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.
Immunopathological and microbial signatures of inflammatory bowel disease in partial RAG deficiency
R. Castagnoli and F. Pala are co-first authors.
P. Subramanian and C. Oguz contributed equally to this paper.
Disclosures: B.R. Ward reported grants from Swedish Orphan Biovitrum, Astra Zeneca, and Blueprint Medicines, and personal fees from Carilion Services outside the submitted work. S.R. Daley reported grants from Resseptor Therapeutics Ltd. and personal fees from Resseptor Therapeutics Ltd. outside the submitted work. No other disclosures were reported.
R. Castagnoli’s current affiliations are Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy and Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
A.I. Lim’s current affiliation is Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
