Abnormal skin barrier in the etiopathogenesis of atopic dermatitis

Abstract

Purpose of review: Many recent studies have revealed the key roles played by Th1/Th2 cell dysregulation, IgE production, mast cell hyperactivity, and dendritic cell signaling in the pathogenesis of atopic dermatitis. Accordingly, current therapy has been largely directed towards ameliorating Th2-mediated inflammation and/or pruritus. We will review here emerging evidence that the inflammation in atopic dermatitis results from inherited and acquired insults to the barrier and the therapeutic implications of this new paradigm.

Recent findings: Recent molecular genetic studies have shown a strong association between mutations in FILAGGRIN and atopic dermatitis, particularly in Northern Europeans. But additional acquired stressors to the barrier are required to initiate inflammation. Sustained hapten access through a defective barrier stimulates a Th1 --> Th2 shift in immunophenotype, which in turn further aggravates the barrier. Secondary Staphylococcus aureus colonization not only amplifies inflammation but also further stresses the barrier in atopic dermatitis.

Summary: These results suggest a new 'outside-to-inside, back to outside' paradigm for the pathogenesis of atopic dermatitis. This new concept is providing impetus for the development of new categories of 'barrier repair' therapy.

Figure 1. Lamellar body secretion codelivers key components of both permeability and antimicrobial barriers

hBD2, human-β-defensin 2; LL-37, cathelicidin. Modified from Elias [11].

Figure 2. Abnormal maturation of stratum corneum lamellar membranes results in decreased ceramides in atopic dermatitis

β-GlcCer’ase, β-glucocerebrosidase; hBD2, human-β-defensin 2; LL-37, cathelicidin; SM’ase, acidic sphingomyelinase; sPLA2, secretory phospholipase A2.

Figure 3. Convergence of inherited and acquired mechanisms activate serine proteases, impacting multiple stratum corneum functions, but by divergent mechanisms

DSG, desmoglein; FLG, filaggrin; LEKTI, lymphoepithelial Kazal-type trypsin inhibitor; PAR2, plasminogen activator receptor, type 2; SPI, serine protease inhibitor. Modified from Elias et al. [41].

Figure 4. Filaggrin proteolytic pathway impacts multiple stratum corneum functions: potential implications for pathogenesis of atopic dermatitis

UCA, urocanic acid. Modified from Elias et al. [41].

Figure 5. Secondary infections further aggravate barrier abnormality in atopic dermatitis

Modified from Elias et al. [41].

Figure 6. ‘Outside-inside’ initial provocation of atopic dermatitis eventually leads to ‘outside-inside-outside’ vicious cycle by multiple mechanisms

Cer, ceramides; FLG, filaggrin; hBD2, human-β-defensin 2; NGF, nerve growth factor. Modified from Elias et al. [41].