Treg cell dysfunction and cutaneous exposure to S. aureus underlie eczema in DOCK8 deficiency

Wilkie H 1 , Das M 1 , Pelovitz T 1 , Bainter W 1 , Woods B 1 , Alasharee M 1 Show all authors , Sobh A 2 , Baris S 3 , Eltan SB 3 , Al-Herz W 4 , Barbouche MR 5 , Ben-Mustapha I 6 , Ben-Ali M 6 , Sallam MTH 7 , Awad A 8 , Lotfy S 9 , El Marsafy A 9 , Ezzelarab M 10 , Farrar M 11 , Schmidt BAR 12 , NandyMazumdar M 13 , Guttman-Yassky E 13 , Sheets A 14 , Vidic KM 14 , Murphy G 14 , Schlievert PM 15 , Chou J 1 , Leyva-Castillo JM 1 , Janssen E 1 , Timilshina M 16 , Geha RS 16

Affiliations 

  • 1 Division of Immunology, Boston Children's Hospital and Department of Pediatrics Harvard Medical School, Boston, MA, USA
  • 2 Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, 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
  • 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, MN
  • 12 Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA
  • 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, MA
  • 15 Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa Health Care, Iowa City, IA
  • 16 Division of Immunology, Boston Children's Hospital and Department of Pediatrics Harvard Medical School, Boston, MA, USA,. Electronic address: timelsena@gmail.com
J Allergy Clin Immunol, 2024 Jan 05.
PMID: 38185418 DOI: 10.1016/j.jaci.2023.12.020

Abstract

BACKGROUND: DOCK8-deficient patients have severe eczema, elevated IgE and eosinophilia, features of Atopic Dermatitis (AD).

OBJECTIVE: To understand the mechanisms of eczema in DOCK8 deficiency.

METHODS: Skin biopsies were characterized for histology, immuno-fluorescence microscopy, and gene expression. Skin barrier function was measured by trans-epidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous (EC) sensitization with ovalbumin (OVA) or cutaneous application of S. aureus.

RESULTS: Skin lesions of DOCK8-deficient patients exhibited type-2 inflammation and the patients' skin was colonized by S. aureus, like 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 cells (Tregs) and a normal skin barrier. Dock8-/- mice and mice with an inducible Dock8 deletion in Tregs exhibited increased allergic skin inflammation following EC sensitization with OVA. DOCK8 was shown to be important for Treg stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Tregs (iTregs). Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific iTregs suppressed allergic inflammation in OVA-sensitized skin of Dock8-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels following topical exposure to S. aureus. Both were attenuated following adoptive transfer of WT but not DOCK8 deficient Tregs 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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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