Description of Research Expertise
Identification and functional characterization of inflammatory cells in the normal and abnormal lung, particularly the function of lymphocytes and macrophages in human granulomatous disease.
A primary goal of our research is to understand the mechanisms by which beryllium causes a chronic granulomatous disease. Four approaches to determining the mechanisms of beryllium granulomas are utilized. First, the human T cell lines and clones are being established and the T cell receptors identified and sequenced. Specific subfamilies of T cells appear to be utilized in an oligoclonal response. Second, HLA Class II alleles in patients were identified and compared to exposed but unaffected workers. Not only were specific alleles identified that were associated the beryllium disease, but specific amino acids in hypervariable amino acid positions associated with the binding pockets were found in greater than 90% of cases. Using this information, immortalized B cells from patients with beryllium disease were created and the Class II molecules isolated in the presence and absence of beryllium. Characterization of the peptides bound by these Class II molecules is underway. Initial studies suggest that peptides isolated from HLA Class II DP are able to stimulate beryllium cell lines. Finally, animal models are used to test the importance of specific human proteins in the initiation of the beryllium response and also to determine the nonspecific (adjuvant) effects of beryllium that promote a TH1 or gamma-interferon type response. Similar approaches are being used in other human granulomatous diseases such as sarcoidosis and tuberculosis.