What is the pathophysiology and management of Hypersensitivity Pneumonitis (HP)?

Pathophysiology of Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis results from a dysregulated adaptive immune response in genetically susceptible individuals who develop sensitization to inhaled antigens, leading to lymphocytic alveolitis, granulomatous inflammation, and potentially progressive fibrosis through a shift from Th1 to Th2/Th17 cytokine patterns. 1

Initial Antigen Recognition and Sensitization

The pathophysiologic cascade begins when inhaled antigens—typically organic particles from fungi, bacteria, or avian sources—are recognized by antigen-presenting cells (APCs) such as dendritic cells and macrophages in the distal airways and alveoli 1. This triggers:

• Adaptive immune activation with both humoral (antigen-specific IgG antibodies) and T-helper cell type 1 (Th1) cellular responses 1
• T-cell receptor engagement where CD4+ T cells recognize antigens via class II MHC molecules and CD8+ T cells via class I MHC molecules on APCs 1
• Clonal expansion of antigen-specific T and B cells that home to the lung, creating memory cells and effector subsets 1

The resulting alveolitis is typically self-limited if antigen exposure ceases. However, in susceptible individuals with continued exposure, the disease progresses beyond this initial inflammatory phase 1.

Inflammatory Response and Granuloma Formation

Upon re-exposure to the inciting antigen, primed memory cells orchestrate a robust secondary immune response 1:

• Th1 cytokine production (IFN-γ, TNF-α, IL-2) drives granuloma formation and multinucleated giant cell development 1
• Toll-like receptor activation on APCs enhances antigen-specific responses, facilitating granulomatous inflammation 1
• Lymphocytic infiltration becomes the dominant histologic pattern, with lymphocytes comprising the majority of infiltrating cells in alveolar walls, interstitium, and peribronchiolar parenchyma 1
• Neutrophilic inflammation may play a role early in the disease course 1

This creates the characteristic histopathologic triad: cellular interstitial pneumonia with bronchiolocentric accentuation, poorly formed non-necrotizing granulomas, and organizing pneumonia 1, 2.

Genetic and Host Susceptibility Factors

Disease development requires genetic predisposition beyond simple antigen exposure 1:

• MHC polymorphisms in HLA-DR and HLA-DQ genes affect antigen recognition and processing 1
• Transporter-associated antigen processing variants influence immune response magnitude 1
• Tissue inhibitor of matrix metalloproteinase polymorphisms modulate tissue remodeling 1
• MUC5B promoter variant (rs35705950) increases risk of fibrotic progression and is associated with shortened survival 1
• Telomere-related gene mutations are found in approximately 10% of chronic HP patients and correlate with reduced transplant-free survival 1
• Familial clustering has been documented even among relatives in different environments, confirming genetic susceptibility 1

Progression to Fibrosis

The transition from inflammatory to fibrotic disease involves multiple interconnected mechanisms 1:

Cytokine Pattern Shift

• Th1 to Th2/Th17 transition occurs over time, creating a profibrotic environment 1
• Impaired regulatory T-cell function and decreased γδ T-cell activity fail to suppress inflammation 1
• This cytokine shift promotes fibroblast growth, differentiation, and extracellular matrix synthesis 1

Epithelial-Endothelial Barrier Disruption

• Mononuclear cell recruitment is enabled by endothelial activation and adhesion molecule expression 1
• Chemokine release by inflammatory cells compromises barrier integrity 1
• Epithelial-to-mesenchymal transition expands the fibroblast/myofibroblast population 1

Aberrant Repair and Remodeling

• Fibroblast and fibrocyte migration leads to excessive extracellular matrix accumulation 1
• Abnormal lung remodeling with collagen deposition and architectural destruction occurs 1
• Gene expression changes show enrichment in adaptive immune pathways, B-cell receptor signaling, and extracellular matrix-receptor interaction 1

Critical Pathophysiologic Distinctions

A crucial caveat: In a subset of fibrotic HP cases, disease progression continues despite complete antigen avoidance, suggesting that chronic inflammation triggers self-perpetuating fibrotic mechanisms independent of ongoing antigen exposure 1. This explains why some patients develop progressive fibrosis resembling usual interstitial pneumonia (UIP) pattern, making distinction from idiopathic pulmonary fibrosis challenging 1, 2.

The molecular mechanisms sustaining this progression remain incompletely understood, but likely involve persistent alveolar epithelial injury, aberrant repair responses, and mutually interacting pathways of inflammation and fibrosis that become uncoupled from the original antigenic trigger 1.