Characterization of Pathogenic T cells in Alopecia Areata

描述（由申请人提供）： 为了改善自身免疫性患者的治疗方案，关键是更好地定义所涉及的致病性T细胞群。为了实现这一目标，我们将利用一种新的应用程序，这将是第一次允许高度集中的解剖致病性T细胞库。这项分析将弥合差距，迄今存在的理解效应机制的自身反应性免疫反应，斑秃作为一个原型的例子。由于严重的斑秃病例很少用全身性药物治疗，这种器官特异性自身免疫性疾病代表了一个独特的机会，在没有混杂免疫抑制药物的情况下，纵向表征体内自身反应性免疫应答的演变。迄今为止，没有研究详细跟踪了从患者最初表现到慢性自身免疫建立的自身反应性库。正在测试的特定假设是，通过将CDR-3长度库分析与磁分选和流式细胞术相结合，可以在斑秃患者中鉴定、表征和纵向跟踪致病性自我导向T细胞。目标将是确定：这种致病性T细胞应答如何随时间演变，致病性T细胞的表面表型，以及单个致病性T细胞的体内或直接离体细胞因子分泌谱。具体目标如下。具体目的1：确定活化克隆型T细胞在斑秃患者。具体目标2：确定相同的克隆型T细胞扩增是否存在纵向作为患者的疾病演变。具体目标3：确定病原性T细胞的活化标志物、趋化因子受体和整合素粘附分子的表面表达以及病原性T细胞的细胞因子分泌谱。 公共卫生相关性：在正常情况下，免疫系统保护免受外来入侵病原体，如细菌和病毒。T细胞是免疫系统的一种细胞。这些细胞有能力区分病毒和细菌蛋白质与构成你身体的外源性“自我”蛋白质和细胞。斑秃是一种自身免疫性疾病。在自身免疫中，通常具有保护作用的T细胞错误地将外源性“自身”蛋白识别为外源性，这导致组织和器官损伤。我们建议研究这些T细胞，以确定自身免疫性疾病反应如何随时间演变。我们还将表征自身反应性T细胞的表面及其分泌的分子。

DESCRIPTION (provided by applicant): In order to improve the treatment regimen of patients with autoimmunity it is critical to better define the pathogenic T cell population involved. To accomplish this we will take advantage of a novel application that for the first time will allow a highly focused dissection of the pathogenic T cell repertoire. This analysis will bridge the gap that hitherto existed in understanding the effector mechanisms of an autoreactive immune response, using alopecia areata as a prototypic example. Since severe cases of alopecia areata are rarely managed with systemic agents, this organ-specific autoimmune disease represents a unique opportunity to longitudinally characterize the evolution of an autoreactive immune response in vivo in the absence of confounding immunosuppressive medications. No study to date has followed in detail an autoreactive repertoire longitudinally from a patient's initial presentation to the establishment of chronic autoimmunity. The specific hypothesis being tested is that pathogenic self-directed T cells can be identified, characterized and followed longitudinally in patients with alopecia areata by combining CDR-3 length repertoire analysis with magnetic sorting and flow cytometry. The goal will be to determine: how this pathogenic T cell response evolves over time, the surface phenotype of the pathogenic T cells, and the in vivo or directly ex vivo cytokine secretion profile of the individual pathogenic T cells. The specific aims are as follows. Specific Aim 1: Identify activated clonotypic T cells in patients with alopecia areata. Specific Aim 2: Determine if the same clonotypic T cell expansions are present longitudinally as a patient's disease evolves. Specific Aim 3: Determine the pathogenic T cell's surface expression of activation markers, chemokine receptors, and integrin adhesion molecules as well as the pathogenic T cell's cytokine secretion profile. PUBLIC HEALTH RELEVANCE: Under normal circumstances the immune system protects against foreign invading pathogens such as bacteria and viruses. The T cells are a type of cell of the immune system. These cells have the ability to distinguish viral and bacterial proteins from enogenous "self" proteins and cells that make up your body. Alopecia areata is an autoimmune disease. In autoimmunity the usually protective T cells mistakingly recognize enogenous "self" proteins as foreign, which leads to tissue and organ damage. We propose to study these T cells to determine how the autoimmune disease response evolves over time. We will also characterize the surface of the autoreactive T cells and the molecules they secrete.