Understanding the role of TREX1 in the innate immunity and autoimmune diseases

描述（申请人提供）：核酸的先天免疫识别是一种重要的防御机制，可以提醒细胞注意入侵者。我们的细胞已经进化出复杂的机制来区分自我和非自我核酸或包含自我核酸以防止对健康细胞的不正确免疫反应，这通常导致自身免疫性疾病。本应用旨在了解TREX1在先天免疫和自身免疫性疾病中的作用。TREX1是哺乳动物细胞质中最丰富的3‘-5’外释酶。我们的实验室之前已经确定了与系统性狼疮红斑（SLE）相关的TREX1突变。2%的SLE患者携带TREX1突变，这代表了已确定的单基因SLE的最常见原因。高外显率的原因狼疮是罕见的，因此重要的研究，因为他们有可能提供直接的见解发病机制。其他TREX1突变体也被发现与aicardii - goutieres综合征（AGS）、视网膜血管病变和脑白质营养不良（RVCL）有关。Trex1-/-小鼠出现与SLE和AGS相似的自身免疫性炎症表型，如I型干扰素a （IFNa）升高。在逆转录过程中，内源性逆转录因子驱动的胞质ssDNA被发现在Trex1-/-细胞中积累，这可能是IFN反应的触发因素。使用逆转录病毒模拟内源性逆转录因子，我发现它刺激了Trex1-/-细胞中逆转录因子相同的信号通路，从而代表了研究Trex1在先天免疫中的功能的强大的基于细胞的感染系统。本应用程序的总体主题是了解TREX1如何抑制先天免疫对来自逆转录元件和逆转录病毒的胞质DNA的反应，以及在TREX1缺失的情况下，由逆转录（RT DNA）产生的DNA如何被先天免疫识别。我的目标1是验证从初步研究中发现的先天免疫因子在逆转录病毒刺激的IFN反应中的作用。我已经确定了一些先天免疫因子对逆转录病毒的先天免疫反应有积极或消极的作用。验证这些因素为研究潜在途径建立了框架。Aim 2的研究将使用系统的多学科方法定义识别RT DNA和激活IFN的信号通路。

DESCRIPTION (provided by applicant): Innate immune recognition of nucleic acid is an important defense mechanism to alert the cell of an invader. Our cells have evolved sophisticated mechanism to distinguish self verse non-self nucleic acid or to contain self nucleic acid to prevent incorrect immune response to healthy cells that often lead to autoimmune diseases. This application seeks to understand the role of TREX1 in the innate immunity and autoimmune diseases. TREX1 is the most abundant 3'-5' exonulease in the cytosol of mammalian cells. Our lab has previously identified TREX1 mutations that are associated with systemic lupus erythematosis (SLE). Two percent of SLE patients harbor mutations in TREX1, representing the single most common cause of monogenic SLE identified. High penetrance causes of lupus are rare and therefore important to study because they have the potential to provide immediate insights into pathogenesis. Other TREX1 mutants have also been identified to associate with Aicardi-Goutieres syndrome (AGS) and retinal vasculopathy and cerebral leukodystrophy (RVCL). Trex1-/- mice develop autoimmune inflammatory phenotypes that are similar to SLE and AGS, such as elevated type I interferon a (IFNa). Cytosolic ssDNA drived from endogenous retroelements during reverse transcription were found to accumulate in Trex1-/- cells that may be the trigger for the IFN response. Using retrovirus to mimic endogenous retroelements, I found that it stimulates the same signaling pathway as described for retroelements in Trex1-/- cells, thereby representing a robust cell-based infection system for studying TREX1 function in the innate immunity. The overall theme of this application is to understand how TREX1 suppresses innate immune response to cytosolic DNA derived from retroelements and retroviruses, and in the absent of TREX1, how DNA generated by reverse transcription (RT DNA) is recognized by the innate immunity. My Aim 1 is to validate innate immune factors uncovered from preliminary studies for their roles in retrovirus-stimulated IFN response. I have identified a few innate immune factors that act positively or negatively on the innate immune response to retrovirus. Validating these factors sets up the framework for studying the underlying pathway. Studies in Aim 2 will define the signaling pathway that recognizes RT DNA and activates IFN using a systematic multidisciplinary approach. Public health relevance TREX1 mutations in humans cause systemic lupus erythematosis (SLE), familial chilblain lupus (FCL), Aicardi-Goutieres syndrome (AGS), and retinal vasculopathy and cerebral leukodystrophy (RVCL). Many of these diseases display autoimmune inflammatory phenotypes such as elevated IFNa. My study will unravel the molecular mechanism of the underlying innate immune signaling pathway. Understanding how TREX1 function in the innate immunity will have broad impact on its genetically linked autoimmune diseases. Innate immune recognition of genetic materials from an invading pathogen alerts the cell by inducing antiviral cytokine responses. Our cell has evolved ways to distinguish self vs non-self nucleic acid such as DNA in the cytosol. Incorrect recognition of self DNA causes immune response to healthy cells that often leads to autoimmune diseases. TREX1 has recently been implicated in inducing interferon in response to endogenous retroelements; and TREX1 gene is mutated in inflammatory diseases of childhood that mimic congenital viral infection and in autoimmune disease, including systemic lupus erythematosis. This study will improve understanding of how TREX1 keeps cytosolic retroelement DNA under the radar of innate immunity, and in the absent of TREX1, how these DNA could be detected. It may also point the way to novel therapies and drug targets for treating autoimmunity.