Post Translational Modifications in Tolerance and Autoimmunity

项目总结/摘要 本提案是AR 48120的修订版、竞争性延续， 翻译修饰的耐受性和自身免疫性”。我们最初的提议 详细描述了自身蛋白质的一种新特性， 系统性红斑狼疮（SLE）的鼠模型。正如我们在最初的 一种被称为异戊酰的翻译后蛋白质修饰， 在pH和温度的生理条件下自发地进行。而 已知修饰存在于细胞中已有多年，对这种修饰的免疫力已经降低。 只有我们的实验室描述了自身蛋白质内的修饰。这些 所有类型的细胞都会发生这种变化， 淋巴细胞与我们的工作相关，针对其他蛋白质修饰的自身抗体， 尤其是瓜氨酸蛋白，已经成为自身免疫综合征的诊断剂， 类风湿关节炎本提案的总体意图是确定如何 自身蛋白质内自发的生化修饰可以改变免疫系统， 通常对自身蛋白质建立的耐受性。我们已经确定了两个 蛋白质修饰的重要机制可以引发自身免疫。第一，异戊基 修饰的自身抗原可以经历改变的抗原加工，潜在地导致 新型隐蔽自身肽的表达。特别是，组蛋白H2 B蛋白经历 可能以这种方式触发自身免疫的广泛的异丙酰基修饰。 第二，细胞内蛋白质修饰的积累被发现在细胞中， 狼疮倾向MRL小鼠引起异常T细胞过度增殖，并与 自身免疫性疾病的发病 目前的建议将研究的机制， 修饰改变蛋白质的免疫原性并改变淋巴细胞功能。在 特别是，我们将开发具有条件蛋白修复系统的新型小鼠品系， 改变CD 4 T细胞中的蛋白质修饰。我们将确定自身抗原 在蛋白质修饰的存在下， 蛋白质触发自身抗体反应。这些研究的总体目标是确定 翻译后蛋白修饰在狼疮样细胞发生中的作用 自身免疫项目叙述 系统性自身免疫性疾病的特征是异常的免疫反应 针对细胞内蛋白质中的一个选择组。我们工作的重点是确定 新的翻译后蛋白质修饰，可能是关键的诱导， 自身免疫性疾病这些研究的优先性是显而易见的， 几种蛋白质修饰，特别是瓜氨酸，在风湿性关节炎中的临床意义 疾病目前的研究集中在一种称为“异戊酰基”的蛋白质修饰上， 在真核细胞中自发发生，并在细胞应激条件下增强 和炎症。我们之前已经发现了异戊酰的存在 在两个狼疮自身抗原，snRNP核糖核蛋白和组蛋白H2 B的修饰。 我们将研究在这种修饰的背景下产生的免疫原性， 确定如何改变自身免疫过程中， 修饰在体内被修复。这项工作的目标是确定 自发性蛋白质修饰在B和T细胞免疫耐受和自身免疫中的作用 病理

Project Summary/Abstract The present proposal is a revised, competing continuation of AR48120, "Post- Translational Modifications in Tolerance and Autoimmunity". Our original proposal detailed a novel property of self proteins that may confer autoimmune responses in murine models of systemic lupus erythematosus (SLE). As introduced in our original proposal, a post-translational protein modification, termed isoaspartyl, can occur spontaneously under physiologic conditions of pH and temperature. While the modification has been known to exist in cells for many years now, the immunity to such modifications within self proteins has only been described by our laboratory. These modifications occur in all cell types and are enhanced in aged and stressed lymphocytes. With relevance to our work, autoantibodies to other protein modifications, notably citrulline proteins, have become diagnostic for autoimmune syndromes such as rheumatoid arthritis. The overall intent of this proposal is to determine how spontanteous biochemical modifications within self proteins can change the immunologic tolerance that is normally established to self proteins. We have identified how two important mechanisms of protein modification can elicit autoimmunity. First, isoaspartyl modified self antigens can undergo altered antigen processing, potentially leading to the expression of novel cryptic self peptides. In particular, histone H2B protein undergoes extensive isoaspartyl modification that may trigger autoimmunity in this manner. Second, an accumulation of intracellular protein modifications is found in the cells of lupus-prone MRL mice causing abnormal T cell hyperproliferation and is coincident with the onset of autoimmune pathology. The present proposal will examine the mechanisms of how isoaspartyl protein modifications alter immunogenicity of proteins and alter lymphocyte functions. In particular, we will develop novel mouse strains with conditional protein repair systems that alter protein modification in CD4 T cells. We will determine how autoantigen processing is altered in the presence of protein modification and how modified histone protein triggers autoantibody responses. The overall goal of these studies are to identify the roles of posttranslational protein modifications in the genesis of lupus-like autoimmunity. Project Narrative Systemic autoimmune diseases are characterized by aberrant immune responses directed at a select group in intracellular proteins. The focus of our work is to identify novel posttranslational protein modifications that may be critical in the induction of autoimmune disease. Precedence for these studies is apparent by the diagnostic and clinical relevance of several protein modifications, notably citrulline, in rheumatic disease. The present studies focus on a protein modification termed `isoaspartyl' that occurs spontaneously in eukaryotic cells and is enhanced in conditions of cellular stress and inflammation. We have previously identified the presence of isoaspartyl modifications in two lupus autoantigens, the snRNP ribonucleoprotein and histone H2B. We will examine the immunogenicity that arises in the context of this modification and determine how the course of autoimmunity is altered when isoaspartyl protein modifications are repaired in vivo. The goal of this work is to determine the importance of spontaneous protein modification in B and T cell immune tolerance and autoimmune pathology.