BERYLLIUM-INDUCED DISTURBANCES OF THE MURINE IMMUNE-SYSTEM REFLECT SOME PHENOMENA OBSERVED IN SARCOIDOSIS

Sarcoidosis is a systemic granulomatous disorder of unknown origin. In respect to clinical and immunological characteristics, it is indistinguishable from berylliosis. As an approach to develop a murine model reflecting some aspects of sarcoidosis, we attempted to induce berylliosis in mice by treating inbred F1 mice (C57B16xDBA/2) with 3 mg beryllium sulfate (BeSO4) per kg body weight intraperitoneally. Either pure BeSO4 or BeSO4 in combination with incomplete Freund's adjuvant was administered. Alternatively, pure BeSO4 was injected 2 days after a single application of cyclophosphamide (150 mg/kg). The spleen index, the spontaneous and phorbolmyristate acetate (PMA)-induced radical oxygen intermediates (ROI) released by peritoneal macrophages, and the proliferative activity of spleen mononuclear cells in response to BeSO4 and concanavalin A (ConA) were evaluated and compared to the corresponding changes observed in sarcoidosis. In all three modes of BeSO4 treatment, the spontaneous ROI release by peritoneal macrophages was significantly elevated. These elevations were very similar to those observed with alveolar macrophages in active sarcoid alveolitis. After BeSO4 treatment, a small proliferative activity of spleen mononuclear cells in response to BeSO4 could be observed. Further, BeSO4-treated spleen mononuclear cells exhibited a markedly reduced response to ConA stimulation (approximate to 20% of control) which parallels the reduced proliferative capacity of sarcoid peripheral blood mononuclear cells (approximate to 45% of control). This reduction could be abolished by pretreating the mice with cyclophosphamide. BeSO4 treatment in combination with incomplete Freund's adjuvant resulted in a significant increase of spleen mononuclear cell proliferation (1.9-fold) after in vitro stimulation with BeSO4, and prevented the low responsiveness to ConA. All these findings were maximal after 2 and vanished after 5 weeks. In conclusion, BeSO4 treatment of mice yields immunological disturbances which parallel some immunopathological phenomena of patients with sarcoidosis.