We are working on the identification, description, and treatment of congenital and acquired syndromes of increased susceptibility to infection primarily affecting the phagocytes, including those related to nontuberculous mycobacteria. These organisms are important pathogens only in the immunocompromised host, so we have sought to identify patients without recognized forms of immunocompromise who have these infections and then determine the nature of their susceptibility. In this way we can identify the pathways involved in the control of mycobacteria and potentially other intracellular pathogens such as Salmonella. We have identified several discrete abnormalities in these patients. These abnormalities center around macrophage/lymphocyte interactions leading to the production of or response to interferon gamma and, more recently, the response to tumor necrosis factor. The study of these "experiments of nature" highlights the critical role of the macrophage/ lymphocyte interaction in control of mycobacteria. These observations have led to the development of therapies that may have important applications to the treatment of tuberculosis.