Pembrolizumab and nivolumab are PD-1 checkpoint inhibitors. Immune-related adverse events (irAEs) are their main toxicity. Which cytokine pathway is primarily responsible for pembrolizumab-induced pneumonitis?

• A Anti-PD-1 antibody directly activates complement in pulmonary vasculature causing endothelial damage
• B Pembrolizumab induces autoantibody production targeting surfactant protein C in type II pneumocytes
• C Increased systemic TNF-alpha from activated macrophages causes ARDS-like pulmonary toxicity
• D Unleashing of auto-reactive T cells through PD-1/PD-L1 pathway disruption allows T cells to infiltrate lung parenchyma; IL-17 and IL-6 from these T cells drive alveolar inflammation ✓

Explanation

PD-1/PD-L1 normally constrains T cell activity in peripheral tissues including the lung, preventing autoimmune inflammation. Checkpoint inhibitors release this brake, allowing auto-reactive and tumor-reactive T cells to infiltrate the lung parenchyma. The resulting pneumonitis is mediated by cytotoxic CD8+ T cells and pro-inflammatory Th1/Th17 cytokines (IFN-gamma, IL-17, IL-6). Pathologically, checkpoint inhibitor pneumonitis resembles organizing pneumonia or hypersensitivity pneumonitis. Management requires corticosteroids (0.5–2 mg/kg/day prednisolone equivalent); grade 3-4 pneumonitis necessitates permanent discontinuation and may require additional immunosuppression (infliximab, mycophenolate).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.