Responsible proteins and genes for the development of intractable vasculitis

系统性血管炎是自身免疫性疾病如SLE和RA的主要并发症。然而，尚不清楚这种并发症是晚期疾病的表现，还是代表可能受遗传因素限制的不同实体。MRL/lpr小鼠株是为数不多的系统性血管炎动物模型之一，同时发展为狼疮样肾炎和关节炎。利用该菌株，我们明确了几个负责蛋白和基因的发展和进展的系统性血管炎如下。1. 利用非血管炎易感性C3H/lpr小鼠杂交小鼠（MRL/lprx C3H/lpr） xMRL/lpr随机发生血管炎的遗传背景重排，阐明巨噬细胞相关细胞因子在血管炎中的致病作用有限。此外，其中一种细胞因子，Eta-1，在这两个菌株的基因转录物的核苷酸序列上具有等位基因差异。2. 一种新发现的来自杂交小鼠的McH5/lpr菌株出现了严重的血管炎，但没有出现肾小球肾炎和关节炎，这表明血管炎是由不同于其他自身免疫性疾病的基因控制的。此外，该菌株的血管炎与抗dna抗体和pANCA.3的增加无关。我们建立了一种具有功能性Fas配体MRL/gld缺陷的新型血管炎易感小鼠，并通过抗Fas抗体治疗成功地改善了血管炎，并且将血管炎转移到正常小鼠身上。4. 我们利用MRL/lprx (MRL/lprx C3H/lpr) F1小鼠与微卫星maker进行血管炎连锁分析，寻找血管炎易感基因位点。5. 将干扰素调节因子-1基因IRF-1转移至MRL/lpr小鼠，可诱导这些小鼠血管炎的抑制，表明血管炎是受IRF-1.6可调节的背景基因控制的。新建立了一株表达可溶性e -选择素的转基因小鼠菌株，该菌株可明显抑制MRL/lpr小鼠单克隆抗体诱导的实验性狼疮性肾炎的发生。说明e -选择素是诱导MRL/lpr小鼠微血管损伤的关键分子。少

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 … More 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