Early-onset pediatric atopic dermatitis is T_H2 but also T_H17 polarized in skin - 18/04/17

Doi : 10.1016/j.jaci.2016.07.013

Hitokazu Esaki, MD ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Patrick M. Brunner, MD ^b,^{^{∗
These authors contributed equally to this work.}}, Yael Renert-Yuval, MD ^a, Tali Czarnowicki, MD, MSc ^b, Thy Huynh, MD ^c, Gary Tran, BA ^c, Sarah Lyon, BA ^c, Giselle Rodriguez, MD ^c, Supriya Immaneni, BS ^c, Donald B. Johnson, BS ^d, Bruce Bauer, MD ^d, Judilyn Fuentes-Duculan, MD ^b, Xiuzhong Zheng, MSc ^b, Xiangyu Peng, MSc ^a, Yeriel D. Estrada, BS ^a, Hui Xu, MSc ^a, Christina de Guzman Strong, PhD ^e, Mayte Suárez-Fariñas, PhD ^a,^b,^f,^g, James G. Krueger, MD, PhD ^b, Amy S. Paller, MD ^c,^{^{‡
These authors contributed equally to this work.}}, Emma Guttman-Yassky, MD, PhD ^a,^b,^⁎,^{^{‡
These authors contributed equally to this work.}}
^a Department of Dermatology and Laboratory for Inflammatory Skin Diseases, Icahn School of Medicine at Mount Sinai, New York, NY
^f Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY
^b Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
^c Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Ill
^d NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, Northbrook, Ill
^e Division of Biology and Biomedical Sciences, Washington University, St Louis, Mo
^g Department of Genetics and Genomics Science, Icahn Institute for Genomics and Multiscale Biology, New York, NY

^∗Corresponding author: Emma Guttman-Yassky, MD, PhD, Department of Dermatology, Icahn School of Medicine at Mount Sinai Medical Center, 5 E 98th St, New York, NY 10029.Department of DermatologyIcahn School of Medicine at Mount Sinai Medical Center5 E 98th StNew YorkNY10029

Abstract

Background

Atopic dermatitis (AD) affects 15% to 25% of children and 4% to 7% of adults. Paradigm-shifting discoveries about AD have been based on adult biomarkers, reflecting decades of disease activity, although 85% of cases begin by 5 years. Blood phenotyping shows only T_H2 skewing in patients with early-onset pediatric AD, but alterations in early pediatric skin lesions are unknown, limiting advancement of targeted therapies.

Objective

We sought to characterize the early pediatric AD skin phenotype and its differences from pediatric control subjects and adults with AD.

Methods

Using immunohistochemistry and quantitative real-time PCR, we assessed biopsy specimens from 19 children with AD younger than 5 years within 6 months of disease onset in comparison with adults with AD or psoriasis and pediatric and adult control subjects.

Results

In lesional skin children showed comparable or greater epidermal hyperplasia (thickness and keratin 16) and cellular infiltration (CD3⁺, CD11c⁺, and FcεRI⁺) than adults with AD. Similar to adults, strong activation of the T_H2 (IL-13, IL-31, and CCL17) and T_H22 (IL-22 and S100As) axes and some T_H1 skewing (IFN-γ and CXCL10) were present. Children showed significantly higher induction of T_H17-related cytokines and antimicrobials (IL-17A, IL-19, CCL20, LL37, and peptidase inhibitor 3/elafin), T_H9/IL-9, IL-33, and innate markers (IL-8) than adults (P < .02). Despite the characteristic downregulation in adult patients with AD, filaggrin expression was similar in children with AD and healthy children. Nonlesional skin in pediatric patients with AD showed higher levels of inflammation (particularly IL-17A and the related molecules IL-19 and LL37) and epidermal proliferation (keratin 16 and S100As) markers (P < .001).

Conclusion

The skin phenotype of new-onset pediatric AD is substantially different from that of adult AD. Although excess T_H2 activation characterizes both, T_H9 and T_H17 are highly activated at disease initiation. Increases in IL-19 levels might link T_H2 and T_H17 activation.

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Key words : Atopic dermatitis, pediatric, adult, skin, T_H2, T_H9, T_H17, IL-17, IL-19, antimicrobials

Abbreviations used : AD, ADQ, AMP, DC, EASI, FOXP3, hARP, IRB, K16, OX40L, PI3, PIQoL, TEWL, TSLPR

Plan

Methods

Patients' characteristics

Immunohistochemistry and immunofluorescence

Quantitative real-time PCR

Statistical analyses

Results

Early pediatric AD exhibits profound epidermal hyperplasia but lacks the filaggrin deficiency of adult AD

T-cell and dendritic cell infiltrates are similarly increased in pediatric and adult patients with AD

Pediatric AD is characterized by T_H17 activation and related antimicrobial peptides

Early pediatric AD shows phenotypic similarities to psoriasis

Correlations of clinical, cellular, and molecular markers in pediatric patients with AD

Discussion

Supported by a research grant from the LEO Foundation. P.M.B. and M.S.-F. were supported in part by grant no. UL1 TR00043 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program.

Disclosure of potential conflict of interest: M. Suárez-Fariñas has received grants from Pfizer, Quorum Consulting, and Genisphere. J. G. Krueger and/or his institution received money from Novartis, Pfizer, Amgen, Lilly, Merck, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, Biogen Idec, Janssen, Delenex, AbbVie, Sanofi, Baxter, Paraxel, Xenoport, and Kineta. A. S. Paller received consultancy fees from Anacor, Galderma, Stiefel/GlaxoSmithKline, Novartis, Regeneron, and Vitae Pharmaceuticals and her institution received grants from Anacor, Astellas, and LEO Pharma. E. Guttman-Yassky received funding for financial activities from Sanofi Aventis, Renereron, Stiefel/GlaxoSmithKline, MedImmune, Celgene, Anacor, Leo Pharma, AnaptysBio, Celsus, Dermira, Galderma, Novartis, Pfizer, and Vitae; consultancy fees from Regeneron, Sanofi Aventis, Medimmune, Celgene, Stiefel/GlaxoSmithKline, Celsus, BMS, Amgen, Drais, AbbVie, Anacor, AnaptysBio, Dermira, Galderma, Leo Pharma, Novartis, Pfizer, Vitae, Mitsubishi Tanabe, and Eli Lilly; and grants from Regeneron, Celgene, BMS, Janssen, Dermira, Leo Pharma, Merck, and Novartis. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 138 - N° 6

P. 1639-1651 - décembre 2016 Retour au numéro

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Early-onset pediatric atopic dermatitis is T_H2 but also T_H17 polarized in skin - 18/04/17

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