Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic <i>RAG</i> 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; Mora, J. Rodrigo; Pesole, Graziano; Vezzoni, Paolo; Poliani, Pietro Luigi; Grassi, Fabio; Villa, Anna; Cassani, Barbara

doi:10.1084/jem.20151116

Cited by 60 publications

(58 citation statements)

References 86 publications

(104 reference statements)

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“…Similar abnormalities have been reported in the thymus of Rag1 S723C and Rag2 R229Q mice, with poor CMD, virtual lack of expression of UEA‐1 ligand and claudin‐4, abundance of immature TEC progenitors, severe reduction in CK8 − CK5 + mTECs, and markedly reduced expression of AIRE and AIRE‐dependent TRAs . Furthermore, the number of both cDC and plasmacytoid DC (pDC) and generation of thymic T reg cells were severely reduced in both Rag1 S723C and Rag2 R229Q mice . The thymic medulla was also very small in Rag1 R972Q , Rag1 F971L , and Rag1 R972W mice, although CMD was partially preserved .…”

Section: Abnormalities Of Central and Peripheral T‐cell Tolerancesupporting

confidence: 71%

“…However, transfer experiments have shown that Rag2 R229Q T reg cells are dysfunctional and unable to prevent colitis. In addition, immunodeficient animals transplanted with Rag2 R229Q CD4 + T cells develop colitis, confirming the pathogenic role of T conv cells in this model . Besides T cells, also B cells may contribute to the immune dysregulation in mucosal tissues.…”

Section: Gut Immune Dysregulation and Rag Hypomorphic Mutationssupporting

confidence: 64%

“…Patients with hypomorphic RAG mutations often present with cutaneous and gastrointestinal clinical manifestations, reflecting immune dysregulation in these compartments. Similar to OS patients, a significant proportion of Rag2 R229Q mice develops spontaneous signs of intestinal disease, with infiltration of the lamina propria by activated T cells expressing high levels of CCR9 (a gut homing receptor) and of Th1 and Th17 cytokines . These mice also show significant accumulation of T reg cells in the gut lamina propria (likely as an attempt to maintain immune tolerance), despite the low number of these cells in peripheral lymphoid tissues.…”

Section: Gut Immune Dysregulation and Rag Hypomorphic Mutationsmentioning

confidence: 99%

“…It is possible that environmental factors may also exacerbate the effects of impaired immune tolerance, triggering autoimmunity. In this regard, mouse models may help investigate the impact of antigen exposure in driving tissue inflammation and immune dysregulation associated with hypomorphic RAG mutations …”

Section: Dysregulation Of Humoral Immunity Associated With Hypomorphimentioning

confidence: 99%

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RAG gene defects at the verge of immunodeficiency and immune dysregulation

Villa

Notarangelo

2018

Immunological Reviews

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Summary Mutations of the Recombinase Activating Genes (RAG) in humans underlie a broad spectrum of clinical and immunological phenotypes that reflect different degrees of impairment of T and B cell development and alterations of mechanisms of central and peripheral tolerance. Recent studies have shown that this phenotypic heterogeneity correlates, albeit imperfectly, with different levels of recombination activity of the mutant RAG proteins. Furthermore, studies in patients and in newly developed animal models carrying hypomorphic RAG mutations have disclosed various mechanisms underlying immune dysregulation in this condition. Careful annotation of clinical outcome and immune reconstitution in RAG-deficient patients who have received hematopoietic stem cell transplantation has shown that progress has been made in the treatment of this disease, but new approaches remain to be tested to improve stem cell engraftment and durable immune reconstitution. Finally, initial attempts have been made to treat RAG deficiency with gene therapy.

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Section: Abnormalities Of Central and Peripheral T‐cell Tolerancesupporting

confidence: 71%

Section: Gut Immune Dysregulation and Rag Hypomorphic Mutationssupporting

confidence: 64%

Section: Gut Immune Dysregulation and Rag Hypomorphic Mutationsmentioning

confidence: 99%

Section: Dysregulation Of Humoral Immunity Associated With Hypomorphimentioning

confidence: 99%

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RAG gene defects at the verge of immunodeficiency and immune dysregulation

Villa

Notarangelo

2018

Immunological Reviews

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“…An important role of the microbiota in sustaining inflammation and autoimmunity has been recently shown in a mouse model of Omenn syndrome 103 . In this model, mucosal B cell deficiency alters the composition of the microbiota and causes bacterial translocation across the intestinal epithelium.…”

Section: Note Added In Proofmentioning

confidence: 99%

Human RAG mutations: biochemistry and clinical implications

et al. 2016

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The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate the V(D)J recombination process, which ultimately enables the generation of T cells and B cells with a diversified repertoire of antigen-specific receptors. Mutations of the RAG genes in humans are associated with a broad spectrum of clinical phenotypes, ranging from severe combined immunodeficiency to autoimmunity. Recently, novel insights into the phenotypic diversity of this disease have been provided by resolving the crystal structure of the RAG complex, by developing novel assays to test recombination activity of the mutant RAG proteins and by characterizing the molecular and cellular basis of immune dysregulation in patients with RAG deficiency.

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Excision of mesenteric lymph nodes alters gut microbiota and impairs social dominance in adult mice

et al. 2023

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Introduction Mesenteric lymph nodes (MLNs) are central in immune anatomy. MLNs are associated with the composition of gut microbiota, affecting the central system and immune system. Gut microbiota was found to differ among individuals of different social hierarchies. Nowadays, excision of MLNs is more frequently involved in gastrointestinal surgery; however, the potential side effects of excision of MLNs on social dominance are still unknown. Methods MLNs were removed from male mice (7–8 weeks old). Four weeks after MLN removal, social dominance test was performed to investigate social dominance; hippocampal and serum interleukin (IL)‐1β, IL‐10, and tumor necrosis factor‐alpha (TNF‐α) were investigated; and histopathology was used to evaluate local inflammation of the ileum. The composition of the gut microbiota was then examined to understand the possible mechanism, and finally intraperitoneal injection of IL‐10 was used to validate the effect of IL‐10 on social dominance. Results There was a decrease in social dominance in the operation group compared to the control group, as well as a decrease in serum and hippocampal IL‐10 levels, but no difference in serum and hippocampal IL‐1β and TNF‐α levels, and no local inflammation of the ileum after MLN removal. 16S rRNA sequencing analysis showed that the relative abundance of the class Clostridia was decreased in the operation group. This decrease was positively associated with serum IL‐10 levels. Furthermore, intraperitoneal injection of IL‐10 in a subset of mice increased social dominance. Conclusions Our findings suggested that MLNs contributed to maintaining social dominance, which might be associated with reduced IL‐10 and the imbalance of specific flora in gut microbiota.

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Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects

Abstract: Rigoni et al. report that hypomorphic Rag2R229Q mutation is associated with altered microbiota composition and defects in the gut–blood barrier and suggest that intestinal microbes may play a critical role in the distinctive immune dysregulation of Omenn syndrome.

Cited by 60 publications

References 86 publications

RAG gene defects at the verge of immunodeficiency and immune dysregulation

RAG gene defects at the verge of immunodeficiency and immune dysregulation

Human RAG mutations: biochemistry and clinical implications

Excision of mesenteric lymph nodes alters gut microbiota and impairs social dominance in adult mice

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