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

  1. Author:
    Rigoni, Rosita
    Fontana, Elena
    Dobbs, Kerry
    Marrella, Veronica
    Taverniti, Valentina
    Maina, Virginia
    Facoetti, Amanda
    D'Amico, Giovanna
    Al-Herz, Waleed
    Cruz-Munoz, Mario Ernesto
    Schuetz, Catharina
    Gennery, Andrew R
    Garabedian, Elizabeth K
    Giliani, Silvia
    Draper, Deborah
    Dbaibo, Ghassan
    Geha, Raif S
    Meyts, Isabelle
    Tousseyn, Thomas
    Neven, Benedicte
    Moshous, Despina
    Fischer, Alain
    Schulz, Ansgar
    Finocchi, Andrea
    Kuhns,Doug
    Fink,Dani
    Lionakis, Michail S
    Swamydas, Muthulekha
    Guglielmetti, Simone
    Alejo, Julie
    Myles, Ian A
    Pittaluga, Stefania
    Notarangelo, Luigi D
    Villa, Anna
    Cassani, Barbara

  2. Author Address

    UOS Milano, IRGB CNR, Milan, Italy; Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy., Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA., Department of Food, Environmental, and Nutritional Sciences (DeFENS), University of Milan, 20133 Milan, Italy., Humanitas University, Rozzano, 20089, Milan, Italy; Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy., Centro Ricerca Tettamanti, Clinica Pediatrica, Universit 224; Milano-Bicocca, Monza (MB), Italy., Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait; Allergy and Clinical Immunology Unit, Pediatric Department, Al-Sabah Hospital, Kuwait City, Kuwait., Facultad de Medicina, Universidad Aut 243;noma del Estado de Morelos, Cuernavaca, Mexico., Department of Pediatrics, Medizinische Fakult 228;t Carl Gustav Carus, Technische Universit 228;t Dresden, Dresden, Germany., Great North Children 39;s Hospital, Clinical Resource Building, Newcastle upon Tyne, UK; Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK., National Human Genome Research Institute, NIH, Bethesda, MD, USA., Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Cytogenetic and Medical Genetics Unit, "A. Nocivelli" Institute for Molecular Medicine, Spedali Civili Hospital, Brescia, Italy., Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon., Division of Immunology, Boston Children 39;s Hospital, Harvard Medical School, Boston, MA, USA., UZ Leuven, Department of Pediatrics, University Hospitals Leuven, Herestraat 49, Leuven, Belgium; Laboratory for Inborn Errors of Immunity, Department of Immunology, Microbiology and Transplantation, KU Leuven, Leuven, Belgium., Department of Imaging and Pathology, Lab for Translational Cell and Tissue Research, KU Leuven, Leuven, Belgium., Imagine Institute, Paris Descartes - Sorbonne Paris Cit 233; University, Paris, France; Pediatric Immuno-Hematology Unit, Necker Children Hospital, Assistance-Publique Hopitaux de Paris, Paris, France., Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany., Department of Pediatrics, Children 39;s Hospital Bambino Ges 249;, Rome, Italy., Neutrophil Monitoring Laboratory, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD., Fungal Pathogenesis Section, LCIM, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA., Laboratory of Pathology, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA., Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA. Electronic address: luigi.notarangelo2@nih.gov., UOS Milano, IRGB CNR, Milan, Italy; Telethon Institute for Gene Therapy (SR-Tiget), Division of Regenerative Medicine, Stem Cells, and Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: villa.anna@hsr.it., UOS Milano, IRGB CNR, Milan, Italy; Humanitas Clinical and Research Center IRCCS, Rozzano, 20089 Milan, Italy; Lead Contact. Electronic address: barbara.cassani@humanitasresearch.it.,
    1. Year: 2020
    2. Date: NOV
    3. Epub Date: 2020 04 17
  2. Journal: The Journal of allergy and clinical immunology
    1. 146
    2. 5
    3. Pages: 1165-+
  4. Type of Article: Article
  5. ISSN: 0091-6749
  1. 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 Rag2R229Q mouse model. Homing phenotype 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 (DSS). Results: We show that memory/activated T cells from OS patients and from the Rag2R229Q mouse model of OS abundantly express the skin homing receptors Cutaneous Lymphocyte Associated Antigen (CLA) and CCR4, associated with high levels of CCL17 and CCL22 chemokines. 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 upon 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. Copyright © 2020. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.jaci.2020.04.005
  3. PMID: 32311393
  4. View record in Web of Science®
  5. WOS: 000588153700019
  6. PII : S0091-6749(20)30492-9

Library Notes

  1. Fiscal Year: FY2019-2020
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