Immunological endotypes and fibrotic biomarkers in patients with advanced fibrotic hypersensitivity pneumonitis undergoing lung transplantation

Abstract Hypersensitivity pneumonitis (HP) is an interstitial lung disease, with approximately 40% of patients progressing to pulmonary fibrosis. The aim of this study was to characterize the immunological profile of patients with advanced fibrotic HP undergoing lung transplantation. A cross-sectional study was conducted including 19 patients with fibrotic HP, 10 patients with idiopathic pulmonary fibrosis (IPF), and 8 healthy donors as controls. Lung tissue and pre-transplant serum samples were collected. Levels of Th1-, Th2-, Th17-, and pro-inflammatory cytokines, as well as the fibrotic biomarkers Krebs von den Lungen-6 (KL-6) and mucin 16 (MUC16), were analyzed in both tissue and serum samples. Fifty percent of HP patients exhibited a pronounced Th2-high profile, characterized by elevated IL-5, IL-6, IL-1β, IL-8, G-CSF, and MCP-1 compared with Th2-low HP patients. Th2-high HP patients also showed increased IL-7, IL-12p70, TNF-α, IL-13, GM-CSF and IL-17A, while Th2-low patients had higher IL-2, IL-13, GM-CSF and IL-23 relative to healthy controls. KL-6 expression was higher in HP lung tissue than in healthy controls, and serum KL-6 levels were elevated in HP compared with IPF, particularly in Th2-low patients. MUC16 tissue expression was maximal in IPF patients and exceeded that of Th2-high HP patients, although serum levels did not differ between groups. Cytokine levels in serum were largely comparable, except for IL-10, which was higher in Th2-high HP patients versus IPF. Fibrotic HP appears to involve two distinct immunological profiles: Th2-high and Th2-low profiles. Th2-high patients may exhibit heightened adaptive immune activation and increased granulocyte recruitment, suggesting that immune endotyping may provide insights into disease pathogenesis and potentially inform personalized therapeutic strategies.