Immune Activation of Fibroblasts

描述（由申请人提供）： 成纤维细胞活化在启动炎症反应中起重要作用。来自特定解剖区域的成纤维细胞的表型属性被认为是与某些疾病相关的特殊表现模式的基础。其他成纤维细胞特征似乎是全局性的，例如包括IL-16（一种CD 4特异性配体）和RANTES（一种C-C趋化因子）在内的趋化因子的表达。我们已经发现，来自格雷夫斯病（GD）患者的成纤维细胞，当用其IgG（GD-IgG）处理时，变得活化并表达高水平的IL-16和RANTES。来自没有自身免疫性疾病的供体的对照成纤维细胞不能对这些IgG应答。具有疾病特异性的GD-IgG似乎与成纤维细胞上展示的胰岛素样生长因子1受体（IGF-1 R）结合。我们假设IGF-1 R是一种重要的激活性自身抗原。我们现在提出以下研究来检验我们的中心假设。1)探讨GD特异性抗IGF-1 R IgG上调成纤维细胞IL-16和RANTES表达的机制：2）检测自身免疫性Graves病患者和正常人血清中GD-IgG、IL-16和RANTES水平，并探讨其临床应用价值; 3）在体内测试IGF-1 R是GD中的关键自身抗原的假设，当与GD-IgG连接时，激活IL-16和RANTES表达和T细胞浸润。候选人和导师在过去的一年里密切合作，建立了富有成效的关系。研究职业发展奖，继续指导和一般临床研究中心的可用性，将允许候选人进一步调查和回答这些临床相关的问题。候选人将发展科学知识基础，解决问题的能力和技术技能，发展成为一名独立的研究人员。

DESCRIPTION (provided by applicant): Fibroblast activation plays an important role in initiating the inflammatory response. Phenotypic attributes of fibroblasts from specific anatomic regions are thought to underlie the peculiar pattern of manifestations associated with certain disease. Other fibroblast characteristics appear global, such as the expression of chemoattractants including IL-16, a CD4-specific ligand and RANTES, a C-C chemokine. We have found that fibroblasts from patients with Graves' disease (GD), when treated with their IgGs (GD-IgG), become activated and express high levels of IL-16 and RANTES. Control fibroblasts from donors without autoimmune disease fail to respond to these IgGs. GD-IgG which are disease specific, appear to be binding to the insulin-like growth factor 1 receptor (IGF-1R) displayed on fibroblasts. We hypothesize that IGF-1R represents an important activational self-antigen. We now propose the following studies to test our central hypothesis. 1) To define the mechanism(s) involved in the GD-specific anti IGF-1R IgG upregulation of IL-16 and RANTES expression by fibroblasts; 2) To determine the serum levels of GD-IgG, IL-16 and RANTES in autoimmune graves disease patients and normal controls and determine the clinical utility of these parameters; 3) To test in vivo the hypothesis that IGF-1R is a critical self-antigen in GD that when ligated with GD-IgG, activates IL-16 and RANTES expression and T cell infiltration. The candidate and mentor have worked closely together for the last year in a productive relationship. The research career development award, continued mentoring and the availability of the General Clinical Research Center, will allow the candidate to further investigate and answer these clinically relevant questions. The candidate will develop the scientific knowledge base, problem solving abilities and technical skills to develop into an independent researcher.