Ichthyosis molecular fingerprinting shows profound Th17-skewing and a unique barrier genomic signature

Publication date: Available online 24 May 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Kunal Malik, Helen He, Thy Nhat Huynh, Gary Tran, Kelly Mueller, Kristina Doytcheva, Yael Renert-Yuval, Tali Czarnowicki, Shai Magidi, Margaret Chu, Yeriel D. Estrada, Huei-Chi Wen, Xiangyu Peng, Hui Xu, Xiuzhong Zheng, James G. Krueger, Amy S. Paller, Emma Guttman-Yassky
BackgroundIchthyoses 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.ObjectiveTo profile the molecular fingerprint of the most common orphan ichthyoses.MethodsGene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma/CIE, n=9; lamellar ichthyosis/LI, n=8; epidermolytic ichthyosis/EI, n=8; and Netherton syndrome/NS, n=4), as well as age-matched healthy controls (n=14), psoriasis (n=30), and atopic dermatitis/AD (n=16) patients.ResultsUsing fold-change>2 and false-discovery-rate<0.05 criteria, 132 differentially expressed genes/DEGs were commonly shared among all ichthyoses, including many IL-17 and TNFα co-regulated genes, considered hallmarks of psoriasis (DEFB4A, KYNU, VNN3). While striking up-regulation of Th17 pathway genes (IL17F, IL36B/G), resembling psoriasis, was common to all ichthyoses in a severity-related manner, NS showed greatest T-cell activation (ICOS) and a broader immune phenotype with Th1/IFNγ, OASL, and Th2/IL4R/IL5 skewing, albeit less than AD (all P<0.05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of AD (LOR, FLG, CLDN 1), but showed characteristic alterations in lipid metabolism genes (ELOVL3, GAL), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except EI, suggesting phenotypic variations. TEWL, a functional barrier measure, significantly correlated with IL-17-regulated genes (IL-17F, IL-36α/IL-36β/IL-36γ).ConclusionSimilar to AD and psoriasis where 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 ichthyosis patients, similar to psoriasis.

Teaser

DNA alterations are progressively understood in ichthyoses. However, comprehensive phenotyping could direct much-needed targeted therapeutics. Our molecular fingerprinting highlights IL-17/IL-36 responses and unique associated barrier alterations in ichthyoses, advocating for IL-17/IL-36-directed antagonism for these patients.


https://ift.tt/2krieLz