Responsible proteins and genes for the development of intractable vasculitis

系统性脉管炎是系统性红斑狼疮和类风湿性关节炎等自身免疫性疾病的主要并发症。然而，目前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。一种MRL/LPR品系的小鼠是为数不多的系统性血管炎的动物模型之一，通常会发展成狼疮性肾炎和动脉炎。利用该菌株，我们阐明了以下几种与系统性脉管炎的发生和发展有关的蛋白质和基因。1.利用与非血管炎易感C3H/LPR小鼠(MRL/LPrx C3H/LPR)xMRL/LPR杂交小鼠随机发生血管炎的特点，阐明巨噬细胞相关细胞因子在血管炎发病中的作用有限。此外，其中一种细胞因子Eta-1在这两个菌株之间的基因转录物的核苷酸序列上存在等位基因差异。2.A Ne…从杂交小鼠中建立的McH5/LPR品系更多地发生了严重的血管炎，而不是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，该菌株的血管炎与增加的抗DNA抗体和pANCA无关。我们建立了一种新的具有功能性Fas配体MRL/GLD缺陷的血管炎易感小鼠，并通过抗Fas抗体的治疗成功地改善了血管炎，而且还成功地将血管炎转移到了正常小鼠。4.以MRL/Lprx(MRL/Lprx C3H/LPR)F1小鼠为研究对象，利用微卫星标记对血管炎的易感基因座进行连锁分析。5.将干扰素调节因子-1基因IRF-1转移到MRL/LPR小鼠体内，可抑制这些小鼠的血管炎，表明血管炎受IRF-1.6可调控的背景基因控制。建立了一株异常表达可溶性E-选择素的转基因小鼠，对MRL/LPR小鼠产生的单抗诱导的实验性狼疮性肾炎有明显的抑制作用。提示E-选择素是导致MRL/LPR小鼠微血管损伤的关键分子。较少

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