Pathogenic Mycobacterial Proteins in Sarcoidosis

结节病中的致病性分枝杆菌蛋白

• 批准号: 7069230
• 负责人: David R Moller
• 金额: $ 38.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-11 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069230
• 关键词: B lymphocyte; Mycobacterium tuberculosis; Propionibacterium; T lymphocyte; bacteria infection mechanism; bacterial antigens; bacterial proteins; bronchoscopy; catalase; clinical research; cytokine; diagnostic respiratory lavage; granuloma; host organism interaction; human subject; immunogenetics; immunoglobulins; in situ hybridization; inflammation; laboratory rat; microorganism immunology; pathologic process; peroxidases; pulmonary fibrosis /granuloma; sarcoidosis; tissue /cell culture

DESCRIPTION (provided by applicant): Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that involves the lungs in over 90% of affected individuals and may cause end-stage pulmonary fibrosis and death. The pathologic hallmark of sarcoidosis is non-caseating granulomatous inflammation. A major step in understanding sarcoidosis would be the identification of infectious agents that trigger sarcoidosis. Recently, using a limited proteomic approach with matrix-associated laser desorption/ionization-time of flight mass spectrometry, we identified Mycobacterium tuberculosis catalase-peroxidase (mKatG) as a tissue antigen and target of the immune response in sarcoidosis, supporting a mycobacterial etiology of sarcoidosis. Our preliminary studies have shown that many sarcoidosis patients with active untreated disease have antigen-specific T cell and/or B cell responses to mKatG proteins. The goal of this application is to test the hypothesis that mKatG is a dominant pathogenic antigen in sarcoidosis as part of an adaptive immune response driving granulomatous inflammation in many, if not most, patients with sarcoidosis. We plan to test this hypothesis by identifying mKatG DNA in sarcoidosis tissues, by evaluating the T cell and B cell responses to mKatG proteins in patients with acute remitting and non-acute chronic sarcoidosis from both the US and Sweden, and by testing mKatG as a pathogenic antigen in experimental models of granulomatous inflammation. In Sweden, we will specifically evaluate Lofgren-prone DR17 positive sarcoidosis patients with good prognoses and DR17 negative patients who tend to have chronic disease for their T and B cell responses to mKatG proteins. These studies have the potential to establish one specific mycobacterial protein, mKatG, as a dominant pathogenic antigen in sarcoidosis that triggers and/or sustains the inflammation causing this disease. With this new information and an improved understanding of sarcoidosis, novel strategies aimed at curing or even preventing sarcoidosis may be devised. (End of Abstract)

描述（由申请人提供）： 结节病是一种未知病因的多系统肉芽肿性疾病，涉及超过90％的受影响个体的肺部，并可能导致终末期肺纤维化和死亡。结节病的病理标志是无造成的肉芽肿性炎症。理解结节病的主要步骤是鉴定引发结节病的传染剂。最近，使用有限的蛋白质组学方法，与基质相关的激光解吸/离子化质谱法的电离时间，我们确定了结核分枝杆菌的结核分枝杆菌过氧化物酶 - 过氧化物酶（MKATG）是组织抗原，并且是肌动病中免疫反应的靶标，并支持肌动物病学的肌动物病学。我们的初步研究表明，许多活跃未经治疗疾病的结节症患者具有抗原特异性T细胞和/或B细胞对MKATG蛋白的反应。该应用的目的是检验以下假设：MKATG是结节症中主要的致病抗原，这是许多（如果不是大多数）结节病患者的自适应免疫反应驱动肉芽肿性炎症的一部分。我们计划通过鉴定结节病组织中的MKATG DNA来检验这一假设，通过评估来自美国和瑞典的急性恢复和非急性慢性结节病的患者的T细胞和B细胞对MKATG蛋白的反应，并通过在实验性的granulations intermatient of Granulations中测试Mkatg作为一种致病的抗原模型。在瑞典，我们将专门评估具有良好预后和DR17阴性患者的Lofgren-易DR17阳性结节症患者，这些患者往往患有慢性疾病，因为其对MKATG蛋白的T和B细胞反应。这些研究有可能建立一种特定的分枝杆菌蛋白MKATG作为结节病中的主要致病抗原，从而触发和/或维持引起这种疾病的炎症。借助这些新信息并提高了对结节病的理解，可以设计旨在治愈甚至预防结节病的新型策略。 （抽象的结尾）