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性疾病的免疫机制以及自身免疫中免疫应答操纵的后果，以便将这些信息应用于预防人类自身免疫。该资助申请解决了这些目标，以了解调节CD 4效应T细胞和Treg的命运和功能的机制。具体来说，我们解决了IL-2/STAT 5和IL-6/STAT 3细胞因子信号通路的改变如何导致T1 D，MS和CD患者失去这种平衡。已知这两种途径对Treg的功能和发育以及潜在致病性CD 4效应细胞的发育具有相反的影响。遗传变异将IL-2 R/STAT 5途径与T1 D、MS和IBD联系起来，将IL- 6/STAT 3途径与MS和CD联系起来。在这项研究中，我们提出了一个假设，即在自身免疫性个体中，STAT 3磷酸化增强和STAT 5磷酸化减少建立了一个功能程序，该程序将细胞因子反应偏向于一个偏斜的促自身免疫性特征。我们将通过确定通过STAT 5和STAT 3的信号传导在三种自身免疫性疾病中改变的程度来测试这一假设; 1型糖尿病（T1 D），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联合导致Treg和Th 17细胞之间的失衡和/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变化的分子机制，使用疾病相关的遗传多态性作为路标。目标1.我们将解决这一假设，钝化STAT 5信号在响应IL-2的结果在T1 D，CD和MS的Treg的诱导，功能和稳定性降低。我们将在血液的背景下检查这个问题，然后将这些研究扩展到组织中的CD设置。然后，我们将确定导致每种疾病中IL-2 R信号传导缺陷的生化和遗传机制。目标二。我们将解决的假设，增强磷酸化的STAT 3在响应IL-6导致的发展和持久性的致病性T细胞在自身免疫，通过促进表达ROR？t，抑制FOXP 3的表达并增强效应T细胞对Treg抑制的抗性。我们将使用基因型对照来研究这个问题，以解决分子机制和T1 D，MS和CD患者解决疾病表型。目标3。我们将检验这样的假设，即增强的STAT 3磷酸化和减弱的STAT 5磷酸化组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享的遗传变异和免疫途径-为我们提供了一种工具来了解连接自身免疫性疾病的机制，并确定具有广泛疗效的治疗靶点。在这项研究中，我们将重点关注GWAS在自身免疫途径中的两个重要免疫途径（IL-2/STAT 5和IL-6/STAT 3信号传导），包括T1 D，MS和克罗恩病。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，并为具有预防疾病潜力的适当患者选择治疗方法。

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.