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