Sarcoidosis is characterized by lung accumulated activated CD4+ T cells that are believed to be of central importance for the inflammatory reaction, which results in granuloma formation and in some patients in the development of fibrosis. We previously found that a subset of patients, HLA-DR17 positive, most often present with Lofgren's syndrome and have a good prognosis. These patients are very common in Sweden, making up more than one third of new cases at our clinic. Analyzing cells obtained by bronchoalveolar lavage (BAL), i.e. from the focus of the inflammation, we discovered a strict correlation between HLA-DR17 and lung-restricted accumulations of CD4+ cells expressing the T cell receptor Valfa2.3 gene segment. Our central hypothesis is that the Valfa2.3+ BAL T cells recognize and proliferate in response to a sarcoidosis-associated antigen. The main objectives of our project is (1) to identify a sarcoidosis-specific antigen by in vitro stimulation of Valfa2.3+ cells with candidate antigens and with peptides, which we successfully have sequenced after elution from BAL cells of DR17 positive patients. (Thus for the first time we will be able to identify, and use in experimental systems, the antigenic peptides presented in vivo in the human lung). (2) to determine the cytokine profile of Valfa2.3+ cells. (3) to study the role of CD4+CD25+ regulatory T cells, and (4) to further characterize immune responses in sarcoidosis, comparing Lofgren-prone DR17 positive patients with good prognosis and DR17 negative patients who tend to have chronic disease. Specifically we want to investigate Toll-like receptor (TLR) expression and function on monocytes and monocyte-derived dendritic cells, study alveolar macrophages with regard to TLR expression, cytokine and chemokine profiles, and identify disease-associated proteins in BAL fluid. With improved understanding of innate and adaptive immune mechanisms in sarcoidosis, in particular the identification of a sarcoidosis antigen, novel strategies aimed at curing or even preventing sarcoidosis can be devised.
