The Role of Transmethylation Reactions in Autoimmunity

项目摘要/摘要 这个项目的重点是确定转甲基化在先天和获得性免疫反应中的作用。 与全身性自身免疫有关。这是免疫学研究的一个新领域，它基于最近的 我们和其他人的研究表明，抑制转甲基化会影响正常免疫和自身免疫 回应。我们假设转甲基化对炎症和免疫反应至关重要， 阻断这一翻译后过程可能会抑制全身自身免疫。为了支持这一点，我们有 在已发表的和初步的研究中特别记录了对S-腺苷-L-同型半胱氨酸的抑制作用 水解酶(SAHase)，参与转甲基化的主要酶，通过减少 参与TCR信号转导的几个关键蛋白的磷酸化/激活。令人惊讶的是，这种影响在 而不是CD8T细胞，并且与Vav1的精氨酸甲基化减少相关。我们还记录了 不同的TLR配体刺激和随后产生的炎性细胞因子显著 通过抑制转甲基化而减少。更重要的是，器官特异性自身免疫的治疗 使用可逆SAHase抑制剂的小鼠模型(EAE)和狼疮小鼠模型(MRL-Faslpr和BXSB) 显著降低疾病的发生率、严重程度和进展。在这里，我们建议表演 进一步确定蛋白质甲基化影响正常的特异性和途径的机制研究 和具有以下三个特定目标的自身免疫反应：1)确定PRMT(蛋白质精氨酸 甲基转移酶)成员存在于T细胞中，识别使T细胞中Vav1甲基化的特定PrMT(S T细胞，并确定特定的PRMT在T细胞、B细胞和巨噬细胞功能中的作用；2)定义 转甲基化抑制干扰TLR依赖和非TLR依赖的分子途径 被认为与狼疮有关的核酸及其复合体诱导炎性介质 发病机制；以及3)描述由于转甲基化而发生的细胞和功能变化 狼疮模型中疾病进展过程中的抑制。这些研究应该会大大推进我们的 了解翻译后修饰如何影响正常和异常免疫反应，以及 确定治疗自身免疫性疾病的新靶点的可能性。

Project Summary/Abstract 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.