Chronic Hypersensitivity Pneumonitis (CHP), an Interstitial Lung Disease (ILD) with Distinct Molecular Signatures

Abstract

Background: Chronic hypersensitivity pneumonitis (CHP) is caused by an immune response to antigen inhalation and is characterized by progressive pulmonary fibrosis. The histopathological and clinical features of CHP are variable, however, a subset of CHP patients have usual interstitial pneumonia and behave clinically similar to patients with idiopathic pulmonary fibrosis (IPF). To determine the common and unique molecular features of CHP and IPF, we conducted a transcriptome analysis of lung samples from CHP (N=82), IPF (N=103), and unaffected controls (N=103). Methods: Gene expression in lung tissue was determined adjusting for sex, race, age, explant site, and smoking history, and using false discovery rate (FDR) to control for multiple comparisons. Findings: When compared to controls, we identified 413 upregulated and 317 downregulated genes in CHP, and 861 upregulated and 322 downregulated genes in IPF. Concordantly up/down-regulated genes in CHP and IPF were related to collagen catabolic processes and epithelial development, whereas genes specific to CHP were related to chemokine-mediated signaling and immune responsiveness. Using weighted gene co-expression network analysis (WGCNA), we found that among subjects with CHP, genes involved in adaptive immunity or epithelial cell development were associated with improved or reduced lung function respectively, and that MUC5B expression was associated with epithelial cell development. MUC5B expression was also associated with lung fibrosis and honeycombing. Interpretation: Gene expression analysis of CHP and IPF identified signatures common to CHP and IPF, as well as genes uniquely expressed in CHP. Select modules of gene expression are characterized by distinct clinical and pathological features of CHP. Funding Statement: NHLBI (R01-HL097163, P01-HL092870, UH3-HL123442, and DoD W81XWH17-1-0597). Declaration of Interests: None of the authors report conflicts of interest relevant to this study. D.A.S. is the founder and chief scientific officer of Eleven P15, a company focused on the early diagnosis and treatment of pulmonary fibrosis. D.A.S. has an awarded patent (US patent no: 8,673,565) for the treatment and diagnosis of fibrotic lung disease. Ethics Approval Statement: This study conformed to the Declaration of Helsinki and was approved by the Colorado Multiple Institution Board (COMIRB) 15-1147.