Establishment of murine strains separately with various autoimmune diseases

1. MRL/lpr而不是C3 H/lpr小鼠，发展自身免疫性疾病，同时涉及血管炎、关节炎和肾小球肾炎（GN）。从MRL/lpr和C3 H/lpr品系中建立了两种新的同类系小鼠，分别发生严重的血管炎和关节炎，表明这些疾病是在抑制基因和增强基因的控制下。2.利用MRL/lpr x（MRL/lpr x C3 H/ lpr）F1小鼠，对血管炎的微卫星标记进行连锁分析，寻找相应的背景基因位点。3.我们从MRL/lpr小鼠中获得了产生致肾炎抗体的B细胞克隆，并成功克隆了其种系VH基因。这些基因也定位在正常品系的小鼠中。因此，GN的背景基因本身不是免疫球蛋白基因，这些基因有助于致肾炎抗体的诱导机制。4. Eta-1/Op诱导巨噬细胞和多克隆B细胞活化。我们观察到MRL和C3 H株之间Eta-1基因转录本的等位基因差异，这足以引起功能差异。这可能是自身免疫性疾病的疾病敏感基因之一。5.我们新建立了一个携带Fas配体突变基因gld的MRL小鼠品系，该品系小鼠与MRL/ipr小鼠一样发生自身免疫性疾病。抗Fas抗体治疗可抑制和改善这些疾病，表明这些疾病是由于Fas/FasL相互作用缺陷所致。6.将干扰素调节因子-1基因（IRF-1）转移到MRL/lpr小鼠中可诱导MRL/lpr小鼠中自身免疫性疾病的选择性抑制。这表明，一些自身免疫性疾病，但不是所有的，是由IRF-1调控的背景基因的控制下。

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.