Pathogenesis
* Genetic predisposition (more than 80 genes in AD) & environmental factors influence 3 major categories of AD pathogenesis
1) Epidermal barrier dysfunction
* Portal for irritants, allergens & microbes = activation of immune responses
- Loss of function filaggrin gene mutation ↓ filaggrin protein → ↓ epidermis hydration, ↓ acid mantle formation, ↓ lipid processing & abnormal corneocyte formation
- ↑ protease (KLK5 & KLK7) & ↓ protease inhibitor:
- Proteolysis due to protease inhibitor deficiency, ↑ skin pH & exogenous proteases (allergens, Staph aureus, Malassezia) → ↑ desmosome degradation → abnormal corneocyte adhesion
- Abnormal lipids:
- 2nd to filaggrin-deficiency → abnormal lamellar body & lipid processing → ↑ permeability
2) Immune dysregulation
* 3 main cells: keratinocytes, T-cells & APC
A- Adaptive immune dysregulation
- Acute lesions:
- Th2 response (IL-4, IL-5, IL-13, IL-31) with keratinocyte cytokines (TSLP, IL-1, IL-25, IL-33) contributing to Th2, activation of eosinophils & mast cells, production of IgE, and a Th17 response
- Chronic lesions:
- Th1, Th17 & Th22 responses
B- Innate immune dysregulation
- Innate lymphoid cell group (signal Th2 inflammation via interactions with other immune cells)
3) Cutaneous microbiome
90% AD colonized with S.aureus due to abnormal acid mantle, altered cytokines & ↓ antimicrobial peptides (cathelicidins, defensins)
- With AD flare → ↑ burden of S.aureus (from 35% to 90%) composing the microbiome
- Skin exposed to S.aureus superantigen → IL-31 (Th2 cytokine & pruritus)
- S. aureus δ-toxin → mast cell degranulation & contributes to Th2 activation
- S. aureus α-toxin → filaggrin deficiency ↑ risk of cytotoxicity in keratinocytes