Chronic Hypersensitivity Pneumonitis, an Interstitial Lung Disease with Distinct Molecular Signatures

Abstract

Rationale: Chronic hypersensitivity pneumonitis (CHP) is caused by an immune response to antigen inhalation and is characterized by variable histopathological and clinical features. A subset of subjects with CHP have usual interstitial pneumonia and appear to be clinically similar to subjects with idiopathic pulmonary fibrosis (IPF).Objectives: To determine the common and unique molecular features of CHP and IPF.Methods: Transcriptome analysis of lung samples from CHP (n = 82), IPF (n = 103), and unaffected controls (n = 103) was conducted. Differential gene expression was determined adjusting for sex, race, age, and smoking history and using false discovery rate to control for multiple comparisons.Measurements and Main Results: When compared with controls, we identified 413 upregulated and 317 downregulated genes in CHP and 861 upregulated and 322 downregulated genes in IPF.Concordantly upregulated or downregulated genes in CHP and IPF were related to collagen catabolic processes and epithelial development, whereas genes specific to CHP (differentially expressed in CHP when compared with control and not differentially expressed in IPF) were related to chemokine-mediated signaling and immune responsiveness. Using weighted gene coexpression network analysis, 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.Conclusions: 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.

Diagnosis and Evaluation of Hypersensitivity Pneumonitis

“…The MUC5B promoter variant rs35705950 and mutations in genes associated with telomere biology have been correlated with an increased risk of pulmonary fibrosis development. 154,155 In sensitized and susceptible individuals, the presence of primed antigen-specific, long-lived memory T and B cells helps orchestrate a robust secondary dysfunctional immune response upon re-encountering the IA. During the disease course, CD4þ T cells (Th0) can differentiate into several functional subclasses.…”

“…In HP, gene expression is enriched with adaptive immune responses and B-cell receptor signaling. 155,165,166 However, fibrotic HP pathway analyses also exhibit developmental pathways such as those involved in epithelial cell development and extracellular matrix-receptor interaction. In a subset of HP cases, despite complete IA avoidance, alveolar epithelial injury and subsequent aberrant repair, abnormal fibroblast proliferation, extracellular matrix remodeling, excessive collagen deposition, and destruction of the lung architecture occur as a direct consequence of chronic inflammation or by the independent or mutually interacting mechanisms of lung inflammation and fibrosis.…”

“…In a subset of HP cases, despite complete IA avoidance, alveolar epithelial injury and subsequent aberrant repair, abnormal fibroblast proliferation, extracellular matrix remodeling, excessive collagen deposition, and destruction of the lung architecture occur as a direct consequence of chronic inflammation or by the independent or mutually interacting mechanisms of lung inflammation and fibrosis. 155,167…”

Biomarkers in Progressive Fibrosing Interstitial Lung Disease: Optimizing Diagnosis, Prognosis, and Treatment Response

“…Transcriptomic analysis of lung tissue has emerged as an exciting arena of biomarker research. Furusawa et al recently employed this methodology to identify gene signatures unique to patients with IPF and CHP that may allow for better diagnostic discrimination if this can be implemented using less invasive measures ( 195 ). Transcriptomic analysis of lung tissue obtained by transbronchial biopsy has resulted in the first commercially available ILD biomarker.…”

The Bloom Is in Bud for Interstitial Lung Diseases

“…In this issue of the Journal , Furusawa and colleagues (pp. 1430–1444 ) were able to demonstrate that two separate ILDs—idiopathic pulmonary fibrosis (IPF) and chronic hypersensitivity pneumonitis (CHP)—likely share common final pathways in their pathologic “roots” ( 2 ). Their study also suggests that differences between IPF and CHP may be indicative of inciting injuries and etiologies, along with their differing immunologic responses.…”