Pathogen Specific Immunity in Sarcoidosis

描述(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的方法具有重要意义。以结节病为特征的免疫反应和肉芽肿组织形成与在各种传染病中观察到的相似。然而，在结节病中触发炎症反应的特异性抗原(S)的性质仍然不清楚。在空间相关的聚集性中发生结节病，以及家庭和卫生保健环境强烈支持人与人之间的传染病传播，这是这种疾病的潜在原因之一。结节病与多种感染性病原体有关，但没有一种可以培养。痤疮丙酸杆菌(P.acne)和结核分枝杆菌(Mtb)是以聚合酶链式反应为基础的最常见的感染性病原体，被认为与本病的发生有关。结节病的免疫学研究主要集中在对患者和对照组的结构性、免疫反应以及血细胞和肺细胞表型的描述上。在这项建议中，我们将利用记忆免疫反应作为搜索工具，寻找接触痤疮或结核分枝杆菌的免疫印记。将比较II期和/或III期结节病患者和健康对照组的外周血单核细胞和支气管肺泡细胞。我们将用ELISPOT法研究：(1)病原体特异性产生干扰素-7和IL-10的细胞的频率；(2)以痤疮或结核杆菌感染的自体单核细胞和肺泡巨噬细胞为靶细胞的病原体特异性颗粒酶B释放的细胞毒性T细胞和自然杀伤细胞的频率。最后，我们将测试利用DNA微阵列从健康对照组和活动期结节病患者的粉刺和结核分枝杆菌刺激的血细胞中鉴定病原体特异性转录宿主基因表达谱的可行性，并将这些基因表达谱与自体、未刺激的原位肺细胞的基因表达谱进行比较。我们的研究将探讨痤疮假单胞菌和结核分枝杆菌在结节病病因学中的作用，并将作为未来涉及其他可能的传染性或非传染性病原体/抗原发展结节病的基础或模型。

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.