title: Tight junction defects in patients with atopic dermatitis.
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 T(H)2 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Dermatology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: De Benedetto
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Rafaels
authors.forename: Laura Y
authors.initials: LY
authors.lastname: McGirt
authors.forename: Andrei I
authors.initials: AI
authors.lastname: Ivanov
authors.forename: Steve N
authors.initials: SN
authors.lastname: Georas
authors.forename: Chris
authors.initials: C
authors.lastname: Cheadle
authors.forename: Alan E
authors.initials: AE
authors.lastname: Berger
authors.forename: Kunzhong
authors.initials: K
authors.lastname: Zhang
authors.forename: Sadasivan
authors.initials: S
authors.lastname: Vidyasagar
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Mark
authors.initials: M
authors.lastname: Boguniewicz
authors.forename: Tissa
authors.initials: T
authors.lastname: Hata
authors.forename: Lynda C
authors.initials: LC
authors.lastname: Schneider
authors.forename: Jon M
authors.initials: JM
authors.lastname: Hanifin
authors.forename: Richard L
authors.initials: RL
authors.lastname: Gallo
authors.forename: Natalija
authors.initials: N
authors.lastname: Novak
authors.forename: Stephan
authors.initials: S
authors.lastname: Weidinger
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.forename: Donald Y M
authors.initials: DY
authors.lastname: Leung
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Barnes
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Beck
mesh_terms: D000328:Adult; D017668:Age of Onset; D002478:Cells, Cultured; D062445:Claudin-1; D003876:Dermatitis, Atopic / Q000453:epidemiology / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D019108:Tight Junctions / Q000276:immunology*
chemical_list: C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins