Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency

Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature. Restriction of fecal microbial diversity, abundance of pathogenic bacteria, and depletion of microbial species producing short-chain fatty acid were observed, which were associated with impaired induction of lamina propria peripheral Treg cells in Rag1w/w mice. The use of vedolizumab in Rag1w/w mice and of ustekinumab in a pRD patient were ineffective. Antibiotics ameliorated gut inflammation in Rag1w/w mice, but only bone marrow transplantation (BMT) rescued the immunopathological and microbial signatures. Our findings shed new light in the pathophysiology of gut inflammation in pRD and establish a curative role for BMT to resolve the disease phenotype.

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Publication Details

Journal
The Journal of Experimental Medicine
Published
2025-05-02
DOI
https://doi.org/10.1084/jem.20241993
Citations
2
Primary Topic
Gut microbiota and health
Type
article
Field-Weighted Citation Impact
1.61

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article

Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency

Heather Kenney, Deanna Riley, Vasileios Oikonomou, Eric Bohrnsen et al.
2 citations
The Journal of Experimental Medicine
Gut microbiota and health
1.61
article

Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency

Heather Kenney, Deanna Riley, Vasileios Oikonomou, Eric Bohrnsen, Stefania Pittaluga, Laura Poskitt, Karlla W. Brigatti, Francesco Licciardi, Douglas B. Kuhns, Marita Bosticardo, Kevin A. Strauss, Michail S. Lionakis, Heidi H. Kong, Luigi Daniele Notarangelo, Jolán E. Walter, Joseph Dasso, Ottavia M. Delmonte, Svetlana Sharapova, Ivan Vujkovic-Cvijin, Melis Yilmaz, Elena Fontana, Angelina Angelova, Cihan Oguz, Dimana Dimitrova, Danielle A Fink, Ana Brett, Grace Smith, Riccardo Castagnoli, Benjamin Schwarz, Gian Luigi Marseglia, Steven M. Holland, Guisela Alva‐Lozada, Srdjan Pašić, Lisa Ott de Bruin, Alexandra F. Freeman, Brant R. Ward, Cristina Corsino, Yasmine Belkaid, Ai Ing Lim, Francesca Pala, Cullen M. Dutmer, Stephen R. Daley, Hanadys Ale, Lucas dos Santos Dias, Poorani Subramanian, Jenna Bergerson, Anna Villa, Andrew S. Burns, David Evan Potts, Julia A. Segre, Cole D. Kimzey
article en
2 citations

Abstract

Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature. Restriction of fecal microbial diversity, abundance of pathogenic bacteria, and depletion of microbial species producing short-chain fatty acid were observed, which were associated with impaired induction of lamina propria peripheral Treg cells in Rag1w/w mice. The use of vedolizumab in Rag1w/w mice and of ustekinumab in a pRD patient were ineffective. Antibiotics ameliorated gut inflammation in Rag1w/w mice, but only bone marrow transplantation (BMT) rescued the immunopathological and microbial signatures. Our findings shed new light in the pathophysiology of gut inflammation in pRD and establish a curative role for BMT to resolve the disease phenotype.

The Journal of Experimental MedicineVol. 222(8)
Leidos (United States) (US), Cedars-Sinai Medical Center (US), National Institutes of Health (US), Clinic for Special Children (US), Children's National (US), Johns Hopkins University (US), Emory University (US), Institut Pasteur (FR), Queensland University of Technology (AU), University of Pavia (IT), University of South Florida (US), Leiden University Medical Center (NL), University of Belgrade (RS), National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), National Human Genome Research Institute (US), Hospital Nacional Cayetano Heredia (PE), Grade Medical (Czechia) (CZ), Memorial Healthcare System (US), Johns Hopkins All Children's Hospital (US), Institute of Genetic and Biomedical Research (IT), Frederick National Laboratory for Cancer Research (US), National Institute of Allergy and Infectious Diseases (US), Ospedale Regina Margherita (IT), National Cancer Institute (US), The San Raffaele Telethon Institute for Gene Therapy (IT), Children's Healthcare of Atlanta (US), Belarusian Research Center For Pediatric Oncology and Hematology (BY), Policlinico San Matteo Fondazione (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Joe DiMaggio Children's Hospital (US), IRCCS Humanitas Research Hospital (IT), University of Coimbra (PT)
U.S. Department of Health and Human Services, Crohn's and Colitis Foundation of America, Cedars-Sinai Medical Center, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, NHLBI Division of Intramural Research
Good health and well-being
Openalex Percentile: Top 17%
Gut microbiota and health
1.61
DOISourceOpenAlex
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