Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 132, Issue 2, Pages 361-370Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2013.04.046
Keywords
Atopic dermatitis; eczema; extrinsic; intrinsic; IgE; T cell; human skin; keratinocytes; S100 proteins
Categories
Funding
- Rockefeller University Seminar
- Rockefeller University
- Amgen
- Centocor
- Lilly
- Merck
- Pfizer
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Background: Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an allergic/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly TH2/TH22 polarization, and epidermal barrier defects. Objective: We sought to define whether both variants share a common pathogenesis. Methods: We stratified 51 patients with severe AD into extrinsic AD (n 5 42) and intrinsic AD (n 5 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry. Results: A significant correlation between IgE levels and SCORAD scores (r = 0.76, P < 10(-5)) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including T(H)2) was detected in patients with intrinsic AD, particularly T(H)17 and T(H)22 cytokines. Positive correlations between T(H)17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and (T)H2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin). Conclusions: Although differences in T(H)17 and T(H)22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a T(H)2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions.
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