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Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome

Lookup NU author(s): Professor Andrew GenneryORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 2020 The Authors. Background: Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS). Objective: The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified. Methods: We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2R229Q/R229Q (Rag2R229Q) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt. Results: We show that memory/activated T cells from patients with OS and from the Rag2R229Q mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad TH1/TH2/TH17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2R229Q mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2R229Q mice results in increased frequency of Ccr4+ splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by TH1 effector T cells. Conclusions: These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS.


Publication metadata

Author(s): Rigoni R, Fontana E, Dobbs K, Marrella V, Taverniti V, Maina V, Facoetti A, D'Amico G, Al-Herz W, Cruz-Munoz ME, Schuetz C, Gennery AR, Garabedian EK, Giliani S, Draper D, Dbaibo G, Geha RS, Meyts I, Tousseyn T, Neven B, Moshous D, Fischer A, Schulz A, Finocchi A, Kuhns DB, Fink DL, Lionakis MS, Swamydas M, Guglielmetti S, Alejo J, Myles IA, Pittaluga S, Notarangelo LD, Villa A, Cassani B

Publication type: Article

Publication status: Published

Journal: Journal of Allergy and Clinical Immunology

Year: 2020

Volume: 146

Issue: 5

Pages: 1165-1179.e11

Print publication date: 01/11/2020

Online publication date: 17/04/2020

Acceptance date: 06/04/2020

Date deposited: 29/05/2020

ISSN (print): 0091-6749

ISSN (electronic): 1097-6825

Publisher: Mosby Inc.

URL: https://doi.org/10.1016/j.jaci.2020.04.005

DOI: 10.1016/j.jaci.2020.04.005

PubMed id: 32311393


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