Ichthyosis molecular fingerprinting shows profound T H 17 skewing and a unique barrier genomic signature

Kunal Malik, Helen He, Thy Nhat Huynh, Gary Tran, Kelly Mueller, Kristina Doytcheva, Yael Renert-Yuval, Tali Czarnowicki, Shai Magidi, Margaret Chou, Yeriel D. Estrada, Huei Chi Wen, Xiangyu Peng, Hui Xu, Xiuzhong Zheng, James G. Krueger, Amy S. Paller, Emma Guttman-Yassky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Background: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. Objective: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. Methods: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). Results: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α–coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with T H 1/IFN-γ OASL, and T H 2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P <.05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17–regulated gene expression (IL17F and IL36A/IL36B/IL36G). Conclusion: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36–targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.

Original languageEnglish (US)
Pages (from-to)604-618
Number of pages15
JournalJournal of Allergy and Clinical Immunology
Issue number2
StatePublished - Feb 2019


  • IL-17
  • IL-36
  • Netherton syndrome
  • Psoriasis
  • TNF-α
  • atopic dermatitis
  • congenital ichthyosiform erythroderma
  • epidermal barrier
  • epidermolytic ichthyosis
  • immune
  • inflammation
  • lamellar ichthyosis
  • precision medicine
  • targeted therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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