title: Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis.
abstract: BACKGROUND
  Atopic dermatitis (AD) is classified as extrinsic and intrinsic, representing approximately 80% and 20% of patients with the disease, respectively. Although sharing a similar clinical phenotype, only extrinsic AD is characterized by high serum IgE levels. Because most patients with AD exhibit high IgE levels, an "allergic"/IgE-mediated disease pathogenesis was hypothesized. However, current models associate AD with T-cell activation, particularly TH2/TH22 polarization, and epidermal barrier defects.
  
  
  OBJECTIVE
  We sought to define whether both variants share a common pathogenesis.
  
  
  METHODS
  We stratified 51 patients with severe AD into extrinsic AD (n = 42) and intrinsic AD (n = 9) groups (with similar mean disease activity/SCORAD scores) and analyzed the molecular and cellular skin pathology of lesional and nonlesional intrinsic AD and extrinsic AD by using gene expression (real-time PCR) and immunohistochemistry.
  
  
  RESULTS
  A significant correlation between IgE levels and SCORAD scores (r = 0.76, P < 10(-5)) was found only in patients with extrinsic AD. Marked infiltrates of T cells and dendritic cells and corresponding epidermal alterations (keratin 16, Mki67, and S100A7/A8/A9) defined lesional skin of patients with both variants. However, higher activation of all inflammatory axes (including TH2) was detected in patients with intrinsic AD, particularly TH17 and TH22 cytokines. Positive correlations between TH17-related molecules and SCORAD scores were only found in patients with intrinsic AD, whereas only patients with extrinsic AD showed positive correlations between SCORAD scores and TH2 cytokine (IL-4 and IL-5) levels and negative correlations with differentiation products (loricrin and periplakin).
  
  
  CONCLUSIONS
  Although differences in TH17 and TH22 activation exist between patients with intrinsic AD and those with extrinsic AD, we identified common disease-defining features of T-cell activation, production of polarized cytokines, and keratinocyte responses to immune products. Our data indicate that a TH2 bias is not the sole cause of high IgE levels in patients with extrinsic AD, with important implications for similar therapeutic interventions.
authors.affiliation: Laboratory for Investigative Dermatology, Rockefeller University, New York, NY, USA.
authors.forename: Mayte
authors.initials: M
authors.lastname: Suárez-Fariñas
authors.forename: Nikhil
authors.initials: N
authors.lastname: Dhingra
authors.forename: Julia
authors.initials: J
authors.lastname: Gittler
authors.forename: Avner
authors.initials: A
authors.lastname: Shemer
authors.forename: Irma
authors.initials: I
authors.lastname: Cardinale
authors.forename: Cristina
authors.initials: C
authors.lastname: de Guzman Strong
authors.forename: James G
authors.initials: JG
authors.lastname: Krueger
authors.forename: Emma
authors.initials: E
authors.lastname: Guttman-Yassky
mesh_terms: D000328:Adult; D000368:Aged; D016207:Cytokines / Q000378:metabolism; D003876:Dermatitis, Atopic / Q000276:immunology* / Q000473:pathology*; D005260:Female; D000091344:Filaggrin Proteins; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007249:Inflammation / Q000473:pathology; D015603:Keratinocytes / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D012867:Skin / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D007073:Immunoglobulin E
keywords: AD; Atopic dermatitis; DC; Dendritic cell; FLG; FOXP3; Filaggrin; Forkhead box protein 3; IHC; IgE; Immunohistochemistry; OX40 ligand; OX40L; RT-PCR; Real-time PCR; S100 proteins; TNF ligand superfamily 10; TRAIL; T cell; eczema; extrinsic; human skin; intrinsic; keratinocytes