An IL-17-dominant immune profile is shared across the major orphan forms of ichthyosis

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Amy S. Paller, Yael Renert-Yuval, Maria Suprun, Hitokazu Esaki, Margeaux Oliva, Thy Nhat Huynh, Benjamin Ungar, Norma Kunjravia, Rivka Friedland, Xiangyu Peng, Xiuzhong Zheng, Yeriel D. Estrada, James G. Krueger, Keith A. Choate, Mayte Suárez-Fariñas, Emma Guttman-Yassky
BackgroundThe ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking, since the underlying molecular basis is poorly understood.ObjectiveTo characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics.MethodsWe analyzed biopsies from 21 genotyped ichthyosis patients (congenital ichthyosiform erythroderma (n=6), lamellar ichthyosis (n=7), epidermolytic ichthyosis, (n=5) and Netherton syndrome (n=3)) by immunohistochemistry and RT-PCR and compared them with healthy controls, and atopic dermatitis (AD) and psoriasis patients. Clinical measures included an ichthyosis severity score (IASI) which integrates erythema (IASI-E) and scaling (IASI-S), transepidermal water loss (TEWL), and pruritus.ResultsIchthyosis samples showed increased epidermal hyperplasia (increased thickness and K16 expression) and T-cell and dendritic-cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1β), and some Th1/IFN (IFNγ) markers in ichthyosis were comparable to psoriasis or AD. TNFα levels in ichthyosis were elevated only in Netherton syndrome, but were much lower than in psoriasis and AD. Expression of Th2 cytokines (IL-13, IL-31) was similar to controls. The striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNFα (IL-17A/C, IL-19, CXCL1, PI3, CCL20, IL36G; p<0.05) in ichthyosis was similar to psoriasis. IASI and IASI-E strongly correlated with IL-17A (r=0.74, p<0.001) and IL-17/TNF-synergistic/additive genes. These markers also significantly correlated with TEWL, suggesting a link between the barrier defect and inflammation in ichthyosis.ConclusionOur data associates a shared Th17/IL-23 immune fingerprint with the major orphan forms of ichthyosis and raises the possibility of IL-17-targeting strategies.Clinical ImplicationsThe link between increased expression of Th17 pathway cytokines and clinical disease severity raises the possibility of a new therapeutic paradigm of targeted IL-17/IL-23 intervention for ichthyosis patients.

Teaser

CIE, LI, EI and NS subtypes of ichthyosis are Th17-skewed. IL-17/TNF-synergistic/additive genes are predominantly increased and significantly correlated with disease severity scores and functional barrier abnormalities (TEWL).


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