Abstract Rationale Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by occupational beryllium (Be) exposure. We aimed to define systems-level lung-compartment protein changes in Be sensitization (BeS) and CBD, with the long-term goal to build comprehensive bronchoalveolar lavage fluid (BALF) classifiers for these conditions. Methods We analyzed paired BAL cells and BALF from 125 participants: 50 with CBD, 50 with BeS, and 25 healthy controls (HC). Trypsin-digested peptides from BAL whole-cell lysates and medium- and low-abundance BALF proteins were analyzed using LC-MS/MS on an Orbitrap Eclipse instrument with Data-Independent Acquisition (DIA)-MS. Protein detection and quantification were performed with EncyclopeDIA v4.7.11 against the Human UniProt database and a PROSIT-predicted spectral library. Differential protein abundance was assessed using linear regression models in the limma R package, with significance determined by FDR 0.05 to correct for multiple comparisons. Gene Ontology (GO) enrichment analysis was conducted using the enrichR R package. Results We detected 4488 proteins in BAL cells and 2063 in BALF, which revealed distinct but related signatures across CBD and BeS. In BAL cells, CBD showed increased abundance of mucins (MUC5A, MUC5B), extracellular matrix proteins (FINC, BP1B1), and others. BeS displayed similar but attenuated changes; direct CBD–BeS comparison identified proteins elevated in CBD (RFTN1, MMP14, GBP1). The differentially abundant proteins are involved in canonical immune and stress response pathways in BeS and CBD versus controls, including neutrophil degranulation, interferon signaling, and MHC class I antigen processing. Upregulation of EIF2 and unfolded protein response pathways indicated enhanced protein synthesis and ER stress, while Rho GTPase and actin cytoskeleton signaling reflected increased immune cell motility and cytoskeletal remodeling. In BALF, several proteins demonstrated differential abundance (Figure 1). CBD exhibited increased extracellular matrix and inflammatory proteins (VCAM1, FBLN1, PLTP, CHIT1) and reduced antioxidant or mitochondrial proteins (MAA2A2, THTM, DAF), whereas BeS showed modest increases in stress response and adhesion proteins (IF4B, APOBR, CO6A1). BALF proteins map to lipid transport and coagulation pathways in CBD, oxidative and cytoskeletal remodeling in BeS, and downregulation of epithelial proliferation and ERK/MAPK signaling in cases versus controls. Conclusions CBD and BeS exhibit distinct but overlapping proteomic signatures in BAL cells and BALF. CBD is characterized by enhanced lipid transport, coagulation, and epithelial-stromal activation, whereas BeS reflects oxidative stress and cytoskeletal remodeling. These findings suggest progressive immune activation and stress adaptation from BeS to CBD and highlight the potential of BAL-derived proteomic profiles for biomarker and classifier development. This abstract is funded by: NIH
Bhargava et al. (Fri,) studied this question.
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