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Journal of Allergy and Clinical Immunology

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Tight junction defects in patients with atopic dermatitis - 10/08/11

Doi : 10.1016/j.jaci.2010.10.018 
Anna De Benedetto, MD a, Nicholas M. Rafaels, MS b, Laura Y. McGirt, MD c, Andrei I. Ivanov, PhD d, Steve N. Georas, MD e, Chris Cheadle, PhD b, Alan E. Berger, PhD b, Kunzhong Zhang, PhD f, Sadasivan Vidyasagar, MD, PhD f, Takeshi Yoshida, PhD a, Mark Boguniewicz, MD g, Tissa Hata, MD h, Lynda C. Schneider, MD i, Jon M. Hanifin, MD l, Richard L. Gallo, MD h, Natalija Novak, MD m, Stephan Weidinger, MD n, Terri H. Beaty, PhD o, Donald Y.M. Leung, MD, PhD g, Kathleen C. Barnes, PhD b, Lisa A. Beck, MD a, ⁎
a Department of Dermatology, University of Rochester Medical Center, Rochester, NY 
d Department of Medicine, University of Rochester Medical Center, Rochester, NY 
e Division of Pulmonary & Critical Care Medicine, University of Rochester Medical Center, Rochester, NY 
f Radiation Oncology, University of Rochester Medical Center, Rochester, NY 
b Lowe Family Genomics Core, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md 
c Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, Md 
g Department of Pediatrics, National Jewish Health, Denver, Colo 
h Division of Dermatology, University of California San Diego, San Diego, Calif 
i Division of Immunology, Children’s Hospital Boston, Boston, Mass 
l Department of Dermatology, Oregon Health & Science University, Portland, Ore 
m Department of Dermatology and Allergy, University of Bonn, Bonn, Germany 
n Department of Dermatology and Allergy, Technische Universität München, Munich, Germany 
o Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md 

Reprint requests: Lisa A. Beck, MD, University of Rochester, Department of Dermatology, 601 Elmwood Ave, Box 697, Rochester, NY 14642.

Abstract

Background

Atopic dermatitis (AD) is characterized by dry skin and a hyperactive immune response to allergens, 2 cardinal features that are caused in part by epidermal barrier defects. Tight junctions (TJs) reside immediately below the stratum corneum and regulate the selective permeability of the paracellular pathway.

Objective

We evaluated the expression/function of the TJ protein claudin-1 in epithelium from AD and nonatopic subjects and screened 2 American populations for single nucleotide polymorphisms in the claudin-1 gene (CLDN1).

Methods

Expression profiles of nonlesional epithelium from patients with extrinsic AD, nonatopic subjects, and patients with psoriasis were generated using Illumina’s BeadChips. Dysregulated intercellular proteins were validated by means of tissue staining and quantitative PCR. Bioelectric properties of epithelium were measured in Ussing chambers. Functional relevance of claudin-1 was assessed by using a knockdown approach in primary human keratinocytes. Twenty-seven haplotype-tagging SNPs in CLDN1 were screened in 2 independent populations with AD.

Results

We observed strikingly reduced expression of the TJ proteins claudin-1 and claudin-23 only in patients with AD, which were validated at the mRNA and protein levels. Claudin-1 expression inversely correlated with TH2 biomarkers. We observed a remarkable impairment of the bioelectric barrier function in AD epidermis. In vitro we confirmed that silencing claudin-1 expression in human keratinocytes diminishes TJ function while enhancing keratinocyte proliferation. Finally, CLDN1 haplotype-tagging SNPs revealed associations with AD in 2 North American populations.

Conclusion

Collectively, these data suggest that an impairment in tight junctions contributes to the barrier dysfunction and immune dysregulation observed in AD subjects and that this may be mediated in part by reductions in claudin-1.

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Key words : Atopic dermatitis, claudin-1, tight junctions

Abbreviations used : AA, AD, ADVN, CLDN1, EA, EASI, FITC, FLG, GAPDH, LD, OPA, OR, PCl/PNa, PHK, qPCR, SNP, SC, siRNA, TEER, TEWL, TJ, ZO


Plan


 Supported by the Atopic Dermatitis and Vaccinia Network NIH/NIAID (contract N01 AI40029 and N01 AI40033), the National Eczema Association (A.D., L.A.B.), and the Mary Beryl Patch Turnbull Scholar Program (K.C.B.).
 Disclosure of potential conflict of interest: A. De Benedetto has received research support from the National Eczema Association and the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID). N. M. Rafaels has received research support from the NIH/NIAID. C. Cheadle has received research support from the NIH/NIAID. T. Yoshida has received research support from the NIH/NIAID. M. Boguniewicz has received research support from the NIH/NIAID. J. M. Hata has received research support from the NIH/NIAID. L. C. Schneider has received research support from Astellas and Novartis. J. M. Hanifin has received consulting fees from Johnson & Johnson and Otsuka Pharmaceutical Co and has received research support from Astellas Pharma US, Basilea, Novartis, Shionogi USA, the NIH/NIAID, and Taisho. R. L. Gallo has received research support from the NIH/NIAID. N. Novak has received research support from the German Research Council and the NIH/NIAID. T. H. Beaty has received research support from the NIH/NIAID. D. Y. M. Leung has received research support from the NIH/NIAID. K. C. Barnes has received research support from the NIH and Sanofi-Aventis. L. A. Beck has consulted for Regeneron, has received research support from the NIH/NIAID and the National Eczema Association. The rest of the authors have declared that they have no conflict of interest.


© 2010  American Academy of Allergy, Asthma & Immunology. Publié par Elsevier Masson SAS. Tous droits réservés.
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