Abstract
Objective To study airway pathophysiology and the role of dendritic cells (DCs) and IL-17 receptor (IL-17R) signals in a mouse model for CBD. Methods Here, we present a CBD mouse model in which mice were exposed to beryllium during three weeks. We also exposed IL-17R-deficient mice and mice in which DCs were depleted. Results Eight weeks after the initial beryllium exposure, an inflammatory response was detected in the lungs. Mice displayed inflammation of the lower airways that included focal dense infiltrates, granuloma-like foci, and tertiary lymphoid structure (TLS) containing T cells, B cells, and germinal centers. Alveolar cell analysis showed significantly increased numbers of CD4+ T cells expressing IFNγ, IL-17, or both cytokines. The pathogenic role of IL-17R signals was demonstrated in IL-17R-deficient mice, which had strongly reduced lung inflammation and TLS development following beryllium exposure. In CBD mice, pulmonary DC subsets including CD103+ conventional DCs (cDCs), CD11b+ cDCs, and monocyte-derived DCs (moDCs) were also prominently increased. We used diphtheria toxin receptor-mediated targeted cell ablation to conditionally deplete DCs and found that DCs are essential for the maintenance of TLS in CBD. Furthermore, the presence of antinuclear autoantibodies in the serum of CBD mice showed that CBD had characteristics of autoimmune disease. Conclusions We generated a translational model of sarcoidosis driven by beryllium and show that DCs and IL-17R signals play a pathophysiological role in CBD development as well as in established CBD in vivo.
Highlights
Sarcoidosis is a systemic inflammatory disease of unknown cause
When we quantified the numbers of CD4+ and CD8+ T cells in the bronchoalveolar lavage (BAL) of chronic beryllium disease (CBD) mice at ~8 weeks after the first exposure to Be/beryllium oxide (BeO), we found that both populations were significantly increased (Figures 1(b) and 1(c))
When we characterized individual lung dendritic cells (DCs) subsets, including CD103+ DCs, CD11b+ DCs, monocyte-derived DCs, and plasmacytoid DCs [38], we found that the numbers of all four subsets were increased in the BAL of CBD mice, compared with control mice (Figures 4(a) and 4(b))
Summary
Sarcoidosis is a systemic inflammatory disease of unknown cause. An inflamed lung is one of the most common features in >90% of these patients [1]. The disease is characterized by the presence of compact, organized, noncaseating granulomas that contain activated T cells, dendritic cells (DCs), macrophages, and histiocytes (epithelioid and macrophagelike cells) [2,3,4]. The disease mechanism and cause are unknown, the immunological phenotype of sarcoidosis patients indicates that the disease is multifactorial. It has been suggested that its etiology involves certain bacterial antigens, such as Mycobacterium, Propionibacterium, and Mkat G [5,6,7].
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