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.
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: Michael D Howell; Natalija Novak; Thomas Bieber; Saveria Pastore; Giampiero Girolomoni; Mark Boguniewicz; Joanne Streib; Cathy Wong; Richard L Gallo; Donald Y M Leung Journal: J Invest Dermatol Date: 2005-10 Impact factor: 8.551
Authors: Michael D Howell; Heather R Fairchild; Byung Eui Kim; Lianghua Bin; Mark Boguniewicz; Jasmina S Redzic; Kirk C Hansen; Donald Y M Leung Journal: J Invest Dermatol Date: 2008-04-03 Impact factor: 8.551
Authors: Emma Guttman-Yassky; Yulia Vugmeyster; Michelle A Lowes; Francesca Chamian; Toyoko Kikuchi; Mark Kagen; Patricia Gilleaudeau; Edmund Lee; Brisdell Hunte; Kathy Howell; Wolfgang Dummer; Sarah C Bodary; James G Krueger Journal: J Invest Dermatol Date: 2008-01-31 Impact factor: 8.551
Authors: Julia K Gittler; Avner Shemer; Mayte Suárez-Fariñas; Judilyn Fuentes-Duculan; Kara J Gulewicz; Claire Q F Wang; Hiroshi Mitsui; Irma Cardinale; Cristina de Guzman Strong; James G Krueger; Emma Guttman-Yassky Journal: J Allergy Clin Immunol Date: 2012-08-27 Impact factor: 10.793
Authors: Mark G Lebwohl; James Q Del Rosso; William Abramovits; Brian Berman; David E Cohen; Emma Guttman; Anthony J Mancini; Lawrence A Schachner Journal: J Clin Aesthet Dermatol Date: 2013-07
Authors: Hitokazu Esaki; David A Ewald; Benjamin Ungar; Mariya Rozenblit; Xiuzhong Zheng; Hui Xu; Yeriel D Estrada; Xiangyu Peng; Hiroshi Mitsui; Thomas Litman; Mayte Suárez-Fariñas; James G Krueger; Emma Guttman-Yassky Journal: J Allergy Clin Immunol Date: 2015-01 Impact factor: 10.793