybrid mice with non-vasculitis-prone C3H/lpr mice, (MRL/lprx C3H/lpr) xMRL/lpr, develop vasculitis at random, resulted from the rearrangement of the genetic background of MRL/lpr mice, we clarified that macrophage-relating cytokines have a limited pathogenic role in vasculitis. Moreover, one of these cytokines, Eta-1, had an allelic difference in the nucleotide sequence of the gene transcript between these two strains. 2. A ne
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wly established strain of mice, McH5/lpr, from the hybrid mice, developed severe vasculitis, but not glomerulonephritis and arthritis, indicating that vasculitis is under the control of genes different from those of other autoimmune diseases. Moreover, vasculitis in this strain was not associated with increased anti-DNA antibodies and pANCA.3. We established a novel vasculitis-prone mice with a deficit in the functional Fas ligand, MRL/gld, and succeeded in ameliorating vasculitis by the treatment with anti-Fas antibodies and, moreover, in transfer of vasculitis to normal mice. 4. By using MRL/lprx (MRL/lprx C3H/lpr) F1 mice, we performed the linkage analysis of vasculitis with microsatellite makers to find out vasculitis-susceptible gene loci. 5. Transfer of the interferon regulatory factor-1 gene, IRF-1, to MRL/lpr mice induced the suppression of vasculitis in these mice, indicating that vasculitis is under the control of the background genes regulatable by IRF-1.6. A transgenic mouse strain aberrantly expressing soluble E-selectin was newly established, in which the development of experimental lupusnephritis induced by the monoclonal antibodies derived from MRL/lpr mice was remarkably inhibited. This indicates that E-selectin is a critical molecule inducing microvascular injury in MRL/lpr mice. Less
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