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背后的免疫机制以及在自身免疫中操纵免疫反应的后果，以便将这些信息应用于人类自身免疫的预防。这项资助申请旨在解决这些目标，以了解调节CD4效应器T细胞和Treg命运和功能的机制。具体地说，我们讨论了IL-2/STAT5和IL-6/STAT3细胞因子信号通路的变化如何导致T1D、MS和CD患者这种平衡的丧失。已知这两条通路对Treg的功能和发育以及潜在致病的CD4效应细胞的发育具有相反的影响。遗传变异将IL-2R/STAT5途径与T1D、MS和IBD联系起来，将IL-6/STAT3途径与MS和CD联系起来。在这项授权中，我们提出假设，在自身免疫个体中，增强的STAT3的磷酸化和减弱的STAT5的磷酸化建立了一个功能程序，使细胞因子的反应偏向于倾斜的、亲自身免疫的特征。我们将通过确定在三种自身免疫性疾病：1型糖尿病(T1D)、多发性硬化症(MS)和克罗恩病(CD)中通过STAT5和STAT3的信号改变的程度来检验这一假设。我们将确定这些独立或联合的磷酸化变化是否会导致Treg和Th17细胞之间的失衡和/或增强效应T细胞(Tef)对抑制的抵抗力。然后，我们将以疾病相关的基因多态为路标，确定导致这些变化的分子机制。目的1.我们将提出假设，即在IL-2反应中钝化STAT5信号会导致T1D、CD和MS中Treg的诱导、功能和稳定性降低。我们将在血液环境中检验这一问题，然后将这些研究扩展到CD环境中的组织。然后，我们将确定在每种疾病中导致IL-2R信号缺陷的生化和遗传机制。目的2.我们将通过促进ROR？T的表达，抑制FOXP3的表达，增强效应T细胞对Treg抑制的抵抗力，来阐明IL-6增强STAT3的磷酸化导致致病T细胞在自身免疫中的发展和持续存在的假说。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，并使用T1D、MS和CD患者来解决疾病表型。目的3.我们将验证这样一种假设，即在抗原攻击时，STAT3的磷酸化增强和STAT5的磷酸化减弱共同逆转了Treg和TJeff功能谱的平衡。 公共卫生相关性：Gwas已经确定了在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，以了解与自身免疫性疾病相关的机制，并确定具有广泛疗效的治疗靶点。在这笔赠款中，我们将重点研究在自身免疫途径(IL-2/STAT5和IL-6/STAT3信号)中涉及的两种免疫，涉及三种疾病T1D、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尚未得到满足的巨大需求，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.