Phosphatases in Systemic Autoimmunity

摘要 ! 系统性红斑狼疮（SLE）表现出严重的T细胞效应功能障碍。白细胞介素-2 （IL-2）缺乏导致感染相关的发病率和死亡率增加， 调节细胞（Treg）功能缺陷和消除自身反应性T细胞的能力受损 细胞与此同时，T细胞产生增加的白细胞介素-17（IL-17）， 组织炎症和损伤。蛋白磷酸酶2A（PP 2A）是第一个丝氨酸/苏氨酸 磷酸酶被认为首先导致人类SLE，然后导致小鼠狼疮 免疫病理学它是一种由支架、催化和调节组成的三分子酶 亚单位。我们已经证明，PP 2Ac表达在SLE患者中增加， 对许多信号传导途径至关重要，包括抑制IL-2的产生 和IL-17的产生的增强，以及调节亚基Bβ调节IL-17。 2剥夺诱导的T细胞死亡，并在SLE患者中减少。一种缺乏PP 2A的小鼠， 由于PP 2Ac是治疗炎症和自身免疫的必需品， 抑制mTORC 1通路。使用新的小鼠和分子工具， 这项工作将检验PP 2Ac是该疾病的主要贡献者的假设。 SLE和自身免疫的免疫发病机制一般通过1）确定的重要性， PP 2A在TGFAP中的表达与自身免疫反应的调节及相关病理 2)确定常规T细胞中PP 2A表达在调节 自身免疫反应和相关病理学;和3）建立 人SLE中的调节亚基Bα，并确定其如何促进IL-17的产生。 该项目将产生新的概念（通过免疫系统对中枢免疫功能的差异调节）。 PP 2A，通过特定的调节亚基调节不同的功能）和新的信息小鼠 (mice在T细胞亚群中缺乏PP 2A和在T细胞中缺乏调节亚基的小鼠）。 理解作为系统表达基础的分子复杂性 自身免疫在我们希望纠正治疗患者的重要途径方面是重要的。 在小鼠和人类中进行平行研究的能力显著增加了 我们工作的翻译价值。 ! ! !

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. ! ! !