Involvement of Dendritic Cells and Th17 Cells in Induced Tertiary Lymphoid Structures in a Chronic Beryllium Disease Mouse Model

Rationale. Sarcoidosis is a systemic inflammatory disorder characterized by the presence of granulomas in various organs, most commonly in the lungs. Although the ethology is unknown, sarcoidosis is thought to be mediated by T helper (Th)1 and Th17 lymphocytes. Chronic airway exposure to beryllium metal leads to chronic beryllium disease (CBD), which shares similarities with pulmonary sarcoidosis. 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.

Analysis of single nucleotide polymorphisms in chronic beryllium disease

Sarcoidosis and chronic beryllium disease (CBD) are phenocopies, however the latter one has a clear trigger factor that is beryllium exposure. This study analyses single nucleotide polymorphisms (SNPs) in a large cohort for beryllium-exposed persons. SNPs were chosen for their relevance in sarcoidosis. Even though one of largest cohorts of beryllium-exposed persons was analysed, no statistically relevant association between any SNP and CBD could be verified. Notably, some SNPs exhibit inverse OR for beryllium sensitization and CBD with nominally statistical significance, which allows hypothesizing about pathophysiological role of genes for the disease triggering and development.

A consistent model for the key complex in chronic beryllium disease

A hypothesis on the structure of the key complex in chronic beryllium disease (CBD) is discussed with respect to the current knowledge on CBD, and with respect to the constraints implied by the coordination chemistry of beryllium and experimental data on the engaged protein complexes. The structure hypothesis is based on the [Be4O]6+ moiety as a coordination center, which is also found in the so called “basic beryllium carboxylates”. The structure of a small molecular model, optimized at the DFT level of theory, is used to compare the structural demands of this coordination center with a structure of the in vitro model of a beryllium immunoprotein complex determined previously by protein crystallography (Clayton & al., Cell2014, 158, 132). 9Be NMR chemical shielding values, quadrupole coupling constants and asymmetry parameters (η) have been calculated.