Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)⁺ T_H2/T_H1 cell imbalance, whereas adults acquire CLA⁺ T_H22/T_C22 cell subsets - 06/10/15

Doi : 10.1016/j.jaci.2015.05.049

Tali Czarnowicki, MD, MSc ^a,^{^{∗
These authors contributed equally to this work.}}, Hitokazu Esaki, MD ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Juana Gonzalez, PhD ^c, Dana Malajian, BA ^a,^d, Avner Shemer, MD ^f, Shinji Noda, MD ^a, Sreya Talasila, MD ^e, Adam Berry, MS ^e, Jayla Gray, BS ^e, Lauren Becker, MD ^e, Yeriel Estrada, BS ^b, Hui Xu, MSc ^b, Xiuzhong Zheng, MSc ^a, Mayte Suárez-Fariñas, PhD ^b,^g,^h, James G. Krueger, MD, PhD ^a, Amy S. Paller, MD ^e,^{^{‡
These authors contributed equally to this work.}}, Emma Guttman-Yassky, MD, PhD ^a,^b,^⁎,^{^{‡
These authors contributed equally to this work.}}
^a Laboratory for Investigative Dermatology, Rockefeller University, New York, NY
^c Translational Technology Core Laboratory, Rockefeller University, New York, NY
^b Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY
^g Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY
^h Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY
^d Columbia University College of Physicians and Surgeons, New York, NY
^e Departments of Dermatology and Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Ill
^f Department of Dermatology, Tel-Hashomer Hospital, Tel Aviv, Israel

^∗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.

Abstract

Background

Identifying differences and similarities between cutaneous lymphocyte antigen (CLA)⁺ polarized T-cell subsets in children versus adults with atopic dermatitis (AD) is critical for directing new treatments toward children.

Objective

We sought to compare activation markers and frequencies of skin-homing (CLA⁺) versus systemic (CLA⁻) “polar” CD4 and CD8 T-cell subsets in patients with early pediatric AD, adults with AD, and control subjects.

Methods

Flow cytometry was used to measure CD69/inducible costimulator/HLA-DR frequency in memory cell subsets, as well as IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines, defining T_H1/cytotoxic T (T_C) 1, T_H2/T_C2, T_H9/T_C9, T_H17/T_C17, and T_H22/T_C22 populations in CD4 and CD8 cells, respectively. We compared peripheral blood from 19 children less than 5 years old and 42 adults with well-characterized moderate-to-severe AD, as well as age-matched control subjects (17 children and 25 adults).

Results

Selective inducible costimulator activation (P < .001) was seen in children. CLA⁺ T_H2 T cells were markedly expanded in both children and adults with AD compared with those in control subjects, but decreases in CLA⁺ T_H1 T-cell numbers were greater in children with AD (17% vs 7.4%, P = .007). Unlike in adults, no imbalances were detected in CLA⁻ T cells from pediatric patients with AD nor were there altered frequencies of T_H22 T cells within the CLA⁺ or CLA⁻ compartments. Adults with AD had increased frequencies of IL-22–producing CD4 and CD8 T cells within the skin-homing population, compared with controls (9.5% vs 4.5% and 8.6% vs 2.4%, respectively; P < .001), as well as increased HLA-DR activation (P < .01).

Conclusions

These data suggest that T_H2 activation within skin-homing T cells might drive AD in children and that reduced counterregulation by T_H1 T cells might contribute to excess T_H2 activation. T_H22 “spreading” of AD is not seen in young children and might be influenced by immune development, disease chronicity, or recurrent skin infections.

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Key words : Atopic dermatitis, T cell, cutaneous lymphocyte antigen, IL-13, IL-22, IFN-γ, inducible costimulator, CD69, HLA-DR

Abbreviations used : AD, CLA, ICOS, PE, PMA, T_C, T_CM, T_EM

Plan

Methods

Patients' characteristics and blood samples

Isolation of PBMCs

Stimulation of blood cell populations for cytokine responses

Cell-surface staining and intracellular staining on PBMCs and stimulated and nonstimulated CD4/CD8 T cells

Statistical analysis

Results

Effector T-cell numbers are uniquely increased in adults with AD

Memory subsets are positively correlated with IgE levels, but not with SCORAD scores, in children with AD

ICOS is highly expressed on CD4 T_CM and T_EM cell subsets of patients with AD

HLA-DR is preferentially expressed on T_CM/T_EM cells in adults but not children with AD

CD69 expression is higher in children compared with adults with AD

Skin-selective T_H1/T_H2 imbalance in pediatric AD

Discussion

Supported by a research grant from the LEO Foundation (research grant no. 0266-2572, GCO no. 13-1310 to E.-G.-Y. and A.S.P.). T.C. was cosponsored by the Center for Basic and Translational Research on Disorders of the Digestive System through the generosity of the Leona M. and Harry B. Helmsley Charitable Trust. J.G. was supported in part by grant no. UL1TR0000 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program. D.M. received funding from the American Dermatological Association Medical Student Fellowship. J.G.K. was supported by grant no. 5UL1RR024143-02 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Blood acquisition was supported by the Northwestern University Skin Disease Research Center (NIAMS P30AR057216).

Disclosure of potential conflict of interest: J. G. Krueger reports that money was paid to his institution by and/or he has received personal fees from Pfizer, Amgen, Janssen, Lilly, Merck, Novartis, Kadmon, Dermira, Boehringer, Innovaderm, Kyowa, BMS, Serono, BiogenIdec, Delenex, AbbVie, Sanofi, Baxter, Parexel, Xenoport, and Kineta. A. S. Paller has received research support from the LEO Foundation; has received consultancy fees from Abbvie, Anacor, Celsus, Chugai Pharma, Galderma, GSK-Stiefel, Novartis, and Promius Pharma; and is an investigator for Abbvie. E. Guttman-Yassky is a board member for Sanofi Aventis, Regeneron, Stiefel/GSK, Medimmune, Celgene, Anacor, and Leo Pharma; has received consultancy fees from Regeneron, Sanofi Aventis, Medimmune, Celgene, Steifel/GSK, Celsus, BMS, Amgen, and Drais; and has received research support from Regeneron, Celgene, BMS, and Janssen. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 136 - N° 4

P. 941 - octobre 2015 Retour au numéro

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Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)⁺ T_H2/T_H1 cell imbalance, whereas adults acquire CLA⁺ T_H22/T_C22 cell subsets - 06/10/15

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