Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency - 04/07/24

Doi : 10.1016/j.jaci.2023.12.020

Hazel Wilkie, PhD ^a, Mrinmoy Das, PhD ^a, Tyler Pelovitz, BS ^a, Wayne Bainter, MSc ^a, Brian Woods, BS ^a, Mohammed Alasharee, BS ^a, Ali Sobh, MD ^b, Safa Baris, MD ^c, Sevgi Bilgic Eltan, MD ^c, Waleed Al-Herz, MD ^d, Mohamed-Ridha Barbouche, MD, PhD ^e, Imen Ben-Mustapha, MD ^f, Meriem Ben-Ali, MD ^f, Mohamed T.H. Sallam, MD, PhD ^g, Amany Awad, MD ^h, Sohilla Lotfy, MD ⁱ, Aisha El Marsafy, MD ⁱ, Moushira Ezzelarab, MD ^j, Michael Farrar, PhD ^k, Brigitta A.R. Schmidt, MD ^l, Monali NandyMazumdar, PhD ^m, Emma Guttman-Yassky, MD, PhD ^m, Anthony Sheets, MD, PhD ⁿ, Katie Maria Vidic, BA ⁿ, George Murphy, MD ⁿ, Patrick M. Schlievert, PhD ^o, Janet Chou, MD ^a, Juan Manuel Leyva-Castillo, PhD ^a, Erin Janssen, MD, PhD ^a, Maheshwor Timilshina, PhD ^a,^⁎ , Raif S. Geha, MD ^a,^⁎
^a Division of Immunology, Boston Children’s Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
^b Department of Pediatrics, Mansoura University Children’s Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
^c Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
^d Department of Pediatrics, Allergy and Clinical Immunology Unit, Al-Sabah Hospital, Kuwait City, Kuwait
^e Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
^f Department of Immunology, Institut Pasteur de Tunis and University Tunis El-Manar, Tunis, Tunisia
^g Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
^h Dermatology, Andrology, and STDs Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
ⁱ Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
^j Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
^k Center for Immunology, Masonic Cancer Center, Department of Laboratory and Pathology, University of Minnesota, Minneapolis, Minn
^l Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^m Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY
ⁿ Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass
^o Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa Health Care, Iowa City, Iowa

^∗Corresponding authors: Maheshwor Timilshina, PhD, and Raif S. Geha, MD, Boston Children’s Hospital, One Blackfan Circle, Boston, MA 02115.Boston Children’s HospitalOne Blackfan CircleBostonMA02115

Graphical abstract

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Abstract

Background

Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD).

Objective

We sought to understand the mechanisms of eczema in DOCK8 deficiency.

Methods

Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus.

Results

Skin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients’ skin was colonized by S aureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8^−/− mice exhibited reduced numbers of cutaneous T regulatory (Treg) cells and a normal skin barrier. Dock8^−/− and mice with an inducible Dock8 deletion in Treg cells exhibited increased allergic skin inflammation after epicutaneous sensitization with OVA. DOCK8 was shown to be important for Treg cell stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Treg cells. Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific, inducible Treg cells suppressed allergic inflammation in OVA-sensitized skin of Dock8^−/− mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels after topical exposure to S aureus. Both were attenuated after adoptive transfer of WT but not DOCK8-deficient Treg cells.

Conclusion

Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to S aureus to drive eczema in DOCK8 deficiency.

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Key words : DOCK8 deficiency, eczema, T regulatory cells, Staphylococcus aureus

Abbreviations used : AD, ARPC1B, dLN, DOCK8, EC, eGFP, FOXP3, FVD, GFP, HSCT, iTreg, LAP, OVA, RT-qPCR, STAT, Teff, TEWL, Treg, WASP, WIP, WT, YFP

Mappa

Methods

Patients

Mice

Laboratory measurements

Tamoxifen treatment

Generation of iTreg cells

iTreg suppression assay

Transepidermal water loss and S aureus recovery from skin

Cutaneous application of S aureus in occlusive patch

Statistical analysis

Results

DOCK8-deficient patients demonstrated allergic inflammation with reduced FOXP3:CD4 ratio in lesional skin

Dock8^−/− mice have decreased skin Treg cells and increased allergic skin inflammation after EC sensitization with OVA

Mice with inducible deficiency of DOCK8 in Treg cells display exaggerated allergic skin inflammation

DOCK8-deficient Treg cells at sites of allergic skin inflammation are unstable and subverted to T_H2 cytokine secretion

DOCK8 is critical for the generation, survival, and function of iTreg cells in vitro

DOCK8 is critical for the function of iTreg cells in vivo

Skin exposure to S aureus drives severe allergic skin inflammation in Dock8^−/− mice

Discussion

Disclosure statement

The last 2 authors contributed equally to this article, and both should be considered senior author.

Esportazione

Vol 154 - N° 1

P. 143-156 - luglio 2024 Ritorno al numero

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Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency - 04/07/24

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Abstract

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Objective

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Conclusion

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