alpha v integrin regulation of B cell tolerance

B 细胞耐受的 α v 整合素调节

基本信息

批准号：
10294130
负责人：
Adam Lacy-Hulbert
金额：
$ 20万
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：
2020
资助国家：
美国
起止时间：
2020-12-16 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10294130
关键词：
Affect Affinity American Animal Model Antigens Apoptotic Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Autophagocytosis B cell differentiation B-Cell Activation B-Cell Development B-Lymphocytes CD19 gene Cell Death Cell Proliferation Cells Chronic Complex DNA Data Development Endosomes Etiology Excision Exposure to Frequencies Genetic Goals Grant Homologous Gene Immune Tolerance Immune response Immune signaling Immune system Immunoglobulin Class Switching Inflammation Inflammatory Integrin alphaV Integrins Interferon-beta Interferons Kidney Knock-out Knockout Mice Ligands Link Mediating Mission Modeling Mouse Strains Mus Nucleic Acids Organ Pathway interactions Patients Pattern recognition receptor Peripheral Plasma Cells Production RNA Receptor Signaling Regulation Regulatory Pathway Research Rheumatoid Arthritis Role Signal Transduction Skin Systemic Lupus Erythematosus Testing Toll-like receptors Transgenic Mice Translating United States National Institutes of Health Work autoreactive B cell autoreactivity base chronic inflammatory disease design experimental study immunoregulation in vivo innovation insight lupus-like mouse model novel novel therapeutic intervention peripheral tolerance recruit response trafficking

项目摘要

PROJECT SUMMARY There is a fundamental need to understand how the immune system discriminates self-antigens and regulates potentially harmful autoimmune responses. Increasing evidence from genetics and functional studies indicate that innate immune signaling in response to products caused by cell death is a major etiological factor in autoimmune and chronic inflammatory disease. Our long-term goal is to better understand how immune tolerance to antigens derived from apoptotic cells and other self-antigens is maintained and how this can break down in autoimmune diseases. The objective in this application is to understand how av integrins and components of the autophagy pathway contribute to B cell tolerance. Our central hypothesis is that av- mediated activation of autophagy components regulates TLR signaling in B cells, limiting cell proliferation, differentiation and production of autoantibodies. The rationale for this grant is that the proposed work will define the role of av-mediated autophagy in B cell tolerance, and develop better models for autoimmune disease. Furthermore, this work has the potential to translate into new therapeutic approaches through the use of existing compounds that target av and autophagy. Based on strong preliminary data, our hypothesis will be tested in three specific aims: (1) Determine how av regulates development of autoreactive B cells and lupus- like autoimmunity in mice. av-knockout mice crossed with an autoreactive BCR heavy chain transgenic mouse strain will be used to follow development of autoreactive B cells, and understand how av regulates tolerance and response to self-antigen. (2) Determine how av-mediated regulation of type I-IFNs regulates B cell tolerance. We will test how increased type I IFN production by B cells and plasmacyotid DCs contribute to B cell activation. (3) Test the hypothesis that non-canonical autophagy regulates B cell TLR signaling to promote tolerance. We will analyze the role of Rubicon in autoreactive B cell activation, and evaluate a potential new component of non-canonical autophagy, Atg16l2 Our approach is innovative as it focuses on a novel role for integrins and autophagy components in regulating immune signaling in B cells. The proposed work is significant because it will establish a new paradigm for B cell recognition of potential self-antigens in immune tolerance and provide a mechanism by which this occurs. Ultimately this has the potential to change our understanding of how immune tolerance is maintained and how autoreactive B cells may escape control to promote autoimmunity.

项目概要基本需要了解免疫系统如何区分自身抗原并调节潜在有害的自身免疫反应。越来越多的遗传学和功能研究证据表明对细胞死亡引起的产物作出反应的先天免疫信号是一个主要的病因自身免疫性疾病和慢性炎症性疾病。我们的长期目标是更好地了解免疫如何对来自凋亡细胞和其他自身抗原的抗原的耐受性得以维持，以及如何打破这种耐受性自身免疫性疾病的发病率下降。本应用的目的是了解 av 整合素和自噬途径的组成部分有助于 B 细胞耐受。我们的中心假设是 av- 自噬成分介导的激活调节 B 细胞中的 TLR 信号传导，限制细胞增殖，自身抗体的分化和产生。这笔赠款的理由是拟议的工作将定义 av 介导的自噬在 B 细胞耐受中的作用，并开发更好的自身免疫模型疾病。此外，这项工作有可能通过使用转化为新的治疗方法针对 av 和自噬的现有化合物。基于强有力的初步数据，我们的假设是测试的三个具体目标是：(1) 确定 av 如何调节自身反应性 B 细胞和狼疮的发育- 就像老鼠的自身免疫一样。 av 基因敲除小鼠与自身反应性 BCR 重链转基因小鼠杂交菌株将用于跟踪自身反应性 B 细胞的发育，并了解 av 如何调节耐受性以及对自身抗原的反应。 (2) 确定av介导的I型-IFNs如何调节B细胞宽容。我们将测试 B 细胞和浆细胞 DC 产生的 I 型干扰素增加如何促进 B 细胞激活。 (3)检验非经典自噬调节B细胞TLR信号传导促进的假设宽容。我们将分析 Rubicon 在自身反应性 B 细胞激活中的作用，并评估潜在的新药物非典型自噬的组成部分 Atg16l2 我们的方法是创新的，因为它侧重于整合素和自噬成分在调节 B 细胞免疫信号中的作用。拟议的工作是意义重大，因为它将建立 B 细胞识别免疫中潜在自身抗原的新范例容忍并提供发生这种情况的机制。最终这有可能改变我们的了解如何维持免疫耐受以及自身反应性 B 细胞如何逃脱控制促进自身免疫。