TY - JOUR
T1 - Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency
AU - Castagnoli, Riccardo
AU - Pala, Francesca
AU - Subramanian, Poorani
AU - Oguz, Cihan
AU - Schwarz, Benjamin
AU - Lim, Ai Ing
AU - Burns, Andrew S.
AU - Fontana, Elena
AU - Bosticardo, Marita
AU - Corsino, Cristina
AU - Angelova, Angelina
AU - Delmonte, Ottavia M.
AU - Kenney, Heather
AU - Riley, Deanna
AU - Smith, Grace
AU - Ott de Bruin, Lisa
AU - Oikonomou, Vasileios
AU - Dos Santos Dias, Lucas
AU - Fink, Danielle
AU - Bohrnsen, Eric
AU - Kimzey, Cole D.
AU - Marseglia, Gian Luigi
AU - Alva-Lozada, Guisela
AU - Bergerson, Jenna R.E.
AU - Brett, Ana
AU - Brigatti, Karlla W.
AU - Dimitrova, Dimana
AU - Dutmer, Cullen M.
AU - Freeman, Alexandra F.
AU - Ale, Hanadys
AU - Holland, Steven M.
AU - Licciardi, Francesco
AU - Pasic, Srdjan
AU - Poskitt, Laura E.
AU - Potts, David E.
AU - Dasso, Joseph F.
AU - Sharapova, Svetlana O.
AU - Strauss, Kevin A.
AU - Ward, Brant R.
AU - Yilmaz, Melis
AU - Kuhns, Douglas B.
AU - Lionakis, Michail S.
AU - Daley, Stephen R.
AU - Kong, Heidi H.
AU - Segre, Julia A.
AU - Villa, Anna
AU - Pittaluga, Stefania
AU - Walter, Jolan E.
AU - Vujkovic-Cvijin, Ivan
AU - Belkaid, Yasmine
AU - Notarangelo, Luigi D.
N1 - Publisher Copyright:
© 2025 Castagnoli et al.
PY - 2025/8/4
Y1 - 2025/8/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105004481415
UR - https://www.scopus.com/inward/citedby.url?scp=105004481415&partnerID=8YFLogxK
U2 - 10.1084/jem.20241993
DO - 10.1084/jem.20241993
M3 - Article
C2 - 40314722
AN - SCOPUS:105004481415
SN - 0022-1007
VL - 222
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 8
ER -