The endosomal SLC15A4 proton-coupled histidine transporter in lupus

描述（由申请方提供）：人类和自发性小鼠模型中的系统性红斑狼疮的特征是针对含有RNA、DNA或两者的细胞核和细胞质物质的自身抗体，大量证据表明这些自身抗体具有直接的病理作用。直到最近的机制参与自身抗体的生产在很大程度上是不清楚的，然而，新兴的知识，各种各样的哺乳动物传感器的核酸，并证明这些传感器的主要参与者在狼疮的发病机制，现在提供了一个更简洁的定义，这种疾病的发起和传播的机制。在狼疮发病机制中涉及的先天免疫细胞中是浆细胞样树突状细胞（pDC），其构成小的（<1%）但不同的细胞群体，其被认为通过含核酸的免疫复合物刺激内体TLR而活化，导致产生促进疾病的I型干扰素。虽然pDC在SLE中的作用的研究以前是不可能的，因为缺乏足够的动物模型，最近在Slc15a4基因中的ENU突变，被称为虚弱，被发现，导致有缺陷的TLR7/9诱导的I型干扰素的生产，特别是pDC。该提案将利用这种独特的模型来确定pDC的作用和这些细胞在狼疮动物模型中产生I型干扰素。我们还将寻求通过高通量筛选来鉴定SLC15A4的药理学抑制剂。从这些研究中获得的见解可能会更好地理解先天传感器和细胞促进疾病的机制，并揭示治疗干预的新靶点。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus in humans and spontaneous mouse models is characterized by autoantibodies to nuclear and cytoplasmic materials that contain RNA, DNA or both, and considerable evidence indicates a direct pathologic role of these autoantibodies. Until recently the mechanisms involved in autoantibody production were to a large extend unclear, however, the emerging knowledge of a diverse array of mammalian sensors for nucleic acids, and the demonstration that these sensors are principal participants in lupus pathogenesis, have now provided a more concise definition of the mechanisms by which this disease is initiated and propagated. Among the innate immune cells implicated in the pathogenesis of lupus is the plasmacytoid dendritic cell (pDC) which constitute a small (<1%), but distinct population of cells that is thought to be activated by nucleic acid-containing immune complex stimulation of endosomal TLRs resulting in the production of disease-promoting type I interferons. Although investigation of the role of pDCs in SLE was previously not possible because of the absence of adequate animal models, recently an ENU mutation in the Slc15a4 gene, called feeble, was discovered that resulted in defective TLR7/9-induced type I interferon production in specifically pDCs. This proposal will utilize this unique model to define the role of pDCs and the production of type I interferons by these cells in animal models of lupus. We will also seek to identify pharmacologic inhibitors of SLC15A4 by high throughput screening. The insights gained from these studies are likely to provide a better understanding of the mechanisms by which innate sensors and cells promote disease, and reveal novel targets for therapeutic intervention.