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Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor.
Godsel, Lisa M; Roth-Carter, Quinn R; Koetsier, Jennifer L; Tsoi, Lam C; Huffine, Amber L; Broussard, Joshua A; Fitz, Gillian N; Lloyd, Sarah M; Kweon, Junghun; Burks, Hope E; Hegazy, Marihan; Amagai, Saki; Harms, Paul W; Xing, Xianying; Kirma, Joseph; Johnson, Jodi L; Urciuoli, Gloria; Doglio, Lynn T; Swindell, William R; Awatramani, Rajeshwar; Sprecher, Eli; Bao, Xiaomin; Cohen-Barak, Eran; Missero, Caterina; Gudjonsson, Johann E; Green, Kathleen J.
Afiliación
  • Godsel LM; Department of Pathology and.
  • Roth-Carter QR; Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • Koetsier JL; Department of Pathology and.
  • Tsoi LC; Department of Pathology and.
  • Huffine AL; Department of Dermatology.
  • Broussard JA; Department of Computational Medicine & Bioinformatics, and.
  • Fitz GN; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
  • Lloyd SM; Department of Pathology and.
  • Kweon J; Department of Pathology and.
  • Burks HE; Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • Hegazy M; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
  • Amagai S; Department of Pathology and.
  • Harms PW; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
  • Xing X; Department of Molecular Biosciences, Northwestern University, Evanston, Illinois, USA.
  • Kirma J; Department of Pathology and.
  • Johnson JL; Department of Pathology and.
  • Urciuoli G; Department of Pathology and.
  • Doglio LT; Department of Dermatology.
  • Swindell WR; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Awatramani R; Department of Dermatology.
  • Sprecher E; Department of Dermatology.
  • Bao X; Department of Pathology and.
  • Cohen-Barak E; Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
  • Missero C; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.
  • Gudjonsson JE; CEINGE Biotecnologie Avanzate, Naples, Italy.
  • Green KJ; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
J Clin Invest ; 132(3)2022 02 01.
Article en En | MEDLINE | ID: mdl-34905516
Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions and multiple allergies, and isolated patient keratinocytes exhibit increased proallergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the 3 tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1-/- skin showed a delay in expression of adhesion/differentiation/keratinization genes at E17.5, a subset of which recovered or increased by E18.5. Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17-skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1-/- mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of 2 Dsg1-deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth, and treatment with a targeted therapy significantly improved skin lesions in patients.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Queratinocitos / Pénfigo / Desmosomas / Desmogleína 1 / Células Th17 Límite: Animals Idioma: En Revista: J Clin Invest Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Queratinocitos / Pénfigo / Desmosomas / Desmogleína 1 / Células Th17 Límite: Animals Idioma: En Revista: J Clin Invest Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos