Post Translational Modifications in Tolerance and Autoimmunity

耐受性和自身免疫性的翻译后修饰

基本信息

批准号：
7782770
负责人：
Mark J Mamula
金额：
$ 40.96万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7782770
关键词：
Affect Animal Model Animals Antibodies Apoptosis Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Biochemical Bypass CD4 Positive T Lymphocytes Cells Cellular Stress Chromatin Citrulline Cytoplasmic Protein Development Diagnostic Disease Enzymes Epitopes Eukaryotic Cell Frequencies Funding Goals Histocompatibility Antigens Class II Histone H2B Histones Human Human Characteristics Immune Immune Tolerance Immune response Immune system Immunity Immunization Individual Inflammation Invaded Knock-in Mouse Knockout Mice Ku70 protein Laboratories Lupus Lymphocyte Lymphocyte Function Manuscripts Methylation Modeling Modification Mouse Strains Mus Nuclear Pathology Patients Peptide Hydrolases Peptides Peripheral Physiological Post-Translational Protein Processing Process Property Proteins Proto-Oncogene Proteins c-akt Regulatory T-Lymphocyte Rheumatism Rheumatoid Arthritis Ribonucleoproteins Role Signal Transduction Signaling Molecule Small Nuclear Ribonucleoproteins Stress Syndrome System Systemic Lupus Erythematosus T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Temperature Text Time Tissues Transferase Work aged antigen processing autoreactive T cell cell type clinically relevant immunogenicity in vivo lupus-like novel pathogen programs repaired response systemic autoimmune disease

项目摘要

DESCRIPTION (provided by applicant): 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 is 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.

描述（由申请人提供）：本提案是AR48120的修订，竞争的延续，“容忍和自身免疫的翻译后修改”。我们的原始建议详细介绍了自蛋白的新型特性，该特性可能会在全身性红斑狼疮的鼠模型中赋予自身免疫反应（SLE）。正如我们最初的提案中引入的那样，在pH和温度的生理条件下，可以自发地发生翻译后蛋白质修饰，称为异源基因甲基。尽管已知这种修饰已经存在多年了，但对自我蛋白质中这种修饰的免疫力仅由我们的实验室描述。这些修饰发生在所有细胞类型中，并在老年和应力的淋巴细胞中得到增强。与我们的工作相关，与其他蛋白质修饰的自身抗体，尤其是瓜氨酸蛋白，已成为自身免疫性综合征（如类风湿关节炎）的诊断。该提案的总体目的是确定自我蛋白质中的自发生化修饰如何改变通常确定为自蛋白的免疫耐受性。我们已经确定了蛋白质修饰的两种重要机制如何引起自身免疫性。首先，异冬酰胺基修饰的自抗原会经历改变的抗原加工，可能导致新型隐性自肽的表达。特别是，组蛋白H2B蛋白经历了广泛的异冬酰胺修饰，可能会以这种方式触发自身免疫性。其次，在容易产生异常T细胞过增殖的狼疮细胞中发现了细胞内蛋白质修饰的积累，并且与自身免疫性病理学的发作是一致的。本提案将研究如何改变蛋白质的免疫原性并改变淋巴细胞功能的机制。特别是，我们将使用有条件的蛋白质修复系统开发新的小鼠菌株，这些蛋白质修复系统改变CD4 T细胞中的蛋白质修饰。我们将确定在存在蛋白质修饰的情况下如何改变自身抗原的加工以及修饰的组蛋白蛋白如何触发自身抗体反应。这些研究的总体目的是确定翻译后蛋白质修饰在类似狼疮的自身免疫的起源中的作用。全身性自身免疫性疾病的特征是针对细胞内蛋白中某些组的异常免疫反应。我们工作的重点是确定新型的翻译后蛋白质修饰，这些修饰可能对诱导自身免疫性疾病至关重要。这些研究的优先次数通过几种蛋白质修饰（尤其是瓜氨酸）在风湿病中的诊断和临床相关性显而易见。本研究的重点是称为“ isoaspartyl”的蛋白质修饰，该蛋白质自发地发生在真核细胞中，并在细胞应激和炎症的条件下增强。我们先前已经确定了两个狼疮自身抗原，SNRNP核糖核蛋白和组蛋白H2B中的等异冬酰胺修饰。我们将检查在这种修饰的背景下产生的免疫原性，并确定当在体内修复等质蛋白质蛋白修饰时自身免疫的过程如何改变。这项工作的目的是确定在B和T细胞免疫耐受性和自身免疫性病理学中自发蛋白质修饰的重要性。