Tight junction defects in patients with atopic dermatitis

Anna De Benedetto, Nicholas M. Rafaels, Laura Y. McGirt, Andrei I. Ivanov, Steve N. Georas, Chris Cheadle, Alan E. Berger, Kunzhong Zhang, Sadasivan Vidyasagar, Takeshi Yoshida, Mark Boguniewicz, Tissa Hata, Lynda C. Schneider, Jon Hanifin, Richard L. Gallo, Natalija Novak, Stephan Weidinger, Terri H. Beaty, Donald Y M Leung, Kathleen C. BarnesLisa A. Beck

Research output: Contribution to journalArticle

327 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)773-786
Number of pages14
JournalJournal of Allergy and Clinical Immunology
Volume127
Issue number3
DOIs
StatePublished - Mar 2011

Fingerprint

Claudin-1
Tight Junctions
Atopic Dermatitis
Zonula Occludens-1 Protein
Keratinocytes
Single Nucleotide Polymorphism
Epithelium
Haplotypes
Population
Genes
Psoriasis
Epidermis
Allergens
Cornea
Permeability
Proteins
Biomarkers
Staining and Labeling

Keywords

  • Atopic dermatitis
  • claudin-1
  • tight junctions

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

De Benedetto, A., Rafaels, N. M., McGirt, L. Y., Ivanov, A. I., Georas, S. N., Cheadle, C., ... Beck, L. A. (2011). Tight junction defects in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology, 127(3), 773-786. https://doi.org/10.1016/j.jaci.2010.10.018

Tight junction defects in patients with atopic dermatitis. / De Benedetto, Anna; Rafaels, Nicholas M.; McGirt, Laura Y.; Ivanov, Andrei I.; Georas, Steve N.; Cheadle, Chris; Berger, Alan E.; Zhang, Kunzhong; Vidyasagar, Sadasivan; Yoshida, Takeshi; Boguniewicz, Mark; Hata, Tissa; Schneider, Lynda C.; Hanifin, Jon; Gallo, Richard L.; Novak, Natalija; Weidinger, Stephan; Beaty, Terri H.; Leung, Donald Y M; Barnes, Kathleen C.; Beck, Lisa A.

In: Journal of Allergy and Clinical Immunology, Vol. 127, No. 3, 03.2011, p. 773-786.

Research output: Contribution to journalArticle

De Benedetto, A, Rafaels, NM, McGirt, LY, Ivanov, AI, Georas, SN, Cheadle, C, Berger, AE, Zhang, K, Vidyasagar, S, Yoshida, T, Boguniewicz, M, Hata, T, Schneider, LC, Hanifin, J, Gallo, RL, Novak, N, Weidinger, S, Beaty, TH, Leung, DYM, Barnes, KC & Beck, LA 2011, 'Tight junction defects in patients with atopic dermatitis', Journal of Allergy and Clinical Immunology, vol. 127, no. 3, pp. 773-786. https://doi.org/10.1016/j.jaci.2010.10.018
De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C et al. Tight junction defects in patients with atopic dermatitis. Journal of Allergy and Clinical Immunology. 2011 Mar;127(3):773-786. https://doi.org/10.1016/j.jaci.2010.10.018
De Benedetto, Anna ; Rafaels, Nicholas M. ; McGirt, Laura Y. ; Ivanov, Andrei I. ; Georas, Steve N. ; Cheadle, Chris ; Berger, Alan E. ; Zhang, Kunzhong ; Vidyasagar, Sadasivan ; Yoshida, Takeshi ; Boguniewicz, Mark ; Hata, Tissa ; Schneider, Lynda C. ; Hanifin, Jon ; Gallo, Richard L. ; Novak, Natalija ; Weidinger, Stephan ; Beaty, Terri H. ; Leung, Donald Y M ; Barnes, Kathleen C. ; Beck, Lisa A. / Tight junction defects in patients with atopic dermatitis. In: Journal of Allergy and Clinical Immunology. 2011 ; Vol. 127, No. 3. pp. 773-786.
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AU - Rafaels, Nicholas M.

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AU - Ivanov, Andrei I.

AU - Georas, Steve N.

AU - Cheadle, Chris

AU - Berger, Alan E.

AU - Zhang, Kunzhong

AU - Vidyasagar, Sadasivan

AU - Yoshida, Takeshi

AU - Boguniewicz, Mark

AU - Hata, Tissa

AU - Schneider, Lynda C.

AU - Hanifin, Jon

AU - Gallo, Richard L.

AU - Novak, Natalija

AU - Weidinger, Stephan

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