Role of kallikreins in lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种病因不明、多器官受累的全身性自身免疫性疾病，以诱导组织损伤的自身抗体为特征。树突状细胞（DC）是免疫系统的哨兵，从外周采集危险信号。它们产生促炎细胞因子，并与次级淋巴器官中的幼稚T细胞相互作用，引起适当的免疫应答，从而桥接先天性免疫和适应性免疫。我们最近已经表明，来自Sle 1，2，3狼疮易感小鼠模型的髓样树突状细胞显示出早于疾病发作的I型干扰素信号。有趣的是，我们已经从来自年轻的患病前狼疮倾向Sle 1，2，3小鼠的骨髓来源的树突状细胞（BMDC）的样品微阵列分析中发现，与C57 BL/6野生型相比，激肽释放酶基因家族的许多成员显示非常低的表达;该结果也已经通过实时PCR验证。此外，全基因组关联研究（GWAS）最近揭示了激肽释放酶家族中的基因与SLE相关，使其成为狼疮发病机制中的重要靶点。到目前为止，尚未有系统的研究激肽释放酶对DC的作用，以及对免疫应答和狼疮自身免疫的影响。本项目的总体目标是分析激肽释放酶-激肽系统（KKS）在调节DC和其他免疫细胞中的干扰素信号中的作用，并研究KKS对狼疮发病机制的影响，并为新的治疗靶点提供见解。自从世纪前发现激肽释放酶（kallikreins）以来，主要已知其在调节血压、氧化还原平衡、肾内纤维化、炎症和细胞凋亡中具有功能。只是在过去的几十年里，文献才开始积累关于激肽释放酶在免疫系统中作用的证据，特别是激肽释放酶-激肽系统可能是一种可以激活树突状细胞的危险信号。在此背景下，我的目的是测试（1）激肽释放酶-激肽系统（KKS）中的推定候选物的作用，特别是对树突状细胞和其他免疫亚群中的IFN型信号传导和相关途径的作用（2）KKS的候选物是否可以改善狼疮疾病。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, with unknown etiopathogenesis and multi-organ involvement, characterized by autoantibodies that induce tissue damage. Dendritic cells (DCs) are the sentinels of the immune system sampling danger signals from the periphery. They produce proinflammatory cytokines, and interact with naive T cells in secondary lymphoid organs evoking an appropriate immune response, thus bridging the innate and adaptive immunity. We have shown recently that myeloid dendritic cells from the Sle 1,2,3 lupus-prone mouse model, show a Type I Interferon Signature that predates disease onset. Interestingly, we have discovered from a sample microarray analysis of bone-marrow-derived dendritic cells (BMDCs) from young pre-diseased lupus-prone Sle 1,2,3 mouse that many members of the kallikrein family of genes show very low expression as compared to the C57BL/6 wild type; the results have been validated by real-time PCR as well. Also Genome Wide Association Studies (GWAS) have recently revealed that the genes in the kallikrein family are associated with SLE, making this an important target in lupus pathogenesis. So far there has been no systematic study on the role of kallikreins on DCs and the impact on immune response and lupus autoimmunity. The overall goal of this project is to analyze the role of kallikrein-kinin system (KKS) in regulating he Interferon Signature in DCs and other immune cells and to study the impact of the KKS on lupus pathogenesis and provide insights to new therapeutic targets. Since their discovery over a century ago, kallikreins, a family of serine peptidases, are majorly known to have functions in regulating blood pressure, redox balance, fibrosis within the kidneys, inflammation and apoptosis. It is only in the last couple of decades that literature is beginning to accumulate evidence on the role of kallikreins in the immune system, especially that the kallikrein-kinin system can be a danger signal that can activate dendritic cells. With this background I aim to test (1) the effects of putative candidates in kallikrein-kinin system (KKS), specifically on Type IFN signaling and related pathways in dendritic cells and other immune subsets (2) if candidates of the KKS can ameliorate lupus disease.