THE ROLE OF INTERFERON REGULATORY FACTOR 5 IN THE PATHOGENESIS OF SLE

系统性红斑狼疮(SLE)是一种发病率较高的系统性自身免疫性疾病。 死亡率。目前的治疗方法包括非特异性免疫抑制，具有许多严重的副作用。 此外，对治疗的反应往往是不完全的。因此，更具体、毒性更低的疗法 必填项。干扰素调节因子5(IRFS)基因多态性与人类遗传密切相关 尽管IRFS在狼疮发病机制中的生物学作用， 如果有的话，目前还不清楚。我们发现IRFS在小鼠的疾病发展过程中是绝对必要的 系统性红斑狼疮模型。此外，由于IRFS杂合子小鼠发育极少，因此需要达到临界水平的IRFS 疾病表现。这表明IRFS可能是SLE的一个关键治疗靶点。应用程序的 目的是详细了解IRFS致病的机制。 SLE的发病机制。具体目标1的目标是确定IRFS在狼疮相关免疫中的作用 通过比较纯合子和杂合子IRFS缺乏症对脑功能的影响来做出反应 树突状细胞和B细胞对含DNA和RNA免疫的TLR刺激的反应 复合体。具体目标2a将通过评估 IRFS缺乏在附加狼疮模型中的作用。具体目标2b将决定在多大程度上 IRFS缺乏对狼疮的有益影响是TLR7和/或TLR9依赖或独立的。特定目标 2C将确定IRFS的过度表达是否能够在野生型或自身免疫倾向患者中诱发疾病 老鼠。具体目标3将通过以下方式确定哪些表达IRFS的细胞是疾病发病所必需的 使用骨髓嵌合体，并通过使用Cre-loxP方法删除特定细胞类型中的IRF 特定的Cre。具体目标4将确定在疾病后删除IRF(在所有细胞类型中)是否 已建立的可以逆转疾病或防止疾病进展。这也将使用CRE-loxP来完成 方法，但使用可诱导的CRE。预计这些研究将增进对 IRFS在SLE发病机制中的作用并有助于开发新的有效、安全和更 特定的疗法。 相关性(请参阅说明)： 一种名为干扰素调节因子S(IRFS)的蛋白质的遗传异常在许多慢性粒细胞白血病患者中被发现 自身免疫性疾病系统性红斑狼疮(SLE)。我们在系统性红斑狼疮的动物模型中发现 IRFS的缺乏阻止了疾病的发展。这表明IRFS可能是一个关键 系统性红斑狼疮的治疗靶点

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with appreciable morbidity and mortality. Current treatment comprises non-specific immunosuppression with many serious side-effects. Furthermore, response to therapy is often incomplete. More specific, and less toxic therapies are thus required. Interferon regulatory factor 5 (IRFS) polymorphisms are strongly associated in human genetic studies with an increased risk of developing SLE although the biological role of IRFS in lupus pathogenesis, if any, is not known. We have found that IRFS is absolutely required for disease development in a mouse model of SLE. In addition, a critical level of IRFS is required as IRFS heterozygous mice develop minimal disease manifestations. This suggests that IRFS might be a key therapeutic target in SLE. The application's objectives are to obtain a detailed understanding of the mechanisms whereby IRFS contributes to disease pathogenesis in SLE. The goal of specific aim 1 is to determine the role of IRFS in lupus-relevant immune responses by comparing the functional effects of homozygous and heterozygous IRFS deficiency on the response of dendritic cells and B cells to TLR stimuli including DNA- and RNA-containing immune complexes. Specific aim 2a will determine the generalizability of the IRFS role in SLE by evaluating the effect of IRFS-deficiency in additional lupus models. Specific aim 2b will determine to what extent the beneficial effect of IRFS-deficiency in lupus is TLR7- and/or TLR9-dependent or independent. Specific aim 2c will determine whether IRFS overexpression is able to induce disease in wildtype or autoimmune-prone mice. Specific aim 3 will determine which IRFS-expressing cells are required for disease pathogenesis by using bone-marrow chimeras, and by deleting IRFS in specific cell types using a Cre-loxP approach with cell- specific Cre. Specific aim 4 will determine whether deleting IRFS (in all cell types) after disease is established can reverse disease or prevent disease progression. This will be done also using a Cre-loxP approach but using an inducible Cre. It is anticipated that these studies will enhance the understanding of the role of IRFS in SLE pathogenesis and contribute to the development of new effective, safer and more specific therapies. RELEVANCE (See instructions): Genetic abnormalities in a protein called interferon regulatory factor S (IRFS) are found in many patients with the autoimmune disease systemic lupus erythematosus (SLE). We have found in an animal model of SLE that deficiency of IRFS prevents the development of disease. This suggests that IRFS might be a key therapeutic target in SLE