Chronic beryllium disease (CBD) is a granulomatous disorder that develops in individuals previously exposed to beryllium usually in the workplace. The lung is the predominant organ involved and granulomatous inflammation is associated with the accumulation of CD4+ T-cells in tissue and broncholveolar lavage (BAL). Studies from the investigators laboratories have found alterations in T-cell receptor (TCR) expression in the BAL of CBD patients including expanded CD4+ T-cell populations that express particular TCR Vbeta regions. Sequencing TCR beta-chain (TCRB) and TCR alpha-chain (TCRA) junctional regions expressed in BAL CD4+ T-cells demonstrated clonal T-cell expansions, and clones from different CBD patients were found to express nearly identical TCRs. The investigators now hypothesize that these expanded CD4+ T-cell clones are responding to beryllium/peptide complexes in the lungs of patients and are important in the pathogenesis of disease. Studies are proposed to verify that these T-cell clones are selectively expanded in CBD patients and, therefore, are not present in the lungs of healthy controls and patients with other granulomatous lung disorders. They will also study BAL in CBD patients at subsequent times of disease progression for the continued presence of these T-cell clones. Using patch testing to BeS04 in these same patients, studies will examine whether similar TCR are used by CD4+ T-cells infiltrating into the skin. The TCR of in vivo clonal expansions will also be compared to TCR expressed by BAL and blood T-cells in CBD patients recognize antigen and are stimulated. CD4+ T-cell hybridomas expressing the TCR of particular clonal expansions in CBD patients will be used to analyze the response to BeS04 and determine whether responses are restricted by self class II major histocompatibility complex (MHC) antigens. Additional studies will examine whether antigenic processing is required for stimulation and will characterize the nature of the beryllium/peptide/MHC complex involved in stimulating beryllium-reactive T-cells.
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