Intracellular nucleic acid detection in autoimmunity

自身免疫中的细胞内核酸检测

基本信息

批准号：
8072707
负责人：
Daniel B Stetson
金额：
$ 37.92万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-15 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8072707
关键词：
Address Affect Antigen-Presenting Cells Antiviral Agents Antiviral Response Autoantibodies Autoimmune Diseases Autoimmune Responses Autoimmunity B-Lymphocytes Biochemistry Biological Models Cell Line Cells Cellular Immunology Chronic Couples DNA DNA Binding Detection Disease Disease Progression Elements Epitopes Exodeoxyribonuclease I Formaldehyde Genes Genetic Goals Host Defense Human Immune Immune response Interferon Activation Interferon Receptor Interferon Type I Interferons Internal Ribosome Entry Site Life Link Lymphocyte Measures Mediating Methods Modeling Molecular Biology Mus NZW Mouse Nature Nucleic Acids Pathology Pathway interactions Production Publishing Receptor Signaling Regulatory T-Lymphocyte Relative (related person)Reporter Reporting Resolution Role Signal Induction Site Source Specificity Symptoms Syndrome System Systemic Lupus Erythematosus T-Lymphocyte Testing Time Tissues Virus Diseases Work autoreactive T cell base crosslink exodeoxyribonuclease in vivo infancy loss of function mutation mouse model mutant novel nucleic acid detection public health relevance reconstitution repaired response tool

项目摘要

DESCRIPTION (provided by applicant): Detection of nucleic acids and production of type I interferons (IFNs) are principal elements of antiviral defense, but can cause autoimmunity if misregulated. In previous work, we discovered the interferon- stimulatory DNA (ISD) pathway, a cell-intrinsic antiviral response that is activated by detection of cytosolic DNA. We then identified 3' repair exonuclease 1 (Trex1) as a cytosolic, ISD-binding DNA exonuclease. Remarkably, loss of function mutations in the human Trex1 gene cause Aicardi-Goutieres Syndrome (AGS), a rare and severe disease that resembles congenitally acquired viral infection. Using Trex1-deficient mice as a model of AGS, we defined Trex1 as an essential negative regulator of the ISD pathway, thus revealing a novel, cell-intrinsic mechanism for initiation of autoimmunity. Specifically, accumulation of endogenous Trex1 DNA substrates within cells triggers type I IFN production through the ISD pathway, which then leads to the activation and recruitment of autoreactive lymphocytes that attack the initiating cells. Our findings raise fundamental new questions about the connections between the innate antiviral response and autoimmunity, with important implications for the treatment of AGS and related diseases. Very little is known about the cells that initiate disease, the source and nature of the DNA that accumulates within these initiating cells, or how detection of this accumulated DNA ultimately links to the autoreactive lymphocyte response. In this proposal, we will develop new tools and apply a combination of genetics, molecular biology, biochemistry, and cellular immunology to address these important questions. In Aim 1, we will apply new genetic tools to visualize the in vivo dynamics of the IFN-dependent autoimmune response with unprecedented resolution. In Aim 2, we will identify and characterize the Trex1 DNA substrates that cause disease. In Aim 3, we will define how cell- intrinsic nucleic acid detection is linked to the adaptive immune response. Our long term goals are twofold: we will rigorously define the basis of disease with the hope of developing new treatments and preventative measures to cure AGS and related diseases, and we will use this model system to probe more general questions about interconnections between innate immune detection of nucleic acids and lymphocyte-mediated antiviral responses. PUBLIC HEALTH RELEVANCE: Detection of foreign nucleic acids is an ancient form of host defense, but can cause autoimmunity if misregulated. We recently characterized a new mouse model of Aicardi Goutieres Syndrome (AGS), a severe human autoimmune disease that presents in infancy with symptoms resembling a viral infection. We will develop new tools to explore the interconnections between nucleic acid detection, antiviral responses, and autoimmunity, with the hope of identifying new treatments for AGS and related diseases.

描述（由申请人提供）：核酸的检测和 I 型干扰素 (IFN) 的产生是抗病毒防御的主要要素，但如果调节不当，可能会导致自身免疫。在之前的工作中，我们发现了干扰素刺激 DNA (ISD) 途径，这是一种细胞固有的抗病毒反应，通过检测胞质 DNA 来激活。然后我们鉴定出 3' 修复核酸外切酶 1 (Trex1) 是一种胞质 ISD 结合 DNA 核酸外切酶。值得注意的是，人类 Trex1 基因的功能缺失突变会导致 Aicardi-Goutieres 综合征 (AGS)，这是一种罕见且严重的疾病，类似于先天性病毒感染。使用 Trex1 缺陷小鼠作为 AGS 模型，我们将 Trex1 定义为 ISD 途径的重要负调节因子，从而揭示了一种启动自身免疫的新型细胞内在机制。具体来说，细胞内内源性 Trex1 DNA 底物的积累会通过 ISD 途径触发 I 型 IFN 的产生，然后导致攻击起始细胞的自身反应性淋巴细胞的激活和募集。我们的研究结果提出了关于先天抗病毒反应和自身免疫之间的联系的根本性新问题，对 AGS 和相关疾病的治疗具有重要意义。对于引发疾病的细胞、这些起始细胞内积累的 DNA 的来源和性质，或者对这种积累的 DNA 的检测最终如何与自身反应性淋巴细胞反应联系起来，人们知之甚少。在本提案中，我们将开发新工具并应用遗传学、分子生物学、生物化学和细胞免疫学的组合来解决这些重要问题。在目标 1 中，我们将应用新的遗传工具以前所未有的分辨率可视化 IFN 依赖性自身免疫反应的体内动态。在目标 2 中，我们将鉴定并表征导致疾病的 Trex1 DNA 底物。在目标 3 中，我们将定义细胞内在核酸检测如何与适应性免疫反应联系起来。我们的长期目标是双重的：我们将严格定义疾病的基础，希望开发新的治疗方法和预防措施来治愈 AGS 和相关疾病，并且我们将使用这个模型系统来探讨有关先天免疫检测之间相互联系的更普遍的问题核酸和淋巴细胞介导的抗病毒反应。公共卫生相关性：外源核酸的检测是一种古老的宿主防御形式，但如果调节不当，可能会导致自身免疫。我们最近描述了一种新的艾卡迪·古蒂埃综合症（AGS）小鼠模型，这是一种严重的人类自身免疫性疾病，在婴儿期出现类似于病毒感染的症状。我们将开发新工具来探索核酸检测、抗病毒反应和自身免疫之间的相互关系，希望找到 AGS 和相关疾病的新疗法。