## Pathophysiology of SJS/TEN **Key Point:** SJS and TEN are severe mucocutaneous reactions characterized by widespread keratinocyte apoptosis mediated by CD8+ cytotoxic T lymphocytes (CTLs). ### Mechanism of Keratinocyte Death 1. **Drug-hapten formation**: Offending drug (or its metabolite) binds to keratinocyte surface proteins, creating a neo-antigen. 2. **CTL activation**: CD8+ T cells recognize the drug-hapten complex via MHC-I presentation. 3. **Apoptosis induction**: Activated CTLs release perforin and granzyme B, triggering keratinocyte apoptosis. 4. **Epidermal necrosis**: Widespread apoptosis → full-thickness epidermal detachment (TEN) or focal involvement (SJS). ### Key Cytokines Involved - **TNF-α**: Amplifies apoptosis and inflammation. - **Fas-FasL interaction**: Enhances CTL-mediated killing. - **Granulysin**: Released by CTLs; directly toxic to keratinocytes. **High-Yield:** The hallmark histology is **full-thickness epidermal necrosis with minimal dermal inflammation** — this distinguishes SJS/TEN from other drug eruptions where inflammation is prominent. **Clinical Pearl:** The delayed onset (typically 1–8 weeks after drug exposure) reflects the time needed for sensitization and CTL expansion, not immediate hypersensitivity. [cite:Robbins 10e Ch 25] 
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