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: Rosita Rigoni, Elena Fontana, Simone Guglielmetti, Bruno Fosso, Anna Maria D'Erchia, Virginia Maina, Valentina Taverniti, Maria Carmina Castiello, Stefano Mantero, Giovanni Pacchiana, Silvia Musio, Rosetta Pedotti, Carlo Selmi, J Rodrigo Mora, Graziano Pesole, Paolo Vezzoni, Pietro Luigi Poliani, Fabio Grassi, Anna Villa, Barbara Cassani
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 213 Issue 3 Pg. 355-75 (Mar 07 2016) ISSN: 1540-9538 [Electronic] United States
• PMID: 26926994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 Rigoni et al.

Chemical References

• Anti-Bacterial Agents
• DNA-Binding Proteins
• Myeloid Differentiation Factor 88
• V(D)J recombination activating protein 2
• Immunoglobulin E

Topics

• Adoptive Transfer
• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Autoimmunity (drug effects)
• B-Lymphocytes (drug effects, immunology)
• Bacterial Load (drug effects)
• Bacterial Translocation (drug effects)
• Colitis (immunology, pathology)
• DNA-Binding Proteins (deficiency, metabolism)
• Gastrointestinal Microbiome (drug effects)
• Immune Tolerance (drug effects)
• Immunoglobulin E (metabolism)
• Immunophenotyping
• Inflammation (immunology, microbiology, pathology)
• Inflammatory Bowel Diseases (immunology, microbiology, pathology)
• Intestinal Mucosa (drug effects, microbiology, pathology)
• Mice, Inbred C57BL
• Myeloid Differentiation Factor 88 (deficiency, metabolism)
• Th1 Cells (immunology)
• Th17 Cells (immunology)
• Tropism (drug effects)