Atopic dermatitis and skin disease
Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis

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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 = 42) and intrinsic AD (n = 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 TH2) was detected in patients with intrinsic AD, particularly TH17 and TH22 cytokines. Positive correlations between TH17-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 TH2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin).

Conclusions

Although differences in TH17 and TH22 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 TH2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions.

Section snippets

Patient population

For this study, we grouped several cohorts of patients with AD previously published by our group,7, 19, 20, 21, 22, 23 as well as 3 new patients (n = 51). Chronic lesional (>72 hours duration with lichenification) and nonlesional (≥10 cm from active lesions) AD skin biopsy specimens and serum samples were collected for these studies under institutional review board–approved protocols. Patients were stratified into extrinsic (42 total; 23 male and 19 female patients; age, 15-81 years; mean age,

Results

We studied a group of 51 patients, of whom 42 were classified as having extrinsic AD and 9 as having intrinsic AD. The disease severity was very similar among these groups (mean SCORAD score, 53 and 54 for extrinsic and intrinsic AD, respectively; P = .46; see patient characteristics in Tables I and E1). In the extrinsic AD group a significant correlation was found between increased IgE levels and higher disease activity, as detected by using the SCORAD score (r = 0.76, P = 3.7 × 10−7); such a

Discussion

Although intrinsic AD represents a minority of patients with AD, it is important to clarify whether it represents a single disease spectrum along with extrinsic AD or whether different immune mechanisms underlie the 2 variants.

Numerous studies have tried to define differences and similarities in pathogenic mechanisms of extrinsic and intrinsic AD.2, 4, 14, 16, 28, 29, 30 Such studies have suggested common disease features of epidermal hyperplasia and increased infiltration of T cells and DC

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    J.G.K., M.S.-F., and N.D. were supported by grant no. 5UL1RR024143-02 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. E.G.-Y. was supported by the Dermatology Foundation Physician Scientist Career Development Award.

    Disclosure of potential conflict of interest: C. de Guzman Strong has received payment for lectures from Rockefeller University Seminar. J. G. Krueger has received grants from Rockefeller University, Amgen, Centocor, Lilly, Merck, and Pfizer and has consultant arrangements with Centocor, Lilly, and Pfizer. E. Guttman-Yassky has consultant arrangements with Leo Pharma, Celgene, Stiefel, Bristol Meyers Squibb, GlaxoSmithKline, Regeneron, Jannsen, and Merck and has received payment for lectures from Celgene and Merck. The rest of the authors declare that they have no relevant conflicts of interest.

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