BCAP regulation of pDC IFNa production in lupus

BCAP 对狼疮 pDC IFNa 产生的调节

• 批准号: 9245545
• 负责人: Jessica A Hamerman
• 金额: $ 22.44万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245545
• 关键词: Agonist; Alpha Cell; Antigen-Antibody Complex; Autoantibodies; Autoimmune Diseases; B-Cell Activation; Cell Maturation; Cell physiology; Cells; Complex; DNA; Data; Dendritic Cells; Development; Disease; Early Endosome; Family; Future; Goals; Human; Immune response; Immune system; In Vitro; Interferon Type I; Interferon-alpha; Interferons; Lupus; Measures; Mediating; Modeling; Molecular; Mus; Nucleic Acids; Pathogenesis; Pathway interactions; Plasma Cells; Process; Production; Proteins; RNA; Regulation; Research Project Grants; Role; SLEB1 gene; Signal Transduction; Splenomegaly; Systemic Lupus Erythematosus; T cell response; T-Lymphocyte; TLR7 gene; Testing; Therapeutic; Type I Epithelial Receptor Cell; base; cell type; cytokine; experimental study; follow-up; immune activation; in vivo; lupus-like; mouse model; novel; overexpression; pleiotropism; response; therapeutic target; trafficking

Project Summary The type I interferon (IFN) cytokine family promotes the development of systemic lupus erythematosus (SLE) and is made by many different cells in response to DNA and RNA. Whereas many cells of the immune system make type I interferon, plasmacytoid dendritic cells (pDC) are a specialized cell type that can produce large quantities of these cytokines in response to nucleic acids in immune complexes, which are abundant in SLE. pDC have been implicated as important type I interferon producing cells in SLE, both in humans and in mouse models. We have made the novel discovery that the signaling adapter BCAP, which is highly expressed in pDC, is required for type I interferon production from these cells. Additionally, deficiency in BCAP in a mouse model of lupus-like disease greatly ameliorates disease. Therefore, BCAP is a potential therapeutic target in SLE to reduce pDC interferon-alpha production. In this proposal, we further examine the function of BCAP in pDC interferon-alpha production and in lupus-like disease. We will explore this idea in two aims: 1) To determine the mechanism by which BCAP regulates plasmacytoid DC type I IFN production, and 2) To determine if BCAP expression in pDC promotes lupus-like disease. Together, these experiments will define a new regulatory mechanism for pDC type I IFN production in vitro and in vivo. BCAP has not previously been implicated in pDC function or in SLE pathogenesis, therefore our proposal tests novel hypotheses focused on determining how BCAP functions in pDC and whether BCAP may be a therapeutic target in SLE.

项目摘要 I型干扰素（IFN）细胞因子家族促进系统性红斑狼疮（SLE）的发展 它是由许多不同的细胞对DNA和RNA做出反应而产生的。而免疫系统的许多细胞 浆细胞样树突状细胞（pDC）是一种专门的细胞类型，可以产生大量的干扰素， 大量的这些细胞因子响应于免疫复合物中的核酸，这在SLE中是丰富的。 pDC在人和小鼠的SLE中都被认为是重要的I型干扰素产生细胞 模型我们已经发现了一个新的发现，信号适配器BCAP，这是高度表达的， pDC是从这些细胞生产I型干扰素所必需的。此外，小鼠中BCAP的缺乏 狼疮样疾病模型极大地改善了疾病。因此，BCAP是一个潜在的治疗靶点， SLE减少pDC干扰素-α的产生。在这个建议中，我们进一步研究了BCAP在以下方面的功能： pDC干扰素-α产生和狼疮样疾病。我们将从两个方面探讨这一想法：1） 确定BCAP调节浆细胞样DC I型IFN产生的机制，以及2） 确定pDC中的BCAP表达是否促进狼疮样疾病。总之，这些实验将定义一个 体外和体内pDC I型IFN产生的新调节机制。BCAP以前没有 与pDC功能或SLE发病机制有关，因此我们的建议测试了新的假设，重点是 确定BCAP如何在pDC中发挥作用以及BCAP是否可以成为SLE的治疗靶点。