Immune Activation of Fibroblasts

描述(由申请人提供)： 成纤维细胞的激活在启动炎症反应中起着重要作用。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。其他成纤维细胞的特征似乎是全球性的，例如表达趋化物质，包括IL-16和RANTES，这是一种CD4特异性配体和RANTES，一种C-C趋化因子。我们发现Graves病(GD)患者的成纤维细胞在其免疫球蛋白(GD-IgG)作用下被激活，并表达高水平的IL-16和RANTES。来自非自身免疫性疾病捐赠者的对照成纤维细胞对这些免疫球蛋白没有反应。Gd-Ig G是疾病特异性的，似乎与成纤维细胞上显示的胰岛素样生长因子1受体(IGF-1R)结合。我们假设IGF-1R代表一种重要的活化性自身抗原。我们现在提出以下研究来检验我们的中心假设。1)明确成纤维细胞表达IL-16和RANTES的机制(S)：2)检测自身免疫性Graves病患者和正常对照组血清中的Gd-Ig G、IL-16和RANTES的水平，并确定这些参数的临床应用价值；3)在体内验证IGF-1R是GD的关键自身抗原的假说，即当与Gd-Ig G结合时，激活IL-16和RANTES的表达和T细胞的浸润。这位候选人和导师在过去一年里一直密切合作，建立了富有成效的关系。研究职业发展奖、持续指导和综合临床研究中心的提供，将使应聘者能够进一步调查和回答这些与临床相关的问题。候选人将发展科学知识基础、解决问题的能力和技能，以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.