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

Castagnoli R.; Pala F.; Subramanian P.; Oguz C.; Schwarz B.; Lim A.I.; Burns A.S.; Fontana E.; Bosticardo M.; Corsino C.; Angelova A.; Delmonte O.M.; Kenney H.; Riley D.; Smith G.; Ott de Bruin L.; Oikonomou V.; Dos Santos Dias L.; Fink D.; Bohrnsen E.; Kimzey C.D.; Marseglia G.L.; Alva-Lozada G.; Bergerson J.R.E.; Brett A.; Brigatti K.W.; Dimitrova D.; Dutmer C.M.; Freeman A.F.; Ale H.; Holland S.M.; Licciardi F.; Pasic S.; Poskitt L.E.; Potts D.E.; Dasso J.F.; Sharapova S.O.; Strauss K.A.; Ward B.R.; Yilmaz M.; Kuhns D.B.; Lionakis M.S.; Daley S.R.; Kong H.H.; Segre J.A.; Villa A.; Pittaluga S.; Walter J.E.; Vujkovic-Cvijin I.; Belkaid Y.; Notarangelo L.D. · The Journal of experimental medicine (2025) · DOI: 10.1084/jem.20241993

Resumen

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.