Phosphatases in Systemic Autoimmunity

全身性自身免疫中的磷酸酶

• 批准号: 10242137
• 负责人: George C Tsokos
• 金额: $ 43.75万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242137
• 关键词: Address; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Binding; Cell Death; Cell physiology; Cells; Clinical Trials; Data; Disease; Dose; Enzymes; Etiology; Functional disorder; Generations; Genes; Genetic Transcription; Glomerulonephritis; Human; IL17 gene; Immune; Immunosuppressive Agents; Infection; Inflammation; Interleukin-17; Interleukin-2; Interleukins; Lupus; Mediating; Messenger RNA; Molecular; Morbidity - disease rate; Mus; Opportunistic Infections; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Phosphoric Monoester Hydrolases; Production; Protein Serine/Threonine Phosphatase; Protein phosphatase; Proteins; Regulation; Regulatory T-Lymphocyte; Role; SP1 gene; Serum; Signal Pathway; Site; Specificity; Surface; Susceptibility Gene; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Work; autoreactive T cell; cytotoxic; deprivation; design; effector T cell; experimental study; immune function; immunopathology; infection rate; lupus prone mice; mortality; nephrogenesis; novel; overexpression; protein phosphatase 2A regulatory subunit 65 kDa; response; scaffold; systemic autoimmunity; tool; transcription factor

Abstract ! Systemic lupus erythematosus (SLE) presents profound T cell effector dysfunction. Interleukin-2 (IL-2) deficiency accounts for the increased infection-related morbidity and mortality rates, the defective regulatory cell (Treg) function and compromised ability to eliminate autoreactive T cells. In parallel, T cells produce increased amounts of interleukin-17 (IL-17) which is involved in tissue inflammation and damage. Protein phosphatase 2A (PP2A) is the first serine/threonine phosphatase recognized to contribute first to human SLE and later to murine lupus immunopathology. It is a trimolecular enzyme consisting of scaffolding, catalytic and regulatory subunits. We have shown that PP2Ac expression is increased in patients with SLE and that it is central to a number of signaling pathways including the suppression of the production of IL-2 and the enhancement of the production of IL-17 and that the regulatory subunit Bβ regulates IL- 2 deprivation-induced T cell death and is decreased in SLE patients. A mouse lacking PP2A in Tregs develops severe inflammation and autoimmunity because PP2Ac is needed for the suppression of the mTORC1 pathway. Using novel mice and molecular tools the proposed work will test the hypothesis that PP2Ac represents a main contributor in the immunopathogenesis of SLE and autoimmunity in general by 1) determining the importance of PP2A expression in Tregs in the regulation of the autoimmune response and related pathology; 2) determining the importance of PP2A expression in conventional T cells in the regulation of the autoimmune response and related pathology; and 3) establishing the aberrant expression of the regulatory subunit Bα in human SLE and determine how it contributes to IL-17 production. This project will generate novel concepts (differential regulation of central immune functions by PP2A, regulation of distinct functions by specific regulatory subunits) and new informative mice (mice lacking PP2A in T cell subsets and mice lacking regulatory subunits in T cells). Understanding the molecular complexity which underlies the expression of systemic autoimmunity is significant to the extent we wish to correct important pathways to treat patients. The ability to carry out parallel studies in mice and humans increases significantly the translational value of our work. ! ! !

抽象的 呢 全身性红斑狼疮（SLE）呈现出深刻的T细胞效应子功能障碍。白介素2 （IL-2）缺乏症解释了与感染相关的发病率和死亡率的增加， 有缺陷的调节细胞（TREG）功能和消除自动反应t的能力受损 细胞。同时，T细胞产生增加量的白介素17（IL-17），这涉及 在组织炎症和损伤中。蛋白质磷酸酶2a（PP2A）是第一个系列/苏氨酸 磷酸酶识别为首先有助于人类SLE，后来又对鼠狼疮做出了贡献 免疫病理学。它是一种三酶，由脚手架，催化和调节性组成 亚基。我们已经表明，SLE患者的PP2AC表达增加，这是 许多信号通路的中心，包括抑制IL-2的生产 以及IL-17的产生的增强，调节子基Bβ调节IL- 2剥夺引起的T细胞死亡，SLE患者减少。一只鼠标缺乏pp2a Tregs会出现严重的感染和自身免疫性，因为需要PP2AC 抑制MTORC1途径。使用新的小鼠和分子工具提出的 工作将检验以下假设：PP2AC代表 总体上，SLE和自身免疫的免疫发病发生1）确定的重要性 自身免疫反应和相关病理的调节中，treg中的pp2a表达； 2）确定PP2A表达在常规T细胞中的重要性 自身免疫反应和相关病理； 3）建立异常表达 人SLE中的调节亚基Bα，并确定其对IL-17产生的贡献。 该项目将产生新颖的概念（通过 pp2a，特定调节亚基对不同功能的调节）和新的信息小鼠 （在T细胞亚群中缺乏PP2A的小鼠和T细胞中缺乏调节亚基的小鼠）。 了解基于全身表达的分子复杂性 在我们希望纠正治疗患者的重要途径的程度上，自身免疫性是重要的。 在小鼠和人类中进行平行研究的能力显着提高了 我们工作的翻译价值。 呢 呢 呢