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年前最初的描述以来，结节病仍然是一种“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重要的目标，对治疗，预测结果，以及确定预防措施的方法具有重要意义。结节病的免疫反应和肉芽肿组织形成特征与在多种传染病中观察到的相似。然而，在结节病中引发炎症反应的特异性抗原的性质仍然难以捉摸。结节病在空间上相关的聚集性以及家庭和卫生保健环境中的发生，有力地支持了传染原的人际传播，认为这是该病的潜在原因之一。结节病与多种感染因子有关，其中没有一种可以培养。痤疮丙酸杆菌（P. acne）和结核分枝杆菌（Mtb）是基于聚合酶链反应（pcr）的方法最常识别的感染性病原体，并被认为与该疾病的发展有关。结节病的免疫学研究主要集中在对患者和对照对象的组成性、免疫反应和血液和肺细胞表型的描述。在这个建议中，我们将利用记忆免疫反应作为搜索工具，从痤疮或结核杆菌暴露的“免疫印记”。将比较II期和/或III期结节病患者和健康对照者的外周血单个核细胞和支气管肺泡细胞。我们将通过ELISPOT检测：(1)病原体特异性ifn -7和il -10产生细胞的频率，(2)利用痤疮P.或mtb感染的自体单核细胞和肺泡巨噬细胞作为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的靶细胞频率。最后，我们将测试通过DNA微阵列鉴定健康对照者和活动性结节病患者的痤疮P.和mtb刺激的血细胞中病原体特异性的转录宿主基因表达谱的可行性，并将其与未刺激的自体原位肺细胞的基因表达谱进行比较。我们的研究将解决痤疮P.和结核分枝杆菌在结节病病因学中的作用，并将为涉及其他可能的感染性或非感染性病原体/抗原的结节病发展的未来工作提供基础或模型。