The Role of Transmethylation Reactions in Autoimmunity

转甲基反应在自身免疫中的作用

• 批准号: 7882531
• 负责人: Brian Lawson
• 金额: $ 47万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7882531
• 关键词: Affect; Antigen-Antibody Complex; Apoptosis; Apoptotic; Area; Arginine; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biochemical Pathway; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Chemotaxis; Chromatin; Complex; Congenic Mice; Dendritic Cells; Disease; Disease Progression; Enzymes; Experimental Autoimmune Encephalomyelitis; Goals; Homocysteine; Homocystine; Hydrolase; Immune; Immune Cell Activation; Immune response; Immunosuppression; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Interferon Type I; Kinetics; Knowledge; Ligands; Lupus; Mediating; Methylation; Modeling; Molecular; Necrosis; Nucleic Acids; Organ; Pathogenesis; Pathway interactions; Phosphorylation; Play; Post-Translational Protein Processing; Process; Production; Protein-Arginine N-Methyltransferase; Proteins; Publishing; Reaction; Receptor Signaling; Research; Role; SLEB1 gene; Severities; Signal Pathway; Signal Transduction; Signaling Protein; Specificity; Staging; T Cell Receptor Signaling Pathway; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Work; arm; base; cytokine; in vivo; inhibitor/antagonist; lupus-like; macrophage; member; mouse model; new therapeutic target; novel; public health relevance; receptor-mediated signaling; release of sequestered calcium ion into cytoplasm; systemic autoimmune disease; transmethylation

DESCRIPTION (provided by applicant): This project focuses on defining the role of transmethylation in the innate and adaptive immune responses relevant to systemic autoimmunity. This is a new area of immunological research that is based on recent studies by us and others showing that inhibition of transmethylation affects normal immune and autoimmune responses. We hypothesize that transmethylation is critical for inflammation and immune responses and that blockade of this post-translational process can curtail systemic autoimmunity. In support of this, we have specifically documented in published and preliminary studies that inhibition of S-adenosyl-L-homocysteine hydrolase (SAHase), a major enzyme involved in transmethylation, leads to immunosuppression by reducing phosphorylation/activation of several key proteins involved in TCR signaling. Strikingly, this effect was noted in CD4, but not CD8 T cells, and correlated with reduced arginine methylation of Vav1. We also documented that stimulation by diverse TLR ligands and the consequent production of inflammatory cytokines was significantly reduced by inhibition of transmethylation. More importantly, treatment of an organ-specific autoimmune mouse model (EAE) and lupus mouse models (MRL-Faslpr and BXSB) with a reversible SAHase inhibitor markedly reduced the incidence, severity, and progression of disease. Here, we propose to perform mechanistic studies to further define the specificity and pathways by which protein methylation affects normal and autoimmune responses with the following three specific aims: 1) determine what PRMT (protein arginine methyltransferase) members are present in T cells, identify the specific PRMT(s) that methylates Vav1 in CD4 T cells, and determine the role of specific PRMTs in T cell, B cell, and macrophage function; 2) define the molecular pathways by which transmethylation inhibition interferes with TLR-dependent and TLR-independent induction of inflammatory mediators by nucleic acids and complexes thereof, thought to be involved in lupus pathogenesis; and 3) characterize the cellular and functional changes that occur due to transmethylation inhibition during disease progression in lupus models. These studies should significantly advance our knowledge of how post-translational modifications affect normal and abnormal immune responses, and have the potential for identifying novel targets for the treatment of autoimmune diseases. PUBLIC HEALTH RELEVANCE: Post-translational modifications such as transmethylation greatly expand the functional repertoire of proteins and have critical effects on immune cell function. Our preliminary studies indicate that transmethylation is required for the full activation of T cells, B cells and macrophages and, importantly, is necessary for the progression of both organ-specific and systemic autoimmune diseases. In this application, we propose to further define the mechanisms by which transmethylation promotes immune cell activation and lupus-like systemic autoimmunity. This work has the potential of identifying novel therapeutic targets for this and other autoimmune diseases.

描述（由申请人提供）：该项目侧重于定义转甲基化在与系统性自身免疫相关的先天性和适应性免疫反应中的作用。这是免疫学研究的一个新领域，基于我们和其他人最近的研究表明，抑制转甲基化会影响正常的免疫和自身免疫反应。我们假设转甲基化对于炎症和免疫反应至关重要，并且阻断这种翻译后过程可以抑制系统性自身免疫。为了支持这一点，我们在已发表的初步研究中专门记录了抑制 S-腺苷-L-高半胱氨酸水解酶 (SAHase)（一种参与转甲基化的主要酶）通过减少参与 TCR 信号传导的几种关键蛋白的磷酸化/激活而导致免疫抑制。引人注目的是，这种效应在 CD4 T 细胞中出现，但在 CD8 T 细胞中没有出现，并且与 Vav1 精氨酸甲基化的减少相关。我们还记录了通过抑制转甲基作用显着减少了多种 TLR 配体的刺激以及随后产生的炎症细胞因子。更重要的是，用可逆性 SAHase 抑制剂治疗器官特异性自身免疫小鼠模型 (EAE) 和狼疮小鼠模型（MRL-Faslpr 和 BXSB）可显着降低疾病的发生率、严重程度和进展。在这里，我们建议进行机制研究，以进一步明确蛋白质甲基化影响正常和自身免疫反应的特异性和途径，具有以下三个具体目标：1）确定T细胞中存在哪些PRMT（蛋白精氨酸甲基转移酶）成员，鉴定甲基化CD4 T细胞中Vav1的特定PRMT，并确定特定PRMT在T细胞、B细胞和巨噬细胞中的作用 功能; 2) 确定转甲基化抑制干扰核酸及其复合物对 TLR 依赖性和 TLR 非依赖性炎症介质诱导的分子途径，被认为与狼疮发病机制有关； 3) 表征狼疮模型疾病进展期间由于转甲基化抑制而发生的细胞和功能变化。这些研究将显着提高我们对翻译后修饰如何影响正常和异常免疫反应的认识，并有可能确定治疗自身免疫性疾病的新靶点。 公共健康相关性：转甲基化等翻译后修饰极大地扩展了蛋白质的功能库，并对免疫细胞功能产生关键影响。我们的初步研究表明，转甲基化对于 T 细胞、B 细胞和巨噬细胞的完全激活是必需的，更重要的是，对于器官特异性和系统性自身免疫性疾病的进展也是必需的。在本申请中，我们建议进一步明确转甲基化促进免疫细胞激活和狼疮样系统性自身免疫的机制。这项工作有可能确定这种疾病和其他自身免疫性疾病的新治疗靶点。