title: RAGs and BUGS: An alliance for autoimmunity.
abstract: Hypomorphic Rag mutations in humans cause Omenn Syndrome (OS) a severe immunodeficiency associated with autoimmune-like manifestations mediated by oligoclonal activated T and B cells. The clinical and immunological spectrum of OS presentation is extremely broad. However, the role played by environmental triggers in the disease pathogenesis remains largely unknown. We have recently shown in a murine model that gut microbiota has a substantial role in determining the distinctive immune dysregulation of OS. Here, we describe how dysbiosis and loss of T cell tolerance to commensals influence the expression of autoimmunity at the barrier site and beyond, and the disease hallmark hyper-IgE. We discuss how commensal antigens and gut-derived pathogenic T cells could potentially modulate skin immunity to determine cutaneous degenerations in OS. These mechanisms may have broader implications for a deeper understanding of the role of gut microbes in influencing barriers integrity and host physiology.
authors: a Milan Unit , Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche , Milan , Italy.|b Humanitas Clinical and Research Center , Rozzano, Milan , Italy.
authors: Rosita
authors: R
authors: Rigoni
authors: c Istituto Nazionale Genetica Molecolare , Department of Medical Biotechnology and Translational Medicine , University of Milan , Milan , Italy.|d Institute for Research in Biomedicine , Bellinzona , Switzerland.
authors: Fabio
authors: F
authors: Grassi
authors: a Milan Unit , Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche , Milan , Italy.|e Telethon Institute for Gene Therapy, Division of Regenerative Medicine, Stem Cells and Gene Therapy, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute , Milan , Italy.
authors: Anna
authors: A
authors: Villa
authors: a Milan Unit , Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche , Milan , Italy.|b Humanitas Clinical and Research Center , Rozzano, Milan , Italy.
authors: Barbara
authors: B
authors: Cassani
mesh_terms: D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000276:immunology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D007073:Immunoglobulin E
keywords: IgA deficiency; RAG; T and B cell autoimmunity; commensal bacteria; dysbiosis; hyperIgE; immunodeficiency