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

干扰素调节因子5在SLE发病中的作用

• 批准号: 8504903
• 负责人: IAN R RIFKIN
• 金额: --
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504903
• 关键词: Adverse effects; Animal Model; Antigen-Antibody Complex; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Biological; Bone Marrow; Cells; Chimera organism; DNA; Dendritic Cells; Development; Disease; Disease Progression; Etiology; Genetic; Genetic Polymorphism; Goals; Heterozygote; Human Genetics; Immune response; Immunosuppression; Instruction; Interferon Type I; Interferons; Lupus; Modeling; Molecular Abnormality; Morbidity - disease rate; Mus; Pathogenesis; Patients; Phenotype; Proteins; RNA; Risk; Role; Stimulus; Systemic Lupus Erythematosus; TLR7 gene; Toll-like receptors; cell type; cytokine; human TLR7 protein; mortality; mouse model; overexpression; prevent; response; systemic autoimmune disease; therapeutic target

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

系统性红斑狼疮（SLE）是一种全身性自身免疫性疾病， mortality.目前的治疗包括具有许多严重副作用的非特异性免疫抑制。 此外，对治疗的反应往往是不完全的。因此，更具体，毒性更小的治疗方法 必需的.干扰素调节因子5（IRFS）多态性与人类遗传 尽管IRFS在狼疮发病机制中的生物学作用， 如果有话，是未知的。我们发现IRFS是小鼠疾病发展所必需的 SLE模型此外，IRFS的临界水平是必需的，因为IRFS杂合子小鼠发育最小的 疾病表现。提示IRFS可能是SLE治疗的一个重要靶点。应用程序的 目标是详细了解IRFS导致疾病的机制 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缺陷对细胞的功能影响， 树突状细胞和B细胞对TLR刺激的应答，包括含DNA和RNA的免疫 配合物具体目标2a将通过评估IRFS在SLE中的作用来确定IRFS的普遍性。 IRFS缺陷在其他狼疮模型中的作用。具体目标2b将决定 IRFS缺陷在狼疮中的有益作用是TLR 7-和/或TLR 9-依赖性或非依赖性的。具体目标 2c将确定IRFS过表达是否能够在野生型或自身免疫易感型中诱导疾病。 小鼠具体目标3将通过以下方式确定疾病发病机制需要哪些IRFS表达细胞： 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IRFS， 特定的Cre。具体目标4将确定在疾病后删除IRFS（在所有细胞类型中）是否 可以逆转疾病或预防疾病进展。这也将使用Cre-loxP 方法，但使用诱导型Cre。预计这些研究将增进对 IRFS在SLE发病机制中的作用，有助于开发新的有效，更安全， 具体治疗。 相关性（参见说明）： 一种称为干扰素调节因子S（IRFS）的蛋白质的遗传异常在许多患有乳腺癌的患者中发现。 系统性红斑狼疮（SLE）的自身免疫性疾病。我们在SLE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 SLE治疗靶点