## Primary Pathophysiology of Atopic Dermatitis **Key Point:** Filaggrin (filament-aggregating protein) is essential for skin barrier integrity. Loss-of-function mutations in the FLG gene are the most significant genetic risk factor for atopic dermatitis. ### Mechanism of Filaggrin Defect Filaggrin is a key structural protein that: - Aggregates keratin filaments in the stratum corneum - Maintains skin hydration and barrier function - Prevents transepidermal water loss (TEWL) - Reduces penetration of allergens and pathogens When filaggrin is deficient or dysfunctional: 1. Impaired stratum corneum structure 2. Increased TEWL 3. Enhanced allergen and irritant penetration 4. Activation of innate and adaptive immune responses 5. Secondary IgE elevation and eosinophilic inflammation **High-Yield:** FLG mutations account for ~30% of atopic dermatitis cases in European populations and are the strongest genetic risk factor identified to date. ### Secondary Immune Features While IgE elevation and Th2 cytokine production (IL-4, IL-13) occur in atopic dermatitis, these are **secondary consequences** of the barrier defect, not the primary pathophysiologic driver. **Clinical Pearl:** Patients with FLG mutations have: - Earlier disease onset - More severe phenotype - Higher risk of associated atopy (asthma, allergic rhinitis) - Increased susceptibility to skin infections (especially *Staphylococcus aureus*) 
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