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）：检测核酸和I型干扰素（IFN）的产生是抗病毒防御的主要元素，但如果误导，可能会导致自身免疫性。在先前的工作中，我们发现了干扰素刺激DNA（ISD）途径，这是一种通过检测胞质DNA激活的细胞内抗病毒反应。然后，我们将3'修复外切核酸酶1（TREX1）确定为胞质，结合DNA外切核酸酶。值得注意的是，人类TREX1基因中功能突变的丧失导致AICARDI-GOTIERES综合征（AGS），这是一种类似于先天获得的病毒感染的罕见且严重的疾病。我们将缺陷小鼠作为AG的模型，将TREX1定义为ISD途径的基本负调节剂，从而揭示了一种新型的自身免疫开始的细胞中性机制。具体而言，细胞内的内源性TREX1 DNA底物的积累触发I型IFN型通过ISD途径的产生，从而导致激活和募集自动反应性淋巴细胞，从而攻击启动细胞。我们的发现提出了有关先天性抗病毒反应与自身免疫之间的联系的基本新问题，对治疗AGS和相关疾病的治疗具有重要意义。关于引发疾病的细胞，在这些引发细胞中积累的DNA的来源和性质，或该累积DNA的检测最终与自动反应性淋巴细胞反应联系起来的细胞知之甚少。在此提案中，我们将开发新的工具，并将遗传学，分子生物学，生物化学和细胞免疫学结合起来解决这些重要问题。在AIM 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力学。在AIM 2中，我们将确定并表征引起疾病的TREX1 DNA底物。在AIM 3中，我们将定义细胞内核酸检测如何与适应性免疫反应有关。我们的长期目标是双重的：我们将严格定义疾病的基础，希望制定新的治疗方法和预防措施来治愈AGS和相关疾病，我们将使用此模型系统来探讨有关先天免疫检测之间互连的更多一般性问题核酸和淋巴细胞介导的抗病毒反应的摄入量。公共卫生相关性：外国核酸的检测是一种古老的宿主防御形式，但如果不调查，可能会引起自身免疫性。我们最近表征了一种新的AICARDI GOTIERES综合征（AGS）的小鼠模型，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。我们将开发新的工具来探索核酸检测，抗病毒反应和自身免疫性之间的互连，并希望鉴定针对AGS和相关疾病的新治疗方法。