Pathogen Specific Immunity in Sarcoidosis

结节病的病原体特异性免疫

• 批准号: 6815578
• 负责人: STEPHAN K SCHWANDER
• 金额: $ 23.21万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815578
• 关键词: Mycobacterium tuberculosis; Propionibacterium; alveolar macrophages; biopsy; clinical research; cytotoxic T lymphocyte; diagnostic respiratory lavage; disease /disorder etiology; enzyme linked immunosorbent assay; gene expression; host organism interaction; human subject; immune response; immunologic memory; inflammation; interferon gamma; interleukin 10; lung disorder; microarray technology; microorganism antigen; monocyte; natural killer cells; patient oriented research; sarcoidosis

DESCRIPTION (provided by applicant): Since its initial description 125 years ago, sarcoidosis continues to be a "challenging" disease. Its etiology remains unknown. Discovering the etiology of sarcoidosis remains a major goal with important implications regarding treatment, predicting outcome, as well as determining approaches for preventive measures. Immunological responses and granulomatous tissue formation characterizing sarcoidosis are similar to those observed in a variety of infectious diseases. However, the nature of the specific antigen(s), which putatively trigger the inflammatory response in sarcoidosis, remains elusive. Occurrence of sarcoidosis in spatially related clusters, and household and health care settings strongly support person-to-person transmission of an infectious agent as one of the potential causes of this disease. Sarcoidosis has been associated with a variety of infectious agents, none of which can be cultured. Propionibacterium acne (P. acne) and M.tuberculosis (Mtb) are the most commonly identifiable infectious pathogens by PCR-based methods and considered to be associated with the development of this disease. Immunological studies in sarcoidosis have focused largely on the assessment of constitutive, immune responses and the description of the phenotypes of blood and lung cells in patients and control subjects. In this proposal we will utilize memory immune responses as search tools for the 'immunological imprints' from P. acne or Mtb exposure. Peripheral blood mononuclear cells and bronchoalveolar cells will be compared from patients with stage II and/or stage III sarcoidosis and from healthy control subjects. We will study by ELISPOT assay: (1) frequencies of pathogen-specific IFN-7-and IL-10-producing cells, and (2) utilizing P. acne- or Mtb-infected autologous monocytes and alveolar macrophages as target cells frequencies of pathogen-specific granzyme B-releasing cytotoxic T lymphocytes and natural killer cells. Finally, we will test the feasibility of identifying by DNA micro array, pathogen specific, transcriptional host gene expression profiles in P. acne- and Mtb-stimulated blood cells from healthy control subjects and patients with active sarcoidosis and to compare these with gene expression profiles from autologous, unstimulated in situ lung cells. Our studies will address the role of P. acne and Mtb in the etiology of sarcoidosis and will also serve as a basis or model for future work involving other possible infectious or non-infectious pathogens/antigens for the development of sarcoidosis.

描述（由申请人提供）：自 125 年前首次描述以来，结节病一直是一种“具有挑战性”的疾病。其病因尚不清楚。发现结节病的病因仍然是一个主要目标，对治疗、预测结果以及确定预防措施方法具有重要意义。结节病的免疫反应和肉芽肿组织形成与多种传染病中观察到的相似。然而，推测引发结节病炎症反应的特定抗原的性质仍然难以捉摸。结节病在空间相关集群、家庭和医疗保健环境中的发生强烈支持传染原的人际传播是该疾病的潜在原因之一。结节病与多种传染原有关，但这些传染原均无法培养。痤疮丙酸杆菌 (P.痤疮) 和结核分枝杆菌 (Mtb) 是基于 PCR 的方法最常识别的传染性病原体，并被认为与该疾病的发生有关。结节病的免疫学研究主要集中在对患者和对照受试者的组成性免疫反应的评估以及血液和肺细胞表型的描述上。在本提案中，我们将利用记忆免疫反应作为搜索工具，搜索痤疮丙酸杆菌或结核分枝杆菌暴露的“免疫印记”。将比较 II 期和/或 III 期结节病患者和健康对照受试者的外周血单核细胞和支气管肺泡细胞。我们将通过 ELISPOT 测定研究：（1）病原体特异性 IFN-7 和 IL-10 产生细胞的频率，以及（2）利用痤疮丙酸杆菌或 Mtb 感染的自体单核细胞和肺泡巨噬细胞作为靶细胞的频率病原体特异性颗粒酶 B 释放细胞毒性 T 淋巴细胞和自然杀伤细胞。最后，我们将测试通过 DNA 微阵列识别健康对照受试者和活动性结节病患者的痤疮丙酸杆菌和结核分枝杆菌刺激的血细胞中病原体特异性转录宿主基因表达谱的可行性，并将其与基因表达谱进行比较来自自体、未刺激的原位肺细胞。我们的研究将探讨痤疮丙酸杆菌和结核分枝杆菌在结节病病因学中的作用，并将作为未来涉及结节病发展的其他可能感染性或非感染性病原体/抗原的工作的基础或模型。