title: Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects.
abstract: Omenn syndrome (OS) is caused by hypomorphic Rag mutations and characterized by a profound immunodeficiency associated with autoimmune-like manifestations. Both in humans and mice, OS is mediated by oligoclonal activated T and B cells. The role of microbial signals in disease pathogenesis is debated. Here, we show that Rag2(R229Q) knock-in mice developed an inflammatory bowel disease affecting both the small bowel and colon. Lymphocytes were sufficient for disease induction, as intestinal CD4 T cells with a Th1/Th17 phenotype reproduced the pathological picture when transplanted into immunocompromised hosts. Moreover, oral tolerance was impaired in Rag2(R229Q) mice, and transfer of wild-type (WT) regulatory T cells ameliorated bowel inflammation. Mucosal immunoglobulin A (IgA) deficiency in the gut resulted in enhanced absorption of microbial products and altered composition of commensal communities. The Rag2(R229Q) microbiota further contributed to the immunopathology because its transplant into WT recipients promoted Th1/Th17 immune response. Consistently, long-term dosing of broad-spectrum antibiotics (ABXs) in Rag2(R229Q) mice ameliorated intestinal and systemic autoimmunity by diminishing the frequency of mucosal and circulating gut-tropic CCR9(+) Th1 and Th17 T cells. Remarkably, serum hyper-IgE, a hallmark of the disease, was also normalized by ABX treatment. These results indicate that intestinal microbes may play a critical role in the distinctive immune dysregulation of OS.
authors.affiliation: Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 20133 Milan, Italy Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy.
authors.forename: Rosita
authors.initials: R
authors.lastname: Rigoni
authors.affiliation: Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia School of Medicine, 25123 Brescia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Fontana
authors.affiliation: Department of Food, Environmental, and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Guglielmetti
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Research Council, 70126 Bari, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fosso
authors.affiliation: Department of Biosciences, Biotechnology, and Pharmacological Sciences, University of Bari, 70121 Bari, Italy Institute of Biomembranes and Bioenergetics, National Research Council, 70126 Bari, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: D'Erchia
authors.affiliation: 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, 20132 Milan, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Maina
authors.affiliation: Department of Food, Environmental, and Nutritional Sciences (DeFENS), University of Milan, 20122 Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Taverniti
authors.affiliation: 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, 20132 Milan, Italy.
authors.forename: Maria Carmina
authors.initials: MC
authors.lastname: Castiello
authors.affiliation: 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, 20132 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Mantero
authors.affiliation: Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 20133 Milan, Italy Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pacchiana
authors.affiliation: Foundation IRCCS Neurological Institute, C. Besta, Neuroimmunology and Neuromuscular Disorders Unit, 20132 Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Musio
authors.affiliation: Foundation IRCCS Neurological Institute, C. Besta, Neuroimmunology and Neuromuscular Disorders Unit, 20132 Milan, Italy.
authors.forename: Rosetta
authors.initials: R
authors.lastname: Pedotti
authors.affiliation: Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy BIOMETRA Department, University of Milan, 20122 Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Selmi
authors.affiliation: Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: J Rodrigo
authors.initials: JR
authors.lastname: Mora
authors.affiliation: Department of Biosciences, Biotechnology, and Pharmacological Sciences, University of Bari, 70121 Bari, Italy Institute of Biomembranes and Bioenergetics, National Research Council, 70126 Bari, Italy.
authors.forename: Graziano
authors.initials: G
authors.lastname: Pesole
authors.affiliation: Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 20133 Milan, Italy Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.affiliation: Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia School of Medicine, 25123 Brescia, Italy.
authors.forename: Pietro Luigi
authors.initials: PL
authors.lastname: Poliani
authors.affiliation: Istituto Nazionale Genetica Molecolare, Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milan, Italy Institute for Research in Biomedicine, 6500 Bellinzona, Switzerland.
authors.forename: Fabio
authors.initials: F
authors.lastname: Grassi
authors.affiliation: Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 20133 Milan, Italy 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, 20132 Milan, Italy barbara.cassani@humanitasresearch.it anna.villa@hsr.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.affiliation: Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, 20133 Milan, Italy Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy barbara.cassani@humanitasresearch.it anna.villa@hsr.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cassani
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D015551:Autoimmunity / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D058491:Bacterial Load / Q000187:drug effects; D018988:Bacterial Translocation / Q000187:drug effects; D003092:Colitis / Q000276:immunology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D000069196:Gastrointestinal Microbiome / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects; D007073:Immunoglobulin E / Q000378:metabolism; D016130:Immunophenotyping; D007249:Inflammation / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D018523:Tropism / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D053594:Myeloid Differentiation Factor 88; C064655:V(D)J recombination activating protein 2; D007073:Immunoglobulin E