ROLE OF IRF5 IN SLE PATHOGENESIS

描述（由申请人提供）：本提案的主要目标是表征干扰素（IFN）调节因子-5 （IRF-5）转录因子在系统性红斑狼疮（SLE）发病机制中的生理作用。SLE是一种慢性系统性自身免疫性疾病，影响约0.1%的美国人口，并导致一系列器官系统的炎症和损伤。虽然SLE的主要病因尚未确定，但病毒感染或免疫系统功能障碍已被提出。一些证据表明先天免疫反应与SLE的发病机制有关。浆细胞样树突状细胞（PDCs）是先天免疫反应的关键介质，特别是通过它们分泌细胞因子的能力。它们也是I型IFN的主要来源，这是一种对病毒感染的一线防御很重要的分子，最近的数据表明，由PDCs产生的IFN可能对SLE发病机制很重要。I型IFN具有显著的促进IFN进一步产生的能力，这可能通过IFN调节因子，如IRF-3、IRF-5和IRF-7发生。最近的数据表明，IRF-5基因的多态性与SLE有关；IRF-5基因中的单核苷酸多态性（snp）在与SLE的连锁和关联的联合分析中显示出强烈的信号。IRF-5主要在免疫系统细胞中组成性表达，特别是在PDC、单核细胞、单核细胞衍生的树突状细胞以及B细胞中。随着最近对多个选择性剪接的IRF-5亚型的鉴定，每个亚型都具有不同的细胞类型特异性表达、调节和功能，因此有合理的证据表明，IRF-5的多态性可能影响一些对自身免疫性疾病（如SLE）发展重要的细胞功能。因此，我们假设IRF-5亚型表达和功能的改变与SLE患者血清中I型ifn水平升高有关，在SLE发病机制中起重要作用。为了验证这一假设，我们设计了以下具体目标：1)表征与SLE发病机制相关的IRF-5亚型表达；2)确定与SLE相关的IRF-5多态性的生理意义。这些研究结果将为我们理解IRF-5在SLE自身免疫和病理现象中的生理作用提供新的见解。

DESCRIPTION (provided by applicant): The primary goal of this proposal is to characterize the physiological role of the interferon (IFN) regulatory factor-5 (IRF-5) transcription factor in the pathogenesis of systemic lupus erythematosus (SLE). SLE is a chronic systemic autoimmune disease that affects about 0.1% of the US population, and results in inflammation and damage to a range of organ systems. While the primary cause of SLE has not been determined, viral infection or dysfunction of the immune system has been suggested. Several lines of evidence have linked innate immune responses with the pathogenesis of SLE. Plasmacytoid dendritic cells (PDCs) are key mediators of innate immune responses, particularly via their ability to secrete cytokines. They are also the primary source of type I IFN, a molecule important in the front-line defense against viral infection, and recent data suggest that IFN produced by PDCs might be important for SLE pathogenesis. Type I IFNs are remarkable in their ability to prime further IFN production, which is likely to occur through the IFN regulatory factors, such as IRF-3, IRF-5, and IRF-7. Recent data indicate that polymorphism within the IRF-5 gene is associated with SLE; single-nucleotide polymorphisms (SNPs) were identified in the IRF-5 gene that displayed strong signals in joint analysis of linkage and association with SLE. IRF-5 is constitutively expressed mainly in cells of the immune system, particularly in PDC, monocytes, monocytederived dendritic cells, as well as in B cells. With the recent identification of multiple alternatively spliced IRF- 5 isoforms, each with distinct cell type-specific expression, regulation, and function, it is reasonable to suggest that polymorphism within IRF-5 may affect several cellular functions of importance for the development of an autoimmune disease such as SLE. As such, we hypothesize that alterations in IRF-5 isoform expression and function play an important role in SLE pathogenesis associated with the elevated levels of type I IFNs in the serum of SLE patients. The following specific aims have been designed to test this hypothesis, 1) Characterization of IRF-5 isoform expression associated with the pathogenesis of SLE, and 2) Determination of the physiological significance of IRF-5 polymorphism associated with SLE. Results from these studies will provide new insight into our understanding the physiological role for IRF-5 in the autoimmune and pathological phenomena of SLE.