BCAP regulation of TLR7/9 signaling in Lupus

BCAP 对狼疮中 TLR7/9 信号传导的调节

基本信息

批准号：
9917228
负责人：
Jessica A Hamerman
金额：
$ 64.08万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917228
关键词：
1-Phosphatidylinositol 3-Kinase Antibody Formation Antibody Response Antigen-Antibody Complex Antigens Area Attention Autoantibodies Autoimmune Diseases B-Lymphocyte Subsets B-Lymphocytes Biological Biological Assay Cell Maturation Cell Surface Receptors Cells Complex Data Dendritic Cells Development Disease Disease model Docking Endosomes Generations Human Immune Immune response Immune signaling Immunoglobulin G In Vitro Inflammatory Interferon-alpha Interferons Ligands Lupus Measures Methods Modeling Mus Nucleic Acids Pathogenesis Pathogenicity Plasma Cells Process Production Proteins Regulation Role SLEB1 gene Signal Transduction Systemic Lupus Erythematosus T cell response TLR7 gene Toll-like receptors autoreactive B cell cell type conditional knockout cytokine human disease human model immune activation in vivo lupus-like macrophage mouse model novel pleiotropism response therapeutic target

项目摘要

PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence of circulating autoantibodies to nucleic acids and to proteins with which they associate. Signaling through the nucleic acid sensing TLRs, TLR7 and TLR9, is critical in SLE pathogenesis, and dysregulated TLR signaling can promote lupus in humans and in mouse models. Plasmacytoid dendritic cells (pDC) and B cells both express these nucleic acid sensing TLR and are important in SLE pathogenesis. Autoreactive B cells produce pathogenic autoantibodies in SLE, and B cell antibody production is promoted by TLR7 and TLR9 signaling. pDC use TLR7 and TLR9 to respond to nucleic acids in immune complexes resulting in the secretion of large quantities of type I IFN cytokines, which have pleiotropic effects on the immune response, including enhancing dendritic cell (DC) maturation, plasma cell formation, and T cell responses, all of which can promote a feed forward loop of immune activation. Therefore, understanding the mechanisms by which TLR7 and TLR9 signaling are regulated in these two critical cell types is important for understanding the pathogenesis of SLE and in defining therapeutic targets for this disease. We have identified the signaling adapter B cell adapter for PI3-kinase (BCAP) as a key modulator of TLR signaling in multiple immune lineages. First, we found that in macrophages BCAP inhibits TLR-induced inflammatory cytokine production via activation of PI3-kinase. We recently showed that BCAP promotes pDC IFNα, but not IL-6, secretion. We have also begun to examine how BCAP regulates B cell TLR7/9 responses, an understudied area. Our preliminary data show that BCAP is a key regulator of B cell TLR7/9 responses in all B cell subsets, with a particularly striking decrease in proliferation and IgG secretion from splenic marginal zone B cells. Additionally, we have found that BCAP- deficiency protects the TLR7.1 mouse lupus model from disease. Together, our findings show an important role of BCAP in endosomal TLR signaling in pDC and B cells, both important in SLE pathogenesis. Given the importance of TLR7 and TLR9 signaling in both B cells and pDC in SLE, the premise of this application is that BCAP regulation of pDC and B cell TLR7/9 signaling is critical in the development of lupus-like disease. Specifically, we will 1) determine the mechanism by which BCAP regulates TLR7/9-induced IFNα production in pDCs, 2) determine the mechanism by which BCAP regulates B cell TLR7/9 responses, and 3) determine the relative contribution of BCAP in pDCs and B cells to lupus-like disease using two mouse models.

项目概要系统性红斑狼疮 (SLE) 是一种复杂的自身免疫性疾病，其特征是存在循环中针对核酸和与其相关的蛋白质的自身抗体。核酸感应 TLR、TLR7 和 TLR9 在 SLE 发病机制和失调的 TLR 信号传导中至关重要可以促进人类和小鼠模型中的浆细胞样树突状细胞 (pDC) 和 B 细胞的狼疮。表达这些感应 TLR 的核酸，并且在自身反应性 B 细胞产生中很重要。 SLE 中存在致病性自身抗体，TLR7 和 TLR9 信号传导促进 B 细胞抗体产生。 pDC 使用 TLR7 和 TLR9 来响应免疫复合物中的核酸，导致分泌大量大量的 I 型干扰素细胞因子，对免疫反应具有多效性作用，包括增强树突状细胞 (DC) 成熟、浆细胞形成和 T 细胞反应，所有这些都可以促进饲料因此，了解 TLR7 和 TLR9 的机制。这两种关键细胞类型中信号传导的调节对于理解 SLE 的发病机制非常重要在确定这种疾病的治疗靶点时，我们已经确定了信号传导适配器 B 细胞适配器。首先，我们发现 PI3 激酶 (BCAP) 作为多种免疫谱系中 TLR 信号传导的关键调节剂。巨噬细胞 BCAP 通过激活 PI3 激酶抑制 TLR 诱导的炎症细胞因子的产生。最近表明，BCAP 促进 pDC IFNα 的分泌，但不促进 IL-6 的分泌，我们也开始研究其作用机制。 BCAP 调节 B 细胞 TLR7/9 反应，这是一个尚未研究的领域。所有 B 细胞亚群中 B 细胞 TLR7/9 反应的关键调节因子，尤其显着降低此外，我们还发现 BCAP- 脾边缘区 B 细胞的增殖和 IgG 分泌。缺陷可以保护 TLR7.1 小鼠狼疮模型免受疾病侵害，我们的研究结果表明了一个重要的结果。 BCAP 在 pDC 和 B 细胞内体 TLR 信号转导中的作用，两者在 SLE 发病机制中都很重要。 TLR7 和 TLR9 信号传导在 SLE 中 B 细胞和 pDC 中的重要性，本应用的前提是 BCAP 对 pDC 和 B 细胞 TLR7/9 信号传导的调节对于狼疮样疾病的发展至关重要。具体来说，我们将 1) 确定 BCAP 调节 TLR7/9 诱导的 IFNα 产生的机制 pDC，2) 确定 BCAP 调节 B 细胞 TLR7/9 反应的机制，以及 3) 确定使用两种小鼠模型观察 pDC 和 B 细胞中 BCAP 对狼疮样疾病的相对贡献。