Beryllium sensitization is characterized by the presence of beryllium- specific CD4+ T cells in the peripheral blood of individuals exposed to beryllium in the workplace. These individuals are asymptomatic and have normal pulmonary function, chest radiographs and lung biopsies. A subset of beryllium-sensitized individuals eventually develops chronic beryllium disease (CBD) at a rate of approximately 10% per year. The factors involved in the localization of beryllium-specific CD4+ T cells to the lung and in the progression from beryllium sensitization to disease remain unknown. It is possible that beryllium sensitization without disease involves the development of peryllium-responsive T cells whereas the evolution to disease involves a particular type of T cell recognition or particular type of T cell function. We now hypothesize that this progression from sensitization to disease is a multifactorial process related to the absolute number of beryllium-responsive T cells in the peripheral blood and changes in the frequency of these beryllium- responsive T cells in the peripheral blood over time can predict this progression to disease. Studies are proposed to verify that beryllium- specific CD4+ T cells are more abundant in the peripheral blood of individuals with CBD as compared to beryllium sensitization. We will also study blood and BAL from CBD patients in order to determine whether the same TCR repertoires exist in beryllium-reactive CD4+ T cells in these different compartments We will also determine whether the pattern of cytokine production by beryllium-reactive CD4+ T cells is different in sensitization versus disease. Separate studies will focus on changes in the frequency of beryllium-reactive CD4+ T cells in the peripheral blood of beryllium-sensitized subjects over time in order to determine whether increases in this frequency are associated with the progression from sensitization to disease. Together, these studies will provide new insights into the immunopathogenesis of beryllium-induced disease.