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.

项目概要 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响应 DNA 和 RNA 而产生的。而免疫系统的许多细胞 浆细胞样树突状细胞 (pDC) 是一种特殊的细胞类型，可以产生 I 型干扰素 这些细胞因子的数量对免疫复合物中的核酸做出反应，而免疫复合物中的核酸在系统性红斑狼疮中含量丰富。 pDC 被认为是人类和小鼠 SLE 中重要的 I 型干扰素产生细胞 模型。我们的新发现是信号适配器 BCAP 在 pDC 是这些细胞产生 I 型干扰素所必需的。此外，小鼠 BCAP 缺陷 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 可减少 pDC 干扰素-α 的产生。在本提案中，我们进一步研究了 BCAP 在以下方面的功能： pDC 干扰素-α 的产生和狼疮样疾病。我们将探讨这个想法有两个目标：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 表达是否会促进狼疮样疾病。这些实验将共同定义一个 pDC I 型干扰素在体外和体内产生的新调控机制。 BCAP 以前没有 与 pDC 功能或 SLE 发病机制有关，因此我们的提案测试了新的假设，重点是 确定 BCAP 如何在 pDC 中发挥作用以及 BCAP 是否可能是 SLE 的治疗靶点。