Defining the role of altered cytokine signaling pathways on autoimmunity

描述（由申请人提供）：CSGADP 计划的目标是了解自身免疫性疾病的免疫机制以及操纵自身免疫中的免疫反应的后果，以便将此信息应用于预防人类自身免疫。该拨款申请旨在解决这些目标，即了解调节 CD4 效应 T 细胞和 Treg 的命运和功能的机制。具体而言，我们探讨了 IL-2/STAT5 和 IL-6/STAT3 细胞因子信号通路的改变如何导致 T1D、MS 和 CD 患者失去这种平衡。已知这两条途径对 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 连接起来，将 IL-6/STAT3 通路与 MS 和 CD 连接起来。在这项资助中，我们提出了这样的假设：在自身免疫个体中，STAT3 磷酸化增强，STAT5 磷酸化减弱，建立了一个功能程序，使细胞因子反应偏向偏向的、促自身免疫的情况。我们将通过确定 STAT5 和 STAT3 信号在三种自身免疫性疾病中改变的程度来检验这一假设。 1 型糖尿病 (T1D)、多发性硬化症 (MS) 和克罗恩病 (CD)。我们将确定这些磷酸化的改变是否单独或组合导致 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，我们将使用与疾病相关的遗传多态性作为路标，确定导致这些改变的分子机制。目标 1. 我们将提出以下假设：IL-2 响应的 STAT5 信号减弱会导致 T1D、CD 和 MS 中 Treg 的诱导、功能和稳定性减弱。我们将在血液背景下研究这个问题，然后将这些研究扩展到 CD 背景下的组织。然后我们将确定导致每种疾病中 IL-2R 信号传导缺陷的生化和遗传机制。目标 2. 我们将通过促进 ROR?t 的表达、抑制 FOXP3 的表达和增强效应 T 细胞对 Treg 抑制的抵抗力来解决这样的假设，即响应 IL-6 的 STAT3 磷酸化增强导致自身免疫中致病性 T 细胞的发育和持续。我们将使用基因分型对照来研究这个问题，以解决分子机制问题，并使用 T1D、MS 和 CD 患者来解决疾病表型。目标 3. 我们将检验以下假设：STAT3 磷酸化增强和 STAT5 磷酸化减弱联合逆转了抗原攻击后 Treg 和 Teff 功能谱的平衡。 公共卫生相关性：GWAS 已经确定了自身免疫性疾病之间共有的遗传变异和免疫通路，为我们提供了一个工具来了解自身免疫性疾病之间的联系机制，并确定具有广泛功效的治疗靶点。在这笔资助中，我们将重点关注 GWAS 涉及的两种在自身免疫途径中很重要的免疫（IL-2/STAT5 和 IL-6/STAT3 信号传导），涉及 T1D、MS 和克罗恩病这三种疾病。了解自身免疫性疾病常见的致病机制将有助于我们解决自身免疫性疾病治疗中大量未满足的需求，并为适当的患者选择具有预防疾病潜力的疗法。

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. PUBLIC HEALTH RELEVANCE: The GWAS have identified genetic variants and immunologic pathways that are shared between autoimmune diseases - giving us a tool to understand mechanisms that connect autoimmune diseases and to identify therapeutic targets with broad efficacy. In this grant, we will focus on two immune implicated by the GWAS as important in autoimmunity pathways (IL-2/STAT5 and IL-6/STAT3 signaling), across three diseases T1D, MS and Crohn's disease. Understanding the pathogenic mechanisms common to autoimmune diseases will help us address a large unmet need in the treatment of autoimmune diseases and the selection of therapies for the appropriate patients with the potential of preventing disease.