• Shinji Katayanagi, Yasuhiro Setoguchi, Sayoko Kitagawa, Tsukasa Okamoto, and Yasunari Miyazaki.
• Department of Respiratory Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
• Chest. 2022 Feb 1; 161 (2): 458-469.

BackgroundChronic hypersensitivity pneumonitis (CHP) is a heterogeneous fibrotic interstitial pneumonia resulting from the immune response of susceptible individuals to inhaled antigens. Genetic predispositions have been suggested in CHP; however, the link between susceptibility genes and fibrotic progression has not been elucidated fully. Recent data suggest that variants in Toll-interacting protein gene (TOLLIP) are associated with lung diseases.Research QuestionCan TOLLIP variants be associated with any clinical features in patients with CHP?Study Design And MethodsWe genotyped rs5743899 and rs3750920 in TOLLIP and analyzed the association with clinical parameters in 101 patients with CHP (67 for the retrospective cohort and 34 for the prospective cohort). We evaluated the expression of TOLLIP and fibrogenic signals in affected lung tissues and periostin in sera. Furthermore, we performed immunologic analysis in the lungs and sera.ResultsThe rs5743899 GG genotype was associated with rapid deterioration in FVC over time, which demonstrated significant annual decline in the retrospective cohort (vs AA, P = .0006; vs AG, P < .0001), prospective cohort (vs AA, P < .0001; vs AG, P = .003), and combined cohort (both P < .0001). The patients with the GG genotype demonstrated lower transcription-translation levels of TOLLIP as well as increased phosphorylation of Smad2 and inhibitor of kappa B in the lung tissues and exhibited higher serum levels of periostin, IL-1α, IL-1β, IL-6, IL-8, tumor necrosis factor α, and IFN-γ.InterpretationThe functional changes by TOLLIP variant were associated with rapid FVC decline through dysregulated Smad/transforming growth factor β and NF-κB signaling in CHP.Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

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