Defining the role of altered cytokine signaling pathways on autoimmunity

描述（由申请人提供）：CSGADP项目的目标是了解自身免疫疾病背后的免疫机制和自身免疫反应操纵的后果，以便将这些信息应用于人类自身免疫的预防。这项拨款申请旨在了解CD4效应T细胞和Treg的命运和功能的调节机制，从而解决这些目标。具体来说，我们研究了IL-2/STAT5和IL-6/STAT3细胞因子信号通路的改变是如何导致T1D、MS和CD患者失去这种平衡的。已知这两条通路对Treg的功能和发育以及潜在致病性CD4效应细胞的发育具有相反的影响。遗传变异将IL- 2r /STAT5通路与T1D、MS和IBD联系起来，将IL- 6/STAT3通路与MS和CD联系起来。在本研究中，我们提出了一个假设，即在自身免疫个体中，STAT3磷酸化的增强和STAT5磷酸化的减少建立了一个功能程序，使细胞因子反应偏向于倾斜的、亲自身免疫的特征。我们将通过确定三种自身免疫性疾病中通过STAT5和STAT3信号传导的改变程度来验证这一假设；1型糖尿病（T1D）、多发性硬化（MS）和克罗恩病（CD）。我们将确定这些磷酸化的改变，无论是单独的还是联合的，是否会导致Treg和Th17细胞之间的不平衡和/或增强效应T细胞（Teff）对抑制的抵抗力。然后，我们将确定导致这些改变的分子机制，使用疾病相关的遗传多态性作为路标。目的1。我们将解决STAT5信号响应IL-2导致T1D， CD和ms中Treg诱导，功能和稳定性降低的假设。我们将在血液背景下检查这个问题，然后将这些研究扩展到CD设置下的组织。然后我们将确定导致每种疾病中IL-2R信号缺陷的生化和遗传机制。目标2。我们将通过促进ROR?的表达来解决STAT3在响应IL-6时磷酸化增强导致自身免疫中致病性T细胞的发展和持续的假设。t，抑制FOXP3的表达，增强效应t细胞对Treg抑制的抗性。我们将使用基因型对照来研究分子机制，并使用T1D、MS和CD患者来研究疾病表型。目标3。我们将验证STAT3磷酸化的增强和STAT5磷酸化的减弱在抗原攻击下逆转Treg和Teff功能谱平衡的假设。

DESCRIPTION (provided by applicant): The goals of the CSGADP program are to understand the immune mechanisms that underlie autoimmune disease and the consequences of manipulation of the immune response in autoimmunity in order to apply this information to the prevention of autoimmunity in humans. This grant application addresses these goals with respect to understanding the mechanisms that regulate the fate and function of CD4 effector T cells and Treg. Specifically we address how alterations in the IL-2/STAT5 and IL-6/STAT3 cytokine signaling pathways contribute to the loss of this balance in individuals with T1D, MS and CD. These two pathways are known to have opposing influences on the function and development of Treg, and the development of potentially pathogenic CD4 effector cells. Genetic variants link the IL-2R/STAT5 pathway to T1D, MS and IBD, and the IL- 6/STAT3 pathway to MS and CD. In this grant, we pose the hypothesis that in autoimmune individuals enhanced phosphorylation of STAT3 and diminished phosphorylation of STAT5 establish a functional program biasing cytokine responses towards a skewed, pro-autoimmune profile. We will test this hypothesis by determining the extent to which signaling via STAT5 and STAT3 is altered in three autoimmune diseases; type 1 diabetes (T1D), multiple sclerosis (MS) and Crohn's Disease (CD). We will determine whether these alterations in phosphorylation, independently and in combination, lead to an imbalance between Treg and Th17 cells and/or enhance the resistance of effector T cells (Teff) to suppression. We will then determine the molecular mechanisms that lead to these alterations, using disease-associated genetic polymorphism as a guidepost. Aim 1. We will address the hypothesis that blunted STAT5 signaling in response to IL-2 results in a diminished induction, function and stability of Treg in T1D, CD and MS. We will examine this question in the context of blood and then extend these studies to the tissue in the setting of CD. We will then determine the biochemical and genetic mechanisms that lead to the defect in IL-2R signaling in each disease. Aim 2. We will address the hypothesis that enhanced phosphorylation of STAT3 in response to IL-6 leads to the development and persistence of pathogenic T cells in autoimmunity, by promoting the expression of ROR?t, restraining expression of FOXP3 and enhancing the resistance of effector T cells to suppression by Treg. We will examine this question using genotyped controls to address molecular mechanism and T1D, MS and CD patients to address disease phenotypes. Aim 3. We will test the hypothesis that enhanced phosphorylation of STAT3 and diminished phosphorylation of STAT5 in combination reverse the balance of Treg and Teff functional profiles upon antigen challenge.