PROFILING AUTOANTIGENS IN UVEITIS

葡萄膜炎中自身抗原的分析

基本信息

批准号：
8006964
负责人：
Wei Li
金额：
$ 14.55万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8006964
关键词：
Acute Affect Affinity Animal Model Animals Anterior uveitis Antibodies Antigens Autoantibodies Autoantigens Autoimmunity B-Lymphocytes Bacteriophages Binding Biological Assay Blindness Blood Ciliary Body Clinical Cytotoxic T-Lymphocytes Data Development Diagnosis Disease Dot Immunoblotting Enzyme-Linked Immunosorbent Assay Etiology Eye Genetic Goals HLA-B27 Antigen Human IgG2 IgG3 IgG4 Immune response Immunoglobulin G Immunohistochemistry In Situ Hybridization Individual Inflammation Knowledge Lead Methods Molecular Probes Nature Pathogenesis Patients Phage Display Principal Investigator Proteins Role Serum Severities Specificity System T cell response T-Cell Proliferation T-Lymphocyte Techniques Tissues Uveitis Western Blotting Work autoimmune uveitis base cytokine disease diagnosis enzyme linked immunospot assay immunogenicity improved monocyte novel outcome forecast peripheral blood programs response statistics tool

项目摘要

DESCRIPTION: Autoimmune uveitis (AU) is a heterogeneous group of diseases with unknown cause, characterized by inflammation in the uveal track in the eye that may lead to loss of vision. Identification of AU-associated autoantigens would markedly improve our understanding of the disease etiology and facilitate the diagnosis and treatment. Although a handful of autoantigens have been identified in animals, it is not known whether these proteins are antigenic targets in humans, how many other autoantigens are yet to be identified and how patient genetic background may influence autoantigen profile. Acute anterior uveitis (AAU) is a clinically distinct entity with approximately half of AAU patients HLA-B27 positive. The hypothesis for this study is that B27+ and B27- AAU patients share some autoantigens common to inflammation-susceptible tissues in the eye, but differ in others. Autoantibodies in patient serum can be used as molecular probes to identify autoantigens by various methods. However, most available techniques are of low sensitivity and efficiency and have not been productive. To investigate the hypothesis, a novel system of subtractive phage display has been developed to identify patient autoantigens, which can be independently verified for binding affinity, patient specificity, immunogenicity and disease relevance. The hypothesis will be investigated with the following aims: 1) To identify autoantigens from B27+ and B27- AAU patients by phage display and to verify the binding affinity and patient specificity of the autoantigens by various antibody-based analyses; 2) To delineate the role of T cells in AAU-associated autoimmunity and to independently validate the immunogenicity of the autoantigens; 3) To define the disease relevance of the autoantigens by statistic comparison of the patients and controls and to correlate the B and T cell responses with the clinical course and severity of AAU. The proposed work capitalizes on a new means of identifying autoantigens that is unbiased, sensitive and efficient. Identified autoantigens will be independently validated without relying on animal models and their complicated cross-species interpretation. This study will also lead to development of autoantigen array, a powerful tool that will allow us to profile hundreds of autoantigens efficiently for individual patients. These efforts will advance our understanding of the disease etiology and prognosis, and improve the diagnosis and therapy.

描述：自身免疫性葡萄膜炎（AU）是一组异质性疾病，其原因未知，其特征是眼睛中的紫veal轨道炎症，可能导致视力丧失。鉴定与Au相关的自身抗原将显着提高我们对疾病病因的理解，并促进诊断和治疗。尽管在动物中已经鉴定出少数自身抗原，但尚不清楚这些蛋白质是否是人类的抗原靶标，尚未鉴定出多少其他自身抗原剂以及患者遗传背景如何影响自身抗原的特征。急性前葡萄膜炎（AAU）是临床上不同的实体，大约一半的AAU患者HLA-B27阳性。这项研究的假设是B27+和B27-AAU患者具有一些与眼睛中炎症的组织共有的自身抗原，但在其他情况下有所不同。患者血清中的自身抗体可以用作分子探针，通过各种方法鉴定自身抗原。但是，大多数可用的技术具有低灵敏度和效率，并且没有生产力。为了研究该假设，已经开发了一种新型的减法噬菌体显示系统来鉴定患者自身抗原，可以独立验证以结合亲和力，患者特异性，免疫原性和疾病相关性。该假设将以以下目的进行研究：1）通过噬菌体显示从B27+和B27-AAU患者中鉴定自动抗原，并通过各种基于抗体的分析来验证自身抗原的结合亲和力和患者特异性； 2）描述T细胞在与AAU相关的自身免疫中的作用，并独立验证自身抗原的免疫原性； 3）通过对患者和对照组的统计比较来定义自身抗原的疾病相关性，并将B和T细胞反应与AAU的临床过程和严重程度相关联。拟议的工作利用了一种新的手段来识别公正，敏感和高效的自动抗原。鉴定出的自身抗原将在不依赖动物模型及其复杂的跨物种解释的情况下进行独立验证。这项研究还将导致自动抗原阵列的开发，这是一种强大的工具，可以使我们有效地为个别患者介绍数百种自身抗原。这些努力将提高我们对疾病病因和预后的理解，并改善诊断和治疗。