The Role of Transmethylation Reactions in Autoimmunity

转甲基反应在自身免疫中的作用

• 批准号: 8286993
• 负责人: Brian Lawson
• 金额: $ 46.53万
• 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 2013-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286993
• 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; Cells; 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; Inflammatory Response; 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; abstracting; arm; base; cytokine; in vivo; inhibitor/antagonist; lupus-like; macrophage; member; mouse model; new therapeutic target; novel; receptor-mediated signaling; release of sequestered calcium ion into cytoplasm; systemic autoimmune disease; transmethylation

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.

项目总结/文摘

项目成果

Critical role of transmethylation in TLR signaling and systemic lupus erythematosus.

• DOI: 10.1016/j.clim.2013.02.018
• 发表时间: 2013-05
• 期刊: Clinical immunology (Orlando, Fla.)
• 作者: Tardif V;Manenkova Y;Berger M;Hoebe K;Zuo JP;Yuan C;Kono DH;Theofilopoulos AN;Lawson BR
• 通讯作者: Lawson BR