Beryllium-induced lung disease exhibits expression profiles similar to sarcoidosis

Abstract

A subset of beryllium-exposed workers develop beryllium sensitisation (BeS) which precedes chronic beryllium disease (CBD). We conducted an in-depth analysis of differentially expressed candidate genes in CBD. We performed Affymetrix GeneChip 1.0 ST array analysis on peripheral blood mononuclear cells (PBMCs) from 10 CBD, 10 BeS and 10 beryllium-exposed, nondiseased controls stimulated with BeSO4 or medium. The differentially expressed genes were validated by high-throughput real-time PCR in this group and in an additional group of cases and nonexposed controls. The functional roles of the top candidate genes in CBD were assessed using a pharmacological inhibitor. CBD gene expression data were compared with whole blood and lung tissue in sarcoidosis from the Gene Expression Omnibus. We confirmed almost 450 genes that were significantly differentially expressed between CBD and controls. The top enrichment of genes was for JAK (Janus kinase)–STAT (signal transducer and activator of transcription) signalling. A JAK2 inhibitor significantly decreased tumour necrosis factor-α and interferon-γ production. Furthermore, we found 287 differentially expressed genes overlapped in CBD/sarcoidosis. The top shared pathways included cytokine–cytokine receptor interactions, and Toll-like receptor, chemokine and JAK–STAT signalling pathways. We show that PBMCs demonstrate differentially expressed gene profiles relevant to the immunnopathogenesis of CBD. CBD and sarcoidosis share similar differential expression of pathogenic genes and pathways.

Beryllium disease and sarcoidosis: still besties after all these years?

“…They also extend support for the concept that many aspects of various pulmonary granulomatous diseases share similar immunological profiles [22]. The authors here found 33 gene products that overlapped significantly between CBD PBMCs and sarcoidosis tissue, including CXCL9, STAT1, TAP1, CCL8 and CXCL11 [20].…”

“…Reassuringly, the present data corroborate the usefulness of peripheral blood transcriptomic signatures for the study of pulmonary granulomatous inflammation [22]. They also extend support for the concept that many aspects of various pulmonary granulomatous diseases share similar immunological profiles [22].…”

“…In this issue of the European Respiratory Journal, LI et al [22] compare gene expression in peripheral blood mononuclear cells (PBMCs) from individuals with CBD, beryllium sensitisation and healthy controls. They then compared the expression profiles of the genes differentially expressed in CBD to those from sarcoidosis populations [23,24].…”

Rare respiratory diseases are ready for primetime: from Rare Disease Day to the European Reference Networks

“…ERN-LUNG is currently made up of 60 centres in 12 countries and is organised into nine core networks representing the diversity of diseases and conditions affecting the respiratory system (figure 2, table 2). The current core networks are interstitial lung diseases [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21], cystic fibrosis [22][23][24][25], pulmonary hypertension [26][27][28][29][30][31], primary ciliary dyskinesia [32][33][34][35][36][37], non-cystic fibrosis bronchiectasis [38][39][40], α 1 -antitrypsin deficiency [41], mesothelioma [42], chronic lung allograft dysfunction [43][44][45] and "other rare lung diseases" (e.g. pulmonary malformations, congenital central hypoventilation syndrome etc) [46][47][48][49].…”

Current Sarcoidosis Models and the Importance of Focusing on the Granuloma

“…However, pulmonary sarcoidosis is clinically and histologically very similar to berylliosis, a human disease linked to genetic variability of T cell receptors for divalent beryllium molecules ( 22 ). Given the clinical similarities, it has been proposed that sarcoidosis and berylliosis may have similar mechanistic underpinnings ( 23 , 24 ). Indeed, the berylliosis animal model produces multicellular aggregates of mononuclear cells in the lung consistent with human sarcoidosis ( 22 ).…”