Pathogen Specific Immunity in Sarcoidosis

点击翻译按钮获取中文摘要

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.