Pathogenic Mycobacterial Proteins in Sarcoidosis

结节病中的致病性分枝杆菌蛋白

• 批准号: 7415235
• 负责人: David R Moller
• 金额: $ 35.72万
• 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/7415235
• 关键词: Acute; Affect; Antigen Targeting; Antigen-Antibody Complex; Antigens; Automobile Driving; B-Lymphocytes; Baltimore; Blood; Cells; Cessation of life; Chronic; Chronic Disease; Collaborations; DNA; Data; Disease; Disorder by Site; Etiology; Experimental Models; Fibrosis; Frequencies; Genotype; Giant Cells; Goals; Granuloma; Granulomatous; Head; Health; IL18 gene; Immune; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunologics; Immunology; In Situ Hybridization; Incidence; Individual; Infectious Agent; Infiltration; Inflammation; Institutes; Interleukin-12; Investigation; Japanese Population; Laboratories; Lasers; Lung; Mass Spectrum Analysis; Mediating; Modeling; Mononuclear; Mycobacterium tuberculosis; Outcome; Pathologic; Patients; Peptides; Peroxidase; Peroxidases; Phagocytes; Population; Production; Propionibacterium acnes; Proteins; Proteomics; Pulmonary Fibrosis; Pulmonary Heart Disease; RNA; Research; Research Personnel; Rodent Model; Role; Sarcoidosis; Specificity; Staging; Stimulus; Subgroup; Sweden; Syndrome; T-Cell Receptor Genes; T-Lymphocyte; TNF gene; Testing; Time; Tissues; Work; abstracting; base; case control; catalase; clinical phenotype; cytokine; follow-up; improved; ionization; microbial; mycobacterial; novel strategies; outcome forecast; prevent; programs; response

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）： 结节病是一种病因不明的多系统肉芽肿性疾病，90%以上的患者累及肺部，可能导致终末期肺纤维化和死亡。结节病的病理特征是非干酪化性肉芽肿性炎症。了解结节病的一个主要步骤是确定引发结节病的感染因子。最近，使用有限的蛋白质组学方法与基质相关的激光解吸/电离飞行时间质谱，我们确定结核分枝杆菌过氧化氢酶-过氧化物酶（mKatG）作为组织抗原和结节病的免疫反应的目标，支持结节病的分枝杆菌病因。我们的初步研究表明，许多患有活动性未治疗疾病的结节病患者对mKatG蛋白具有抗原特异性T细胞和/或B细胞应答。本申请的目的是检验以下假设：mKatG是结节病中的主要致病抗原，是许多（如果不是大多数）结节病患者中驱动肉芽肿性炎症的适应性免疫应答的一部分。我们计划通过鉴定结节病组织中的mKatG DNA，通过评价来自美国和瑞典的急性缓解型和非急性慢性结节病患者的T细胞和B细胞对mKatG蛋白的反应，以及通过在肉芽肿性炎症实验模型中测试mKatG作为致病抗原来验证这一假设。在瑞典，我们将专门评价具有良好预后的Loflavin倾向性DR 17阳性结节病患者和倾向于患有慢性疾病的DR 17阴性患者对mKatG蛋白的T和B细胞应答。这些研究有可能建立一个特定的分枝杆菌蛋白，mKatG，作为一个主要的致病性抗原在结节病，触发和/或维持炎症引起这种疾病。有了这些新的信息和对结节病的进一步了解，可以设计出旨在治愈甚至预防结节病的新策略。(End摘要）