What is the immune-mediated response in hypersensitivity pneumonitis (HP) and how is it managed?

Immune-Mediated Response in Hypersensitivity Pneumonitis and Its Management

The immune-mediated response in hypersensitivity pneumonitis (HP) involves both humoral and T-helper cell type 1 (Th1) cellular immune responses that lead to lymphocytic inflammation and granuloma formation, with management focused on antigen avoidance and, when necessary, immunosuppression or antifibrotic therapy for progressive fibrotic disease. 1

Pathophysiology of Immune Response in HP

Initial Antigen Recognition and Sensitization

• Inhaled antigens are recognized by antigen-presenting cells (APCs) such as dendritic cells and macrophages 1
• This recognition initiates an adaptive immune response with specific memory
• B cells recognize antigen determinants via surface immunoglobulin receptors
• T cells recognize antigen determinants through T-cell receptor coupled with MHC molecules on APCs 1

Immune Response Components

1. Humoral Response:

   • Production of antigen-specific IgG antibodies 1
   • Formation of immune complexes that can activate complement
   • The antibody repertoire from memory B cells is diverse enough to recognize almost any potential antigenic determinant 1

2. Cellular Response:

   • Predominantly Th1-mediated response characterized by:
     • CD4+ T cell differentiation into Th1 cells
     • Production of IFN-γ, TNF-α, and IL-2 cytokines 1
     • These cytokines promote granuloma formation and multinucleated giant cells

3. Neutrophilic Component:

   • Plays a role in early disease course 1
   • Significant increase in neutrophils occurs after antigen exposure
   • Neutrophil chemoattractants (G-CSF, IL-6, IL-8, IL-17, CXCL2) increase in both serum and BALF after antigen exposure 2

Progression to Chronic Disease and Fibrosis

• If exposure continues after sensitization, a subset of individuals develops HP 1
• Progression to fibrosis involves:
  • Shift from Th1 to Th2 or Th17 environment 1
  • Impaired regulatory T cells and decreased γδT-cell activity
  • Fibroblast and fibrocyte migration
  • Epithelial-to-mesenchymal transition
  • Expansion of fibroblasts/myofibroblasts
  • Accumulation of extracellular matrix 1

Genetic and Host Susceptibility Factors

• Polymorphisms in MHC genes (HLA-DR and HLA-DQ) 1
• Variants in transporter-associated antigen processing 1
• Tissue inhibitors of matrix metalloproteinases 1
• TNF-α promoter polymorphisms 1
• MUC5B promoter variant rs35705950 (associated with fibrotic HP) 1
• Telomere-related gene mutations (associated with shortened survival) 1

Management of Hypersensitivity Pneumonitis

Diagnostic Approach

1. Exposure Identification:

   • Thorough history to identify potential inciting agents
   • Common sources include microorganisms, fungi, animal proteins, and chemicals 1
   • Occupational, household, or recreational exposures should be considered 1

2. Imaging:

   • High-resolution CT (HRCT) is essential
   • Non-fibrotic HP: ground-glass opacities, centrilobular nodules, mosaic attenuation 3
   • Fibrotic HP: traction bronchiectasis, honeycombing, often with mid-lung predominance 1

3. Laboratory Testing:

   • Serum IgG testing for specific antigens 3
   • Bronchoalveolar lavage (BAL) showing lymphocytosis 3

4. Histopathology (when necessary):

   • Cellular interstitial pneumonia
   • Cellular bronchiolitis
   • Epithelioid cell granulomas 4
   • Additional fibrotic changes in chronic disease

Treatment Strategies

1. Antigen Avoidance:

   • First and most crucial step in management 5
   • Complete removal of the identified antigen from the patient's environment
   • May require environmental modifications or occupational changes

2. Pharmacological Treatment:

   • For Non-fibrotic HP:

     • Corticosteroids for acute/subacute inflammation
     • Other immunosuppressants (azathioprine, mycophenolate) may be considered

   • For Fibrotic Progressive HP:

     • Nintedanib (tyrosine kinase inhibitor) - FDA-approved for chronic fibrosing ILDs with progressive phenotype 5
     • Immunosuppressants may be used but have not been shown to slow fibrotic progression 5

3. Non-pharmacological Interventions:

   • Oxygen therapy for hypoxemic patients
   • Pulmonary rehabilitation
   • Supportive care 5
   • Lung transplantation consideration for end-stage disease

Clinical Pearls and Pitfalls

• Key Pitfall: Failure to identify and remove the inciting antigen, which is essential for preventing disease progression
• Important Caveat: The presence of fibrosis significantly impacts prognosis and treatment approach 4
• Clinical Challenge: In many cases (up to 30-60%), an exposure is not identified despite thorough investigation 1
• Treatment Consideration: While immunosuppressants are commonly used, they have not been proven to slow progression of fibrotic disease 5
• Monitoring: Regular pulmonary function tests and imaging are needed to assess for disease progression, especially in fibrotic HP

By understanding the complex immune mechanisms involved in HP and implementing appropriate management strategies, clinicians can improve outcomes and quality of life for patients with this challenging interstitial lung disease.