Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Malik, Kunal^1,2  He, Helen^1,2  Thy Nhat Huynh^4,5  Tran, Gary^4,5  Mueller, Kelly^4,5  Doytcheva, Kristina^4,5  Renert-Yuval, Yael⁶  Czarnowicki, Tali^1,2,3  Magidi, Shai^1,2  Chou, Margaret^1,2  Estrada, Yeriel D.^1,2  Wen, Huei-Chi^1,2  Peng, Xiangyu^1,2  Xu, Hui^1,2  Zheng, Xiuzhong³  Krueger, James G.³  Paller, Amy S.^4,5  Guttman-Yassky, Emma^1,2,3 

[1] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Immunol Inst, New York, NY 10029 USA

[3] Rockefeller Univ, Lab Invest Dermatol, 1230 York Ave, New York, NY 10021 USA

[4] Northwestern Univ, Dept Dermatol, Feinberg Sch Med, Chicago, IL 60611 USA

[5] Northwestern Univ, Dept Pediat, Feinberg Sch Med, Chicago, IL 60611 USA

[6] Hebrew Univ Jerusalem, Dept Dermatol, Med Ctr, Jerusalem, Israel

关键词: Psoriasis;    atopic dermatitis;    immune;    inflammation;    epidermal barrier;    Netherton syndrome;    congenital ichthyosiform erythroderma;    lamellar ichthyosis;    epidermolytic ichthyosis;    IL-17;    TNF-alpha;    IL-36;    targeted therapy;    precision medicine;   

DOI  :  10.1016/j.jaci.2018.03.021

来源: Elsevier

【 摘 要 】

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-alpha-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-gamma, 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.

【 授权许可】

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