The endosomal SLC15A4 proton-coupled histidine transporter in lupus

描述(申请人提供)：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或两者的核质和细胞质的自身抗体，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，自身抗体产生的机制在很大程度上还不清楚，然而，对一系列不同的哺乳动物核酸传感器的新知识，以及这些传感器是狼疮发病机制的主要参与者的证明，现在为这种疾病的启动和传播机制提供了更简洁的定义。在涉及狼疮发病机制的先天免疫细胞中，浆细胞样树突状细胞(PDC)是一小部分(1%)但独特的细胞，被认为是由含有核酸的免疫复合体刺激内体TLR而激活的，从而产生促进疾病的I型干扰素。虽然之前由于缺乏合适的动物模型而无法研究pDCs在SLE中的作用，但最近发现了SLC15A4基因的一个ENU突变，称为弱突变，导致TLR7/9诱导的特异性pDCs产生I型干扰素的缺陷。这项建议将利用这一独特的模型来确定pDC的作用以及这些细胞在狼疮动物模型中产生I型干扰素的作用。我们还将通过高通量筛选来寻找SLC15A4的药理抑制剂。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.