Establishment of murine strains separately with various autoimmune diseases

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1. MRL/lpr, but not C3H/lpr mice, develop autoimmune diseases coincidentally involving vasculitis, arthritis and glomerulonephritis (GN). Two novel congenic strains of mice, which separately developed severe vasculitis and arthritis, respectively, were established from the MRL/lpr and C3H/lpr strains, indicating that these diseases are under the control of suppressor and enhancer genes. 2. By using MRL/lpr x (MRL/lpr x C3H / lpr) F1 mice, we analyzed the linkage of vasculitis with microsatellite makers to find out the corresponding background gene locus. 3. We obtained nephritogenic antibody-producing B cell clones from MRL/lpr mice and were succeeded in cloning of their germline VH genes. These genes were localized also in normal strains of mice. The background genes for GN,thus, are not immunoglobulin genes by themselves and these contribute to the inducing mechanisms of nephritogenic antibodies. 4. Eta-1/Op induces macrophage-and polyclonal B cell-activation. We obseved allelic difference in the Eta-1 gene transcript between MRL and C3H strains, which was enough to induce a functional difference. This can be one of disease-sensitive genes for autoimmune diseases. 5. We newly astablished an MRL strain of mice bearing Fas ligand mutant gene, gld, which developed autoimmune diseases as well as MRL/ipr mice. The treatment with anti-Fas antibodies suppressed and ameliorated the diseases, indicating that the diseases are due to the deficit in Fas/FasL interaction. 6. Transfer of the interferon regulatory factor-1 gene, IRF-1, to MRL/lpr mice induced the selective suppression of autoimmune diseases in MRL/lpr mice. This indicates that some autoimmune diseases, but not all, are under the control of the background genes regulatable by IRF-1.