Role of kallikreins in lupus

描述(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，多器官受累，特征是自身抗体导致组织损伤。树突状细胞(DC)是免疫系统的哨兵，从周围采集危险信号。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，从而连接天然免疫和获得性免疫。我们最近已经表明，来自SLE 1，2，3狼疮易感小鼠模型的髓系树突状细胞，显示出在疾病发生之前的I型干扰素信号。有趣的是，我们从对发病前易患狼疮的SLE 1，2，3小鼠骨髓来源的树突状细胞(BMDCs)的样本微阵列分析中发现，与C57BL/6野生型相比，激肽释放酶家族的许多成员表现出非常低的表达；这一结果也得到了实时荧光聚合酶链式反应的验证。此外，基因组广谱关联研究最近发现激肽释放酶家族的基因与系统性红斑狼疮相关，使其成为狼疮发病机制中的一个重要靶点。到目前为止，还没有关于激肽释放酶在DC上的作用以及对免疫反应和狼疮自身免疫的影响的系统研究。本项目的总体目标是分析激肽释放酶-激动素系统(KKS)在DC和其他免疫细胞中调节干扰素信号的作用，研究KKS在狼疮发病机制中的作用，为新的治疗靶点提供见解。自一个多世纪前被发现以来，激肽释放酶是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。只是在最近几十年，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-激肽系统可能是一个危险信号，可以激活树突状细胞。在此背景下，我的目标是测试(1)激肽释放酶-激肽系统(KKS)候选基因的作用，特别是对树突状细胞和其他免疫亚群中的Th1型干扰素信号及相关通路的影响(2)KKS候选基因是否能改善狼疮疾病。

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.