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

Hazel Wilkie; Mrinmoy Das; Tyler Pelovitz; Wayne Bainter; Brian Woods; Mohammed Alasharee; Ali Sobh; Safa Baris; Sevgi Bilgic Eltan; Waleed Al-Herz; Mohamed-Ridha Barbouche; Imen Ben-Mustapha; Meriem Ben-Ali; Mohamed T H Sallam; Amany Awad; Sohilla Lotfy; Aisha El Marsafy; Moushira Ezzelarab; Michael Farrar; Brigitta A R Schmidt; Monali NandyMazumdar; Emma Guttman-Yassky; Anthony Sheets; Katie Maria Vidic; George Murphy; Patrick M Schlievert; Janet Chou; Juan Manuel Leyva-Castillo; Erin Janssen; Maheshwor Timilshina; Raif S Geha

doi:10.1016/j.jaci.2023.12.020

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

J Allergy Clin Immunol. 2024 Jan 5:S0091-6749(24)00005-8. doi: 10.1016/j.jaci.2023.12.020. Online ahead of print.

Authors

Hazel Wilkie¹, Mrinmoy Das¹, Tyler Pelovitz¹, Wayne Bainter¹, Brian Woods¹, Mohammed Alasharee¹, Ali Sobh², Safa Baris³, Sevgi Bilgic Eltan³, Waleed Al-Herz⁴, Mohamed-Ridha Barbouche⁵, Imen Ben-Mustapha⁶, Meriem Ben-Ali⁶, Mohamed T H Sallam⁷, Amany Awad⁸, Sohilla Lotfy⁹, Aisha El Marsafy⁹, Moushira Ezzelarab¹⁰, Michael Farrar¹¹, Brigitta A R Schmidt¹², Monali NandyMazumdar¹³, Emma Guttman-Yassky¹³, Anthony Sheets¹⁴, Katie Maria Vidic¹⁴, George Murphy¹⁴, Patrick M Schlievert¹⁵, Janet Chou¹, Juan Manuel Leyva-Castillo¹, Erin Janssen¹, Maheshwor Timilshina¹⁶, Raif S Geha¹⁷

Affiliations

¹ Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass.
² Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
³ Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey.
⁴ Department of Pediatrics, Allergy and Clinical Immunology Unit, Al-Sabah Hospital, Kuwait City, Kuwait.
⁵ Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain.
⁶ Department of Immunology, Institut Pasteur de Tunis and University Tunis El-Manar, Tunis, Tunisia.
⁷ Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
⁸ Dermatology, Andrology, and STDs Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
⁹ Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt.
¹⁰ Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt.
¹¹ Center for Immunology, Masonic Cancer Center, Department of Laboratory and Pathology, University of Minnesota, Minneapolis, Minn.
¹² Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
¹³ Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
¹⁴ Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass.
¹⁵ Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa Health Care, Iowa City, Iowa.
¹⁶ Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass. Electronic address: timelsena@gmail.com.
¹⁷ Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass. Electronic address: raif.geha@childrens.harvard.edu.

PMID: 38185418
DOI: 10.1016/j.jaci.2023.12.020

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 Saureus, 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 Saureus. 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 Saureus to drive eczema in DOCK8 deficiency.

Keywords: DOCK8 deficiency; Staphylococcus aureus; T regulatory cells; eczema.