PTPN22 and Autoimmunity

PTPN22 和自身免疫

基本信息

批准号：
9113471
负责人：
Nunzio Bottini
金额：
$ 13.43万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113471
关键词：
Affect Agonist Arthritis Autoimmune Process Autoimmunity Biological Cell Differentiation process Cells Collaborations Consensus Defect Dendritic Cells Development Disease Failure Family Genes Genetic Polymorphism Genetic Predisposition to Disease Genotype Goals Grant Health Human Immune Immunosuppressive Agents Individual Inflammation Interferons Interleukin-1 Interleukin-17 Interleukins Joints K/BxN model Knock-out Knockout Mice Knowledge Laboratories Lead Ligands Lymphocyte Mediating Modeling Mus Myeloid Cells PTPN22 gene Pathogenesis Pathway interactions Phenotype Plant Roots Play Production Proteins Receptor Signaling Recurrence Rheumatoid Arthritis Risk Severities Signal Transduction Single Nucleotide Polymorphism T-Cell Receptor TLR3 gene Testing Toll-like receptors Variant Wild Type Mouse autocrine cytokine disorder risk genetic risk factor immune function in vivo knock-down loss of function lymph nodes macrophage monocyte mouse model novel personalized medicine promoter receptor

项目摘要

DESCRIPTION (provided by applicant): A missense single-nucleotide polymorphism in the PTPN22 gene causing an R620W substitution in the PTPN22 protein is one of the strongest genetic risk factors for rheumatoid arthritis. No consensus model has yet emerged on how PTPN22 increases risk of rheumatoid arthritis. As PTPN22 is a negative regulator of signaling through the T cell receptor, most studies to date have focused on the effect of the polymorphism on adaptive immune cell signaling. Here we wish to explore the concept that PTPN22-W620 impinges on the pathogenesis of rheumatoid arthritis through an action on myeloid cell signaling as well. Recent studies from our laboratory revealed a novel function of PTPN22 as a promoter of type 1 interferon release after engagement of myeloid cell toll-like receptors. Within this pathway, rheumatoid arthritis- predisposing PTPN22-W620 behaves as a loss-of-function variant, and macrophages and dendritic cells expressing PTPN22-W620 display a defect in toll-like receptor-induced type 1 interferon production. Type 1 interferon production by myeloid cells triggers several immunosuppressive mechanisms that protect from rheumatoid arthritis in mouse models. These include IL-27-mediated inhibition of arthritogenic Th17 cell differentiation and IL-1Ra-mediated suppression of inflammation in the rheumatoid joint. Here we hypothesize that loss of function of PTPN22 in dendritic cells and macrophages predisposes to rheumatoid arthritis by reducing type 1 interferon-dependent immunosuppressive mechanism. We will test our hypothesis by exploring whether loss of function of PTPN22 promotes myeloid cell-dependent differentiation of arthritogenic Th17 cells (Aim 1) and IL-1 mediated joint inflammation (Aim 2). In Aim 3 we will assess whether loss-of-function of PTPN22 or carriage of PTPN22-W620 impairs the immunoregulatory ability of human myeloid cells. By defining immunological mechanisms that are defective in carriers of the PTPN22-W620 variant, our study will suggest new strategies for personalized therapy of rheumatoid arthritis in genetically predisposed individuals.

描述（由适用提供）：PTPN22基因中的错义单核苷酸多态性，导致PTPN22蛋白在PTPN22蛋白中取代R620W是类风湿关节炎的强大遗传危险因素之一。关于PTPN22如何增加类风湿关节炎的风险，尚无共识模型。由于PTPN22是通过T细胞受体的信号传导的负调节剂，因此迄今为止，大多数研究都集中在多态性对自适应免疫电池信号传导上的影响。在这里，我们希望探讨PTPN22-W620通过对髓样细胞信号传导的作用也影响类风湿关节炎的发病机理的概念。我们实验室的最新研究揭示了PTPN22作为1型干扰素释放的启动子的新功能，在骨髓细胞收费受体接触后。在这一途径中，类风湿关节炎 - 易感性PTPN22-W620表现为功能丧失变体，表达PTPN22-W620的巨噬细胞和树突状细胞在Toll样接收器诱导的1型1型干扰素产生中表现出缺陷。 1型髓样细胞产生1型干扰素，触发了几种免疫抑制机制，可保护小鼠模型中的类风湿关节炎。这些包括IL-27介导的抑制性关节性TH17细胞分化和IL-1RA介导的类风湿关节炎症的抑制。在这里，我们假设PTPN22在树突状细胞和巨噬细胞中的功能丧失通过减少1型干扰素依赖性免疫抑制机制而容易发生类风湿关节炎。我们将通过探索PTPN22功能的丧失来检验假设，是否促进了髓样细胞的依赖性分化关节性TH17细胞（AIM 1）和IL-1介导的关节注射（AIM 2）。无论是PTPN22的功能丧失还是PTPN22-W620的载体会损害人髓样细胞的免疫调节能力。通过定义PTPN22-W620变体载体中有缺陷的免疫机制，我们的研究将提出针对遗传性易感个体类风湿关节炎个性化治疗的新策略。