Beryllium-Induced Disturbances of the Murine Immune System Reflect Some Phenomena Observed in Sarcoidosis

Abstract

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 (C57B16 × DBA/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 (≈20% of control) which parallels the reduced proliferative capacity of sarcoid peripheral blood mononuclear cells (≈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.

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