Mechanisms of T Cell IFNy and IL-17 Production in Juvenile Idiopathic Arthritis

项目概要/摘要 幼年特发性关节炎（JIA）是一种以慢性关节炎为特征的自身免疫性关节炎 炎症辅助性T细胞1型（Th 1）、Th 17和病理性Th17.1细胞以及炎性细胞因子 由这些细胞产生的干扰素γ（IFNγ）和白细胞介素-17（IL-17）与JIA有关 发病机制一个主要的知识缺口是了解这些炎症性Th细胞和细胞因子是如何 开发.该提案概述了一项研究和培训计划，重点是研究IL-17和双IFNγ-IL-12如何影响IL-12的表达。 17产生细胞在JIA Th 1分化期间不适当地发育。这些研究的目标是确定 生物因素，可用于改善诊断和治疗决策。研究人员进行了 研究描述：1）经历Th 1分化的多关节JIA循环细胞产生高的 IL-17和IFNγ水平和双IFNγ-IL-17产生细胞，2）JIA患者罕见功能丧失 GATA 3突变表现出这种表型的夸大形式，3）额外的JIA患者携带罕见的 对Th 1分化重要的基因中的蛋白编码突变。该提案的核心假设是， JIA Th 1分化不适当地产生IL-17和Th1.17细胞，罕见的基因突变有助于 这个phenotype。拟议的具体目标检验了这一假设。目的1确定新的遗传作用， JIA患者在Th 1分化过程中IL-17、IFNγ和Th1.17细胞产生中的突变。目的2 确定导致IL-17和Th1.17细胞产生的细胞因子和STAT信号通路 在多关节JIA Th 1分化期间。该提案涉及人类细胞中的翻译研究， 先进的细胞计数、分子生物学和下一代测序。该提案的一个主要重点是 支持帕特里克博士发展成为一名科学家。她的职业目标是研究JIA的发病机制 在基础研究项目中，并确定产生新的治疗靶点和改善 诊断和治疗决策。她将通过职业目标来实现这一目标， 免疫学专家，获得免疫技术的先进专业知识，建立熟练的使用和 分析下一代测序，并获得技能，成为一个独立的首席研究员。 该提案的研究环境非常出色。帕特里克医生有整个部门和机构 支持她的研究计划的发展。她的导师是免疫学家， 计划先进的技术。范德比尔特拥有一流的设施和共享资源，用于这些方面的培训。 技术.她的指导团队包括免疫学、基因调控和风湿病方面的专家 指导她的独立研究项目的发展。该K 08将支持生成数据， 导致出版物提供深入了解JIA的发病机制和遗传学，并支持成功的 R 01应用程序。

PROJECT SUMMARY/ABSTRACT Juvenile idiopathic arthritis (JIA) is an autoimmune arthritis in children characterized by chronic joint inflammation. T helper type 1 (Th1), Th17, and pathologic Th17.1 cells and the inflammatory cytokines produced by these cells, interferon gamma (IFNγ) and interleukin-17 (IL-17), are implicated in JIA pathogenesis. A major knowledge gap is to understand how these inflammatory Th cells and cytokines develop. This proposal outlines a research and training plan focused on studying how IL-17 and dual IFNγ-IL- 17 producing cells inappropriately develop during JIA Th1 differentiation. A goal for these studies is to identify biologic factors that can be used to improve diagnostic and therapeutic decisions. The investigator conducted studies that described: 1) polyarticular JIA circulating cells that underwent Th1 differentiation produced high levels of IL-17 and IFNγ and dual IFNγ-IL-17 producing cells, 2) a JIA patient with a rare loss-of-function GATA3 mutation exhibited an exaggerated form of this phenotype, and 3) additional JIA patients carry rare protein-coding mutations in genes important for Th1 differentiation. The proposal’s central hypothesis is that JIA Th1 differentiation inappropriately produces IL-17 and Th1.17 cells and rare genetic mutations contribute to this phenotype. The proposed Specific Aims test this hypothesis. Aim 1 identifies the role of novel genetic mutations from JIA patients in production of IL-17, IFNγ, and Th1.17 cells during Th1 differentiation. Aim 2 identifies the cytokine and STAT signaling pathways that lead to the production of IL-17 and Th1.17 cells during polyarticular JIA Th1 differentiation. This proposal involves translational studies in human cells using advanced cytometry, molecular biology, and next generation sequencing. A major focus of this proposal is to support Dr. Patrick’s development as a physician-scientist. Her career goal is to study the pathogenesis of JIA in a basic research program and identify biologic factors that generate novel therapeutic targets and improve diagnostic and therapeutic decisions. She will accomplish this goal through career aims to become an immunology expert, gain advanced expertise in immunologic techniques, establish proficiency in the use and analysis of next-generation sequencing, and acquire skillsets to become an independent principal investigator. The research environment for the proposal is outstanding. Dr. Patrick has full departmental and institutional support for the development of her research program. Her mentors are immunologists with expertise in the planned advanced techniques. Vanderbilt has excellent facilities and shared resources for training in these techniques. Her mentoring team includes experts in immunology, gene regulation, and rheumatologic disease to guide development of her independent research program. This K08 will support the generation of data and lead to publications providing insight into the pathogenesis and genetics of JIA and in support of a successful R01 application.