How experimental models have unlocked hidden mechanisms of hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is a complex immune-mediated interstitial lung disease triggered by repeated or persistent inhalation of a variety of inhaled antigens in genetically predisposed individuals. The disease encompasses a wide clinical spectrum and may present as predominantly inflammatory or fibrotic forms, the latter associated with irreversible architectural distortion and progressive loss of pulmonary function. Although mechanisms involving dysregulated T-cell activation, aberrant antigen processing and maladaptive tissue-repair pathways are recognised as central contributors to HP pathogenesis, the precise mechanisms and the sequence of immunologic events that occur during inflammation and mainly those that drive the transition from inflammation to fibrosis remains unclear. Animal models, particularly murine systems, have helped in dissecting these mechanisms, yet they continue to fall short in fully recapitulating the heterogeneity and chronicity observed in human HP. In this review, we provide an in-depth and critical examination of existing wild-type and genetically modified mouse models used to investigate HP, with emphasis on antigen sources, exposure paradigms and the strengths and limitations of each approach. We synthesise current insights into how specific genes, signalling pathways and immune cell subsets, including T-helper cell polarisation, regulatory T-cell function, dendritic cell activation and immune complexes contribute to disease initiation, amplification and progression.