Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome: Journal of Allergy and Clinical Immunology

R. Rigoni, E. Fontana, K. Dobbs, V. Marrella, V. Taverniti, V. Maina, A. Facoetti, G. D'Amico, W. Al-Herz, M.E. Cruz-Munoz, C. Schuetz, A.R. Gennery, E.K. Garabedian, S. Giliani, D. Draper, G. Dbaibo, R.S. Geha, I. Meyts, T. Tousseyn, B. NevenD. Moshous, A. Fischer, A. Schulz, A. Finocchi, D.B. Kuhns, D.L. Fink, M.S. Lionakis, M. Swamydas, S. Guglielmetti, J. Alejo, I.A. Myles, S. Pittaluga, L.D. Notarangelo, A. Villa, B. Cassani

Research output: Contribution to journalArticlepeer-review


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. © 2020 The Authors
Original languageEnglish
Pages (from-to)1165
JournalJ. Allergy Clin. Immunol.
Issue number5
Publication statusPublished - 2020


  • chemokines
  • cytokines
  • dysbiosis
  • erythroderma
  • gut-skin axis
  • immune-mediated disease
  • LPS
  • RAG
  • skin inflammation
  • T cells
  • chemokine receptor CCR4
  • CXCL9 chemokine
  • dextran sulfate
  • gamma interferon
  • gamma interferon inducible protein 10
  • interleukin 13
  • interleukin 17
  • interleukin 5
  • lipopolysaccharide
  • macrophage derived chemokine
  • RAG2 protein
  • thymus and activation regulated chemokine
  • toll like receptor 4
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • cell activation
  • cell homing
  • clinical article
  • cohort analysis
  • controlled study
  • dermatitis
  • dextran sulfate sodium-induced colitis
  • enteritis
  • enzyme linked immunosorbent assay
  • epithelium cell
  • female
  • flow cytometry
  • homeostasis
  • human
  • human cell
  • immunohistochemistry
  • lymphocyte
  • lymphocytic infiltration
  • male
  • memory T lymphocyte
  • mouse
  • mouse model
  • nonhuman
  • Omenn syndrome
  • priority journal
  • protein blood level
  • protein expression
  • RNA hybridization
  • skin biopsy
  • T lymphocyte activation
  • Th1 cell
  • Th17 cell
  • Th2 cell


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