Atopic dermatitis pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shalinder Singh, M.B.B.S.[2]

Overview

Atopic dermatitis is a chronic inflammatory skin disorder with an immunologic background and occurs in patients with a personal or family history of atopy (i.e. asthma or allergic rhinitis). It is caused by either a skin barrier dysfunction or immune dysregulation of the adaptive and innate immune response leading to an enhanced IgE-mediated, systemic Th2 response. The skin barrier is invaded by exogenous substances, including allergens, irritants and microbes; and the tightly packed structure of the stratum corneum is further compromised. Systemically, a dysfunctional innate and adaptive immune response causes further damage to the epidermis.

Pathophysiology

Physiology

The normal physiology of atopic dermatitis can be understood as follows:

Epidermal barrier function:

Immune response:

Pathogenesis

It is understood that atopic dermatitis is the result of either skin barrier dysfunction or immune dysregulation.[17]

Epidermal barrier dysfunction (outside-in hypothesis):[18]

Immune dysregulation (inside-out’ hypothesis):[29]

  • Innate immune response:
  • Adaptive immune response:
    • Increased allergen penetration through the damaged epidermis leading to a Th2-type milieu is thought to explain the critical link between the barrier defect of atopic dermatitis patients with FLG mutations and Th2 polarization.[33]
    • Enhanced expression of Th2, Th17, and Th22 cytokines, characterize the acute initiation of atopic dermatitis lesions.[34][3]
    • Epidermal barrier function is regulated through Th2 and Th22 cytokines (IL-4, IL-13, IL-31, and IL-22) by:[35][3]
      • Stimulating epidermal hyperplasia
      • Inhibiting the expression of terminal keratinocyte differentiation genes (eg, FLG, loricrin, involucrin)
      • Suppressing the production of AMPs
  • Thymic stromal lymphopoietin:
    • Defective skin barrier and enhanced epidermal protease activity, which is reported in atopic dermatitis, promote TSLP production and Th2 response, leading to atopic dermatitis-like inflammation.[36]
    • TSLP polymorphisms have been linked to the severity of atopic dermatitis.
    • TSLP genetic variants are associated with atopic dermatitis and eczema herpeticum.[37]
    • In patients with defective skin barrier due to FLG mutations, TSLP genetic variants are associated with reduced probability of having persistent atopic dermatitis.[38]

Genetics

Recent studies have established a strong genetic association of atopic dermatitis. Twin studies have indicated high heritability of atopic dermatitis with a concordance rate of 72–86 % for monozygotic twins compared with 21–23 % for dizygotic twins.[39]

Genes involved in the pathogenesis of atopic dermatitis include:[40]

Genes involved in the pathogenesis of atopic dermatitis
Filaggrin Gene mutation
SPINK5 and LEKTI gene
MHC (or HLA) genes
Innate Immune system genes:
Adaptive immune system genes Cytokines and related genes:
Chemokines and related genes:
Drug-metabolizing genes
Other genes
Adapted from Molecular Genetic of Atopic dermatitis: An Update[47]

Associated Conditions

Conditions associated with atopic dermatitis:

Gross Pathology

On gross pathology, characteristic findings of atopic dermatitis include:[48]

  • Acute atopic dermatitis:
  • Chronic atopic dermatitis:
    • Lichenified plaques
    • Prominent skin markings

Microscopic Pathology

On microscopic histopathological analysis, characteristic findings of atopic dermatitis include:[49]

  • Acute vesicular lesions:
    • Epidermal psoriasiform hyperplasia
    • Marked intercellular edema with spongiotic vesiculation
    • Marked perivenular infiltrate
    • Epidermal infiltrate, consisting predominately of a lymphohistiocytic infiltrate in the dermis
  • Chronic lichenified plaque:

References

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