Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 Rag2R229Q 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 Rag2R229Q 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 Rag2R229Q 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 Rag2R229Q 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.

Original languageEnglish (US)
Pages (from-to)355-375
Number of pages21
JournalJournal of Experimental Medicine
Volume213
Issue number3
DOIs
StatePublished - 2016
Externally publishedYes

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Autoimmunity
Severe Combined Immunodeficiency
Inflammation
T-Lymphocytes
Th17 Cells
Microbiota
Immunocompromised Host
Regulatory T-Lymphocytes
Inflammatory Bowel Diseases
Immunoglobulin A
Immunoglobulin E
Colon
B-Lymphocytes
Lymphocytes
Anti-Bacterial Agents
Transplants
Phenotype
Mutation
Gastrointestinal Microbiome
Serum

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Rigoni, R., Fontana, E., Guglielmetti, S., Fosso, B., D'Erchia, A. M., Maina, V., ... Cassani, B. (2016). Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects. Journal of Experimental Medicine, 213(3), 355-375. https://doi.org/10.1084/jem.20151116

Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects. / Rigoni, Rosita; Fontana, Elena; Guglielmetti, Simone; Fosso, Bruno; D'Erchia, Anna Maria; Maina, Virginia; Taverniti, Valentina; Castiello, Maria Carmina; Mantero, Stefano; Pacchiana, Giovanni; Musio, Silvia; Pedotti, Rosetta; Selmi, Carlo; Rodrigo Mora, J.; Pesole, Graziano; Vezzoni, Paolo; Poliani, Pietro Luigi; Grassi, Fabio; Villa, Anna; Cassani, Barbara.

In: Journal of Experimental Medicine, Vol. 213, No. 3, 2016, p. 355-375.

Research output: Contribution to journalArticle

Rigoni, R, Fontana, E, Guglielmetti, S, Fosso, B, D'Erchia, AM, Maina, V, Taverniti, V, Castiello, MC, Mantero, S, Pacchiana, G, Musio, S, Pedotti, R, Selmi, C, Rodrigo Mora, J, Pesole, G, Vezzoni, P, Poliani, PL, Grassi, F, Villa, A & Cassani, B 2016, 'Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects', Journal of Experimental Medicine, vol. 213, no. 3, pp. 355-375. https://doi.org/10.1084/jem.20151116
Rigoni, Rosita ; Fontana, Elena ; Guglielmetti, Simone ; Fosso, Bruno ; D'Erchia, Anna Maria ; Maina, Virginia ; Taverniti, Valentina ; Castiello, Maria Carmina ; Mantero, Stefano ; Pacchiana, Giovanni ; Musio, Silvia ; Pedotti, Rosetta ; Selmi, Carlo ; Rodrigo Mora, J. ; Pesole, Graziano ; Vezzoni, Paolo ; Poliani, Pietro Luigi ; Grassi, Fabio ; Villa, Anna ; Cassani, Barbara. / Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects. In: Journal of Experimental Medicine. 2016 ; Vol. 213, No. 3. pp. 355-375.
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AU - D'Erchia, Anna Maria

AU - Maina, Virginia

AU - Taverniti, Valentina

AU - Castiello, Maria Carmina

AU - Mantero, Stefano

AU - Pacchiana, Giovanni

AU - Musio, Silvia

AU - Pedotti, Rosetta

AU - Selmi, Carlo

AU - Rodrigo Mora, J.

AU - Pesole, Graziano

AU - Vezzoni, Paolo

AU - Poliani, Pietro Luigi

AU - Grassi, Fabio

AU - Villa, Anna

AU - Cassani, Barbara

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N2 - 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 Rag2R229Q 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 Rag2R229Q 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 Rag2R229Q 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 Rag2R229Q 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.

AB - 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 Rag2R229Q 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 Rag2R229Q 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 Rag2R229Q 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 Rag2R229Q 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.

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