Hypomorphic mutations in the RAG genes cause a profound immunodeficiency associated with multisystem autoimmune–like manifestations, mediated by oligoclonal self-reactive T and B cells, named Omenn Syndrome (OS). The clinical and immunological spectrum of OS presentation is extremely broad. Commonly, patients present symptoms very similar to graft-versus-host disease (GVHD) as inflammatory reactions particularly involve the environmental interfaces such as the skin and gut, leading to distinctive early onset erythroderma and protracted diarrhea. However, the complete comprehension of the molecular and cellular mechanisms underlying such autoimmune-like manifestations in OS is still puzzling. Furthermore, the role played by environmental triggers in the disease pathogenesis remains largely unknown. In this thesis, we demonstrated that in hypomorphic Rag2R229Q\R229Q mice, the OS murine counterpart, mucosal B cell deficiency alters the composition of the gut microbiota and causes bacterial translocation across the intestinal epithelium. Furthermore, loss of T cell tolerance to the commensal microbiota leads to gut inflammation sustained by Th1 and Th17 cells. Interestingly, we provided evidence that these gut-derived inflammatory cells disseminate in the periphery, infiltrating target organs. Decreasing gut bacterial load in Rag2R229Q\R229Q mice with long-term dosing of antibiotics reverses most of these abnormalities and normalizes serum hyper-IgE, a hallmark of the disease. Similar mechanisms are involved in the development of skin degeneration in mutant mice. Indeed, we found that compromised skin barrier integrity results in altered microbial load and composition, and dysregulated production of T cell recruiting chemokines by stimulated epithelial cells. Importantly, we found that the chronic intestinal inflammation synergistically supports the activation of skin epithelial cells and the recruitment of gut-derived pathogenic T cells at the cutaneous barrier. Overall, this work provided first time evidence that commensals and/or commensal-derived signals might play a substantial role in shaping immune response and autoimmunity at barrier sites and beyond in RAG-associated immune deficiency
