Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis

• Published in: Journal of allergy and clinical immunology Vol. 124; no. 6; pp. 1235 - 1244.e58
• Main Authors: Guttman-Yassky, Emma, MD, MSc, Suárez-Fariñas, Mayte, PhD, Chiricozzi, Andrea, MD, Nograles, Kristine E., MD, Shemer, Avner, MD, Fuentes-Duculan, Judilyn, MD, Cardinale, Irma, MSc, Lin, Peng, BSc, Bergman, Reuven, MD, Bowcock, Anne M., PhD, Krueger, James G., MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.12.2009; Elsevier; Elsevier Limited
• Subjects: Adolescent; Adult; Aged; Allergic diseases; Allergy and Immunology; altered barrier; Arrays; Atopic dermatitis; Biological and medical sciences; Circuits; Classification; Compaction; cornified envelope; Cytokines; Dermatitis, Atopic - genetics; Dermatitis, Atopic - pathology; Dermatology; Differentiation; Disease; Down-Regulation; Envelopes; Epidermis - ultrastructure; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Profiling; Genes; Genomic analysis; Helper cells; Humans; Hyperplasia; Immunopathology; Inflammation; Keratinocytes; Lipids; Lymphocytes T; Male; Medical sciences; Microscopy; Microscopy, Electron, Transmission; Middle Aged; mRNA; Mutation; Pathogenesis; Patients; Polarity; Psoriasis; Psoriasis - genetics; Psoriasis - pathology; Psoriasis. Parapsoriasis. Lichen; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Skin; Skin allergic diseases. Stinging insect allergies; Skin diseases; terminal differentiation; Up-Regulation; Young Adult; FLG; EDC; Loricrin; Corneodesmosin; Filaggrin; Late cornified envelope; altered barrier; SC; Fold discovery rate; Atopic dermatitis; FDR; Epidermal differentiation complex; Enrichment score; cornified envelope; terminal differentiation; Fold change; CE; AD; CDSN; Stratum corneum; GSEA; ES; LOR; LCE; Gene Set Enrichment Analysis; psoriasis; Small proline rich protein; Involucrin; SPRR; FC; IVL; Allergy; Immunopathology; Skin disease; Psoriasis; Genomics; Cell differentiation; Atopy; Immunology; Differentiation; Genome
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2009.09.031

Background Psoriasis and atopic dermatitis (AD) are common, complex inflammatory skin diseases. Both diseases display immune infiltrates in lesions and epidermal growth/differentiation alterations associated with a defective skin barrier. An incomplete understanding of differences between these diseases makes it difficult to compare human disease pathology to animal disease models. Objective To characterize differences between these diseases in expression of genes related to epidermal growth/differentiation and inflammatory circuits. Methods We performed genomic profiling of mRNA in chronic psoriasis (n = 15) and AD (n = 18) skin lesions compared with normal human skin (n = 15). Results As expected, clear disease classifications could be constructed on the basis of expected immune polarity (TH 1, TH 2, TH 17) differences. However, even more striking differences were identified in epidermal differentiation programs that could be used for precise disease classifications. Although both psoriasis and AD skin lesions displayed regenerative epidermal hyperplasia, which is a general alteration in epidermal growth, keratinocyte terminal differentiation was differentially polarized. In AD, we found selective defects in expression of multiple genes encoding the cornified envelope, with the largest alteration in loricrin (expressed at 2% of the level of normal skin). At the ultrastructural level, the cornified envelope in AD was broadly defective with highly decreased compaction of corneocytes and reduced intercellular lipids. Hence, the entire keratinocyte terminal differentiation program (cytoplasmic compaction, cornification, and lipid release) is defective in AD, potentially underlying the immune differences. Conclusion Our study shows that although alterations in barrier responses exist in both diseases, epidermal differentiation is differentially polarized, with major implications for primary disease pathogenesis.