Role of kallikreins in lupus

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种全身性自身免疫性疾病，病因不明，累及多器官，以自身抗体诱导组织损伤为特征。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，引起适当的免疫反应，从而架起先天免疫和适应性免疫的桥梁。我们最近发现，来自Sle 1,2,3狼疮易感小鼠模型的骨髓树突状细胞，在疾病发作之前显示出I型干扰素信号。有趣的是，我们从骨髓来源的树突状细胞（bmdc）的样本微阵列分析中发现，与C57BL/6野生型相比，klikrein基因家族的许多成员的表达非常低；结果也得到了实时PCR的验证。此外，全基因组关联研究（GWAS）最近发现，kallikrein家族中的基因与SLE相关，使其成为狼疮发病机制的重要靶点。到目前为止，还没有系统的研究碱解酶在dc中的作用以及对免疫反应和狼疮自身免疫的影响。本项目的总体目标是分析kallikrein-kinin系统（KKS）在调节dc和其他免疫细胞干扰素信号中的作用，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。自一个多世纪前被发现以来，kallikreins（一种丝氨酸肽酶家族）主要被认为具有调节血压、氧化还原平衡、肾脏纤维化、炎症和细胞凋亡的功能。只是在过去的几十年里，文献才开始积累证据，证明钾likrein-kinin系统在免疫系统中的作用，特别是钾likrein-kinin系统可以是一个危险的信号，可以激活树突细胞。在此背景下，我的目的是测试(1)KKS系统中假定的候选药物的作用，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影响(2)KKS候选药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.