The Journal of Allergy and Clinical Immunology
Volume 124, Issue 6 , Pages 1235-1244.e58, December 2009

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

  • Emma Guttman-Yassky, MD, MSc

      Affiliations

    • Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
    • Department of Dermatology, Weill-Cornell Medical College, Cornell University, New York, NY
    • These authors contributed equally to this work.
    • ,
  • Mayte Suárez-Fariñas, PhD

      Affiliations

    • Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
    • These authors contributed equally to this work.
    • ,
  • Andrea Chiricozzi, MD

      Affiliations

    • Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
    • Department of Dermatology, University of Rome “Tor Vergata”, Rome, Italy
    • ,
  • Kristine E. Nograles, MD

      Affiliations

    • Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
    • ,
  • Avner Shemer, MD

      Affiliations

    • Tel-Hashomer Hospital and Tel-Aviv University, Tel-Aviv, Israel
    • ,
  • Judilyn Fuentes-Duculan, MD

      Affiliations

    • Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
    • ,
  • Irma Cardinale, MSc

      Affiliations

    • Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
    • ,
  • Peng Lin, BSc

      Affiliations

    • Department of Genetics, Washington University School of Medicine, St Louis, Mo
    • ,
  • Reuven Bergman, MD

      Affiliations

    • Rambam Medical Center and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
    • ,
  • Anne M. Bowcock, PhD

      Affiliations

    • Department of Genetics, Washington University School of Medicine, St Louis, Mo
    • ,
  • James G. Krueger, MD, PhD

      Affiliations

    • Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
    • Corresponding Author InformationReprint requests: James G. Krueger, MD, PhD, Laboratory for Investigative Dermatology, Rockefeller University, 1230 York Avenue, New York, NY 10065.

Received 4 August 2009; received in revised form 15 September 2009; accepted 17 September 2009.

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 (TH1, TH2, TH17) 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.

Key words: Atopic dermatitis, psoriasis, cornified envelope, terminal differentiation, altered barrier

Abbreviations used: AD, Atopic dermatitis, CDSN, Corneodesmosin, CE, Cornified envelope, EDC, Epidermal differentiation complex, ES, Enrichment score, FC, Fold change, FDR, Fold discovery rate, FLG, Filaggrin, GSEA, Gene Set Enrichment Analysis, IVL, Involucrin, LCE, Late cornified envelope, LOR, Loricrin, SC, Stratum corneum, SPRR, Small proline rich protein

 

 Supported by grant number 5UL1RR024143-02 from the National Center for Research Resources, a component of the National Institutes of Health, and the National Institutes of Health Roadmap for Medical Research.

 Disclosure of potential conflict of interest: J. G. Krueger has received research support from Centocor, Amgen, and Wyeth. The rest of the authors have declared that they have no conflict of interest.

PII: S0091-6749(09)01432-8

doi:10.1016/j.jaci.2009.09.031

The Journal of Allergy and Clinical Immunology
Volume 124, Issue 6 , Pages 1235-1244.e58, December 2009

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