Background Atopic dermatitis (AD) is a common disease, with an increasing prevalence. The primary pathogenesis of the disease is still elusive, resulting in the lack of specific treatments. AD is currently considered a biphasic disease, with Th2 predominating acute disease, and a switch to Th1 characterizing chronic disease. Elucidation of the molecular factors that participate in the onset of new lesions and maintenance of chronic disease is critical for the development of targeted therapeutics. Objectives We sought to characterize the mechanisms underlying onset and maintenance of AD. Methods We investigated intrapersonal sets of transcriptomes from non-lesional, acute and chronic lesions of ten AD patients through genomic, molecular and cellular profiling. Results Our study associated the onset of acute lesions with a striking increase in a subset of terminal differentiation proteins, specifically the cytokine-modulated S100A7, S100A8, and S100A9. Acute disease was also associated with significant increases in gene expression levels of major Th22- and Th2- cytokines, and smaller increases in IL-17. A lesser induction of Th1-associated genes was detected in acute disease, although some were significantly up-regulated in chronic disease. Further significant intensification of major Th22 and Th2 cytokines was observed between acute and chronic lesions. Conclusions Our data identified increased S100A7, S100A8 and S100A9 gene expression with AD initiation, and concomitant activation of Th2 and Th22 cytokines. Our findings support a model of progressive activation of Th2 and Th22 immune axes from acute to chronic phases, expanding the prevailing view of pathogenesis, with important therapeutic implications.

Background Atopic dermatitis (AD) is classified as extrinsic (ADe) and intrinsic (ADi), representing approximately 80% and 20% of patients, respectively. While sharing a similar clinical phenotype, only ADe is characterized by high serum IgE. Since most AD patients exhibit high IgE, 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 To define if both variants share a common pathogenesis. Methods We stratified 51 severe AD patients as ADe (42) and ADi (9) (with similar mean disease activity/SCORAD), and analyzed the molecular and cellular skin pathology of lesional and non-lesional ADi and ADe using gene-expression (RT-PCR) and immunohistochemistry. Results A significant correlation between IgE levels and SCORAD (r=0.76, p<10−5) was found only in ADe. Marked infiltrates of T-cells and dendritic cells and corresponding epidermal alterations (K16, Mki67, S100A7/A8/A9) defined lesional skin of both variants. However, higher activation of all inflammatory axes (including Th2) was detected in ADi, particularly Th17 and Th22-cytokines. Positive correlations between Th17-related molecules and SCORAD were only found in ADi, while only ADe showed positive correlations between SCORAD and Th2-cytokines (IL-4, IL-5), and negative correlations with differentiation products (loricrin, periplakin). Conclusions Although differences in Th17 and Th22 activation exist between ADi and ADe, 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 in ADe, with important implications for similar therapeutic interventions. Clinical Implications Both extrinsic and intrinsic AD variants might be treated with T-cell targeted therapeutics or agents that modify keratinocyte responses.

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