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

Rosita Rigoni 1, Elena Fontana 2, Kerry Dobbs 3, Veronica Marrella 1, Valentina Taverniti 4, Virginia Maina 1, Amanda Facoetti 5, Giovanna D'Amico 6, Waleed Al-Herz 7, Mario Ernesto Cruz-Munoz 8, Catharina Schuetz 9, Andrew R Gennery 10, Elizabeth K Garabedian 11, Silvia Giliani 12, Deborah Draper 3, Ghassan Dbaibo 13, Raif S Geha 14, Isabelle Meyts 15, Thomas Tousseyn 16, Benedicte Neven 17, Despina Moshous 17, Alain Fischer 17, Ansgar Schulz 18, Andrea Finocchi 19, Douglas B Kuhns 20, Danielle L Fink 20, Michail S Lionakis 21, Muthulekha Swamydas 21, Simone Guglielmetti 4, Julie Alejo 22, Ian A Myles 3, Stefania Pittaluga 22, Luigi D Notarangelo 23, Anna Villa 24, Barbara Cassani 25

Affiliations

01 November 2020

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doi: 10.1016/j.jaci.2020.04.005

Abstract

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.

Keywords: LPS; RAG; T cells; chemokines; cytokines; dysbiosis; erythroderma; gut-skin axis; immune-mediated disease; skin inflammation.

Figures

Graphical abstract

Graphical abstract

Fig 1 Preferential homing of T cells to the skin in patients with OS. A, Representative FACS plots and frequencies of CLA+ CD45RO+ T cells within the effector CD4+ and CD8+ T-cell populations isolated from PB of patients with OS (n = 13) and aged-matched HDs (n = 31). Frequencies of CCR4+ within the CD4+ CD45RA− T-cell population (n = 11-15). Plasma levels of chemokines (B) and cytokines (C) in HDs (n = 37), in patients with OS (n = 15) as well as in patients with acute graft-versus-host disease (GvHD) (n = 15) and patients with AD (n = 14), as controls of Th1- and Th2-mediated inflammation, respectively. D, Skin biopsies from patients with OS were investigated for IFNG, CXCL9, and CXCL10 mRNA expression using RNAscope. POLR2A mRNA labeling was used as control for the quality of the RNA on paraffin section. Values are mean ± SEM. ∗P < .05, ∗∗P < .01, ∗∗∗P < .005, ∗∗∗∗P < .001. Statistical significance determined by Mann-Whitney U test or by ANOVA. See also Table E1.

Fig 1 Preferential homing of T cells to the skin in patients with OS. A, Representative FACS plots and frequencies of CLA+ CD45RO+ T cells within the effector CD4+ and CD8+ T-cell populations isolated from PB of patients with OS (n = 13) and aged-matched HDs (n = 31). Frequencies of CCR4+ within the CD4+ CD45RA− T-cell population (n = 11-15). Plasma levels of chemokines (B) and cytokines (C) in HDs (n = 37), in patients with OS (n = 15) as well as in patients with acute graft-versus-host disease (GvHD) (n = 15) and patients with AD (n = 14), as controls of Th1- and Th2-mediated inflammation, respectively. D, Skin biopsies from patients with OS were investigated for IFNG, CXCL9, and CXCL10 mRNA expression using RNAscope. POLR2A mRNA labeling was used as control for the quality of the RNA on paraffin section. Values are mean ± SEM. ∗P < .05, ∗∗P < .01, ∗∗∗P < .005, ∗∗∗∗P < .001. Statistical significance determined by Mann-Whitney U test or by ANOVA. See also Table E1.

Fig 2 Rag2R229Q mice exhibit severe T-cell–mediated inflammation in the skin. A, Representative skin sections from Rag2+/+ and Rag2R229Q mice (8-12 weeks old) stained with H&E and CD3 immunostaining. Histogram shows the inflammation score in the skin (n = 12-13). Bars = 200 μm (H&E) and 100 μm (CD3). B, Total cell count from skin suspension for g tissue (n = 7-8 mice/group). C, Frequencies of CD45+ cells in the skin suspension (n = 9-10 mice/group). D, Representative FACS plots and cumulative frequencies of CD4+ and CD8+ T cells inside the CD45+ population of skin suspension (n = 6-12 mice/group). E, Gene expression analysis of Cxcr3 in the skin tissue of Rag2+/+ and Rag2R229Q mice (n = 6-9 mice/group). Target mRNA was normalized to Actb mRNA. RNA contents are shown as arbitrary units (AUs). F, Representative FACS plots and frequencies of Th1, Th17, and Th2 cells inside the CD3+ T-cell population of skin suspension (n = 6-9 mice/group). G, Representative FACS plots showing TCRγδ T cells inside the CD45+ population in the skin of Rag2+/+ and Rag2R229Q mice. Values are mean ± SEM. ∗P < .05; ∗∗P < .01; ∗∗∗P < .005; ∗∗∗∗P < .001. Statistical analysis was performed using Mann-Whitney U test. See also Fig E1.

Fig 2 Rag2R229Q mice exhibit severe T-cell–mediated inflammation in the skin. A, Representative skin sections from Rag2+/+ and Rag2R229Q mice (8-12 weeks old) stained with H&E and CD3 immunostaining. Histogram shows the inflammation score in the skin (n = 12-13). Bars = 200 μm (H&E) and 100 μm (CD3). B, Total cell count from skin suspension for g tissue (n = 7-8 mice/group). C, Frequencies of CD45+ cells in the skin suspension (n = 9-10 mice/group). D, Representative FACS plots and cumulative frequencies of CD4+ and CD8+ T cells inside the CD45+ population of skin suspension (n = 6-12 mice/group). E, Gene expression analysis of Cxcr3 in the skin tissue of Rag2+/+ and Rag2R229Q mice (n = 6-9 mice/group). Target mRNA was normalized to Actb mRNA. RNA contents are shown as arbitrary units (AUs). F, Representative FACS plots and frequencies of Th1, Th17, and Th2 cells inside the CD3+ T-cell population of skin suspension (n = 6-9 mice/group). G, Representative FACS plots showing TCRγδ T cells inside the CD45+ population in the skin of Rag2+/+ and Rag2R229Q mice. Values are mean ± SEM. ∗P < .05; ∗∗P < .01; ∗∗∗P < .005; ∗∗∗∗P < .001. Statistical analysis was performed using Mann-Whitney U test. See also Fig E1.

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