Exposure of cultured murine peritoneal macrophages to low concentrations of beryllium induces increases in intracellular calcium concentrations and stimulates DNA synthesis.

Exposure of humans to beryllium dusts can induce a specific form of chronic pneumonitis that consists mainly of noncaseating granulomas in the lungs. Multiple studies have documented both genetic and immune components of chronic beryl- liosis. Much work has focused on T cells and their reactivity in berylliosis, but less work has focused on the end effector cells in granulomatous inflamma- tion, macrophages. Because macrophages must become activated to form granulomas, and they become activated by responding to numerous im- munomodulatory signals, we investigated the ef- fects of beryllium (BeCl2) on a central signal trans- duction pathway in macrophages, increases in intracellular calcium ((Ca 21 )i). Exposure of cul- tured murine peritoneal macrophages to low, non- toxic concentrations induced successive spikes or oscillations in (Ca 21 )i. Concentrations as low as 5 nM induced significant increases in (Ca 21 )i. The source of the increased (Ca 21 )i was exclusively extracellular in that increases in (Ca 21 )i could be completely blocked by chelating extracellular Ca 21 , were inhibited by the Ca 21 channel blocker verapa- mil, and exposure of macrophages to BeCl2 had no effect on IP3 concentrations. DNA synthesis, a Ca 21 -sensitive function, was enhanced in dividing 1LN cells and induced de novo in quiescent macro- phages. Furthermore, BeCl2 enhanced DNA synthe- sis in the absence of coexposure to the protein kinase C activator phorbol myristate acetate. These data support the hypothesis that beryllium toxicity is in part the result of altered Ca 21 metabolism in mononuclear phagocytes consequent to reversible opening of plasma membrane channels. J. Leukoc. Biol. 65: 786-791; 1999. other toxic metals and dusts. The chronic lung disease, berylliosis, however, is quite unique and different from that induced by other metals. Berylliosis is a chronic inflammatory disease, mainly of the lung, in which noncaseating granulomas very similar to those found in sarcoidosis are formed. These granulomas consist of epithelioid cells, giant cells, macro- phages, monocytes, fibroblasts, and lymphocytes. The disease can be insidious in onset and has a spectrum of symptoms ranging from mild impairment to end-stage lung disease requiring transplantation. Although workplace safety practices have virtually eliminated acute disease in beryllium workers, cases of chronic berylliosis still occur. The exact cause of berylliosis is uncertain, but it is clear from a number of studies that there are distinct autoimmune and genetic aspects to the disease. Workers who develop berylliosis are sensitized to the metal and develop an antigen- driven delayed-type hypersensitivity reaction in skin. Because beryllium is such a small molecular weight substance and cannot induce an immune response to itself, it is thought to act as a hapten sensitizer by combining with some endogenous macromolecule(s). Intradermal injection of pure beryllium salts can cause a granulomatous reaction in patients with berylliosis. Beryllium is mitogenic for T cells taken from patients with berylliosis, whereas other metals are not. Beryllium is also a nonspecific mitogen for murine spleen cells. T cells taken from berylliosis patients display increased responsiveness to other established T cell mitogens. In attempts to establish an animal model of berylliosis, it was discovered that there are distinct species and strain differences in susceptibility to the development of berylliosis. Human studies demonstrated that individuals with certain major histo- compatibility class II (MHC II) antigens (HLA-DPB1) comprise a more than expected proportion of patients with berylliosis; however, patients with other MHC II types can develop the disease.