Endolysosomal transporters and systemic autoimmunity

项目总结 几十年来，该实验室和其他实验室广泛调查了原因和 系统性红斑狼疮的免疫发病机制 自身免疫性疾病。尽管取得了相当大的进展，特别是关于#年的异常情况 关于适应性免疫系统，有几个问题仍然没有答案，包括为什么 这种疾病的自身抗体经常是针对核抗原的，最初的原因是什么？ 即使在无菌条件下也会引发这些异常反应？新兴知识 不同的哺乳动物核酸传感器阵列，以及我们和其他人的演示 这些传感器是狼疮发病的主要参与者，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)是如何引发的调查途径。我们最近 观察到携带失活突变的遗传性狼疮易感小鼠 质子/组氨酸转运体SLC15A4(称为虚弱)显示疾病显著减少 表现形式。其他人通过ENU突变发现的微弱突变已经被 显示了通过内溶酶体TLR7和TLR9以及几乎 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(PDCs)而不影响这些细胞的发育。因为 对SLC15A4功能进行治疗干预的明显潜力，这一建议 将试图通过定义功能性突变来确定微弱的突变如何降低自身免疫力 该分子的特征，狼疮相关先天和先天的微弱突变的影响 适应性致病反应，并最终利用高通量筛查系统 确定这种分子和其他自身核酸所必需的分子的药理抑制剂 感官。从这些研究中获得的见解肯定会为 内溶酶体、TLRs和SLC15A4的生物学，并揭示新的治疗靶点 系统性红斑狼疮和其他自身免疫性疾病的干预。

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.