☆ 4.7 Article

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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY (2017)

期刊

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷 139, 期 1, 页码 152-165

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MOSBY-ELSEVIER

DOI: 10.1016/j.jaci.2016.07.019

关键词

Epidermis; ichthyosis; inflammation; autosomal recessive congenital ichthyosis; congenital ichthyosiform erythroderma; lamellar ichthyosis; Netherton syndrome; epidermolytic ichthyosis; skin; IL-17; TNF-alpha

类别

Allergy Immunology

资金

Foglia Family Foundation Endowment
National Psoriasis Foundation
NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [P30AR057216] Funding Source: NIH RePORTER

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摘要

Background: The ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-basedtherapy is largely lacking because the underlying molecular basis is poorly understood. Objective: We sought to characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. Methods: We analyzed biopsy specimens from 21 genotyped patients with ichthyosis (congenital ichthyosiform erythroderma, n = 6; lamellar ichthyosis, n = 7; epidermolytic ichthyosis, n = 5; and Netherton syndrome, n = 3) using immunohistochemistry and RT-PCR and compared them with specimens from healthy control subjects, patients with atopic dermatitis (AD), and patients with psoriasis. Clinical measures included the Ichthyosis Area Severity Index (IASI), which integrates erythema (IASI-E) and scaling (IASI-S); transepidermal water loss; and pruritus. Results: Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and keratin 16 expression) and Tcell and dendritic cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1 beta), and some TH1/interferon (IFN-gamma) markers in patients with ichthyosis were comparable with those in patients with psoriasis or AD. TNF-alpha levels in patients with ichthyosis were increased only in those with Netherton syndrome but were much lower than in patientswith psoriasis and those withAD. Expression of TH2 cytokines (IL-13 and IL-31) was similar to that seen in control subjects. The striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNF-alpha (IL-17A/C, IL-19, CXCL1, PI3, CCL20, and IL36G; P <.05) in patients with ichthyosis was similar to that seen in patients with psoriasis. IASI and IASI-E scores strongly correlated with IL-17A (r = 0.74, P <.001) and IL-17/TNF-synergistic/additive gene expression. These markers also significantly correlated with transepidermal water loss, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. Conclusion: Our data associate a shared TH17/IL-23 immune fingerprint with the major orphan forms of ichthyosis and raise the possibility of IL-17-targeting strategies.

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Molecular epidemiology of non-syndromic autosomal recessive congenital ichthyosis in a Middle-Eastern population

Janan Mohamad, Liat Samuelov, Natalia Malchin, Tom Rabinowitz, Sari Assaf, Liron Malki, Kiril Malovitski, Shirli Israeli, Meital Grafi-Cohen, Ora Bitterman-Deutsch, Vered Molho-Pessach, Eran Cohen-Barak, Gideon Bach, Ben Zion Garty, Reuven Bergman, Avikam Harel, Arti Nanda, Giles G. Lestringant, John McGrath, Stavit Shalev, Noam Shomron, Jacob Mashiah, Marina Eskin-Schwartz, Eli Sprecher, Ofer Sarig

Summary: Autosomal recessive congenital ichthyosis (ARCI) is a rare skin disorder characterized by pathogenic variants in multiple ARCI-associated genes. Our study in Middle Eastern population revealed a higher prevalence of CYP4F22 and ABCA12 pathogenic variants, and lower prevalence of TGM1 and NIPAL4 variants.

EXPERIMENTAL DERMATOLOGY (2021)