Endolysosomal transporters and systemic autoimmunity

项目摘要 几十年来，这个实验室和其他实验室已经广泛调查了原因， 系统性红斑狼疮（SLE）的免疫发病机制， 自身免疫性疾病尽管取得了相当大的进展，特别是在 适应性免疫系统，几个问题仍然没有答案，包括为什么 这种疾病中的自身抗体经常针对核抗原，最初的抗体是什么？ 在无菌条件下也会发生异常反应的诱因新兴知识 多种哺乳动物核酸传感器的阵列，以及我们和其他人的演示 这些传感器是狼疮发病机制的主要参与者，现在已经提供了新的 关于这种疾病（可能还有许多其他疾病）是如何开始的调查途径。我们最近 观察到，携带失活突变的同种狼疮易感小鼠， 质子/组氨酸转运蛋白SLC 15 A4（称为弱转运蛋白）显示出显著减少的疾病 表现。其他人通过ENU诱变发现的微弱突变， 显示通过内溶酶体TLR 7和TLR 9消除信号传导，连同几乎所有的 完全不产生I型干扰素（IFN-I）和其他促炎细胞因子 通过浆细胞样树突状细胞（pDC）而不影响这些细胞的发育。因为 治疗性干预SLC 15 A4功能的明显潜力， 将试图通过定义功能性免疫缺陷来确定弱突变如何降低自身免疫性。 这种分子的特性，在狼疮相关的先天性和 适应性致病反应，并最终利用高通量筛选系统， 鉴定该分子和其它自身核酸所必需分子的药理学抑制剂 感应从这些研究中获得的见解肯定会提供关于 内溶酶体，TLR和SLC 15 A4的生物学，并揭示治疗的新靶点。 SLE和其他自身免疫性疾病的干预措施。

PROJECT SUMMARY For several decades, this and other laboratories have extensively investigated the causes and immune pathogenesis of systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease. Despite considerable advances, particularly with regard to abnormalities in the adaptive immune system, several questions remained unanswered, including why autoantibodies in this disease are so often directed against nuclear antigens, and what is the initial trigger for these aberrant responses occurring even under sterile conditions? Emerging knowledge of a diverse array of mammalian sensors for nucleic acids, and the demonstration by us and others that these sensors are principal participants in lupus pathogenesis, have now provided new avenues of inquiry as to how this disease (and possibly many others) is initiated. We recently observed that congenic lupus-predisposed mice carrying an inactivating mutation of the proton/histidine transporter SLC15A4 (termed feeble) showed significantly reduced disease manifestations. The feeble mutation, discovered by others through ENU mutagenesis, has been shown to extinguish signaling by the endolysosomal TLR7 and TLR9, together with almost complete absence of production of type I interferons (IFN-I) and other proinflammatory cytokines by plasmacytoid dendritic cells (pDCs) without affecting the development of these cells. Because of the apparent potential to therapeutically intervene with the function of SLC15A4, this proposal will seek to determine how the feeble mutation reduces autoimmunity by defining the functional characteristics of this molecule, the effects of the feeble mutation in lupus-associated innate and adaptive pathogenic responses, and ultimately to utilize high-throughput screening systems to identify pharmacologic inhibitors of this and other molecules necessary for self-nucleic acid sensing. The insights gained from these studies are certain to provide significant data on the biology of endolysosomes, TLRs and SLC15A4, and to reveal novel targets for therapeutic interventions in SLE and other autoimmune diseases.