Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis - 12/08/11

Doi : 10.1016/j.jaci.2009.09.031

Emma Guttman-Yassky, MD, MSc ^a,^b,^{^{These authors contributed equally to this work.}}, Mayte Suárez-Fariñas, PhD ^a,^{^{These authors contributed equally to this work.}}, Andrea Chiricozzi, MD ^a,^c, Kristine E. Nograles, MD ^a, Avner Shemer, MD ^d, Judilyn Fuentes-Duculan, MD ^a, Irma Cardinale, MSc ^a, Peng Lin, BSc ^e, Reuven Bergman, MD ^f, Anne M. Bowcock, PhD ^e, James G. Krueger, MD, PhD ^a,^⁎
^a Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
^b Department of Dermatology, Weill-Cornell Medical College, Cornell University, New York, NY
^c Department of Dermatology, University of Rome “Tor Vergata”, Rome, Italy
^d Tel-Hashomer Hospital and Tel-Aviv University, Tel-Aviv, Israel
^e Department of Genetics, Washington University School of Medicine, St Louis, Mo
^f Rambam Medical Center and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

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

Abstract

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 (T_H1, T_H2, T_H17) 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.

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

Abbreviations used : AD, CDSN, CE, EDC, ES, FC, FDR, FLG, GSEA, IVL, LCE, LOR, SC, SPRR

Plan

Immunofluorescence localization of neutral lipids

Sample preparation for real-time PCR and gene chip analysis

Real-time PCR analysis

Statistical analyses

Results

Disease-defining differences in gene expression

Deeper study of epidermal differentiation

New disease classification based on expression of terminal differentiation genes

Compromised integrity of epidermal barrier in AD

Major differences in epidermal maturation and differentiation between AD and psoriasis

Discussion

	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.