## Pathogenesis of Atopic Dermatitis ### Primary Defect: Filaggrin Mutation **Key Point:** Loss-of-function mutations in the filaggrin (FLG) gene are the most significant genetic risk factor for atopic dermatitis, accounting for approximately 30% of cases in European populations. **High-Yield:** Filaggrin is a filament-associated protein essential for: - Cross-linking keratin filaments in the stratum corneum - Maintaining skin barrier integrity - Preventing transepidermal water loss (TEWL) ### Pathophysiologic Cascade 1. **Barrier Dysfunction** → Increased TEWL and water loss 2. **Allergen Penetration** → Enhanced percutaneous sensitization 3. **Immune Activation** → Th2-skewed response (not Th1) 4. **Chronic Inflammation** → Pruritus and eczematous changes ### Role of Other Factors | Factor | Role in AD | |--------|----------| | IgE elevation | Secondary response; not primary defect | | Th2 cytokines (IL-4, IL-5, IL-13) | Drive inflammation AFTER barrier breach | | Antimicrobial peptides | Reduced, contributing to infection risk | | Staphylococcus aureus colonization | Consequence of barrier defect, not cause | **Clinical Pearl:** Patients with filaggrin mutations often have ichthyosis vulgaris and keratosis pilaris, reflecting the widespread role of filaggrin in cornification. **Mnemonic:** **FILAGGRIN** = **F**ilament **I**ntegrity **L**oss **A**llows **G**erm **G**rowth **R**ashes **I**nflammation **N**eeds treatment [cite:Robbins 10e Ch 25] 
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