Immune checkpoint inhibitors (anti-PD-1/anti-PD-L1) cause immune-related adverse events (irAEs) in multiple organ systems. The pathomechanism of irAEs is:

• A Release of the normal peripheral T-cell tolerance checkpoints, allowing autoreactive T cells to attack self-tissues presenting shared antigens ✓
• B Direct cytotoxic T-cell effect on drug-metabolizing organs due to CYP450 induction
• C Complement-mediated cytotoxicity triggered by antibody-drug conjugate formation
• D Cytokine storm exclusively mediated by NK cell degranulation

Explanation

PD-1/PD-L1 and CTLA-4 are physiological immune checkpoints that maintain peripheral tolerance by restraining autoreactive T cells. Inhibiting these checkpoints releases T cells to attack tumors but also removes restraints on autoreactive lymphocytes that may target normal tissues. This breaks peripheral tolerance, causing organ-specific autoimmune-like inflammation — colitis, hepatitis, pneumonitis, endocrinopathies (thyroiditis, hypophysitis, adrenalitis), dermatitis. The tissue specificity correlates with the degree of PD-L1 expression on the target organ and the T-cell clones released. Treatment is with systemic corticosteroids to reimpose immune suppression.

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

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Written and medically reviewed by the StethoPrep medical team.