INTESTINAL MICROBIAL SIGNALS SUSTAIN INFLAMMATION AND AUTOIMMUNITY INDUCED BY HYPOMORPHIC RAG DEFECTS

Hypomorphic RAG mutations cause profound immunodeficiency associated with autoimmune-like manifestations, mediated by oligoclonal activated T cells, in humans and mice. The role of microbial signals and gut homeostasis in the disease pathogenesis is debated. The Rag2^R229Q/R229Q mice developed an inflammatory bowel disease characterized by marked infiltration of CD4+T cells producing both Th1 and Th17 cytokines. Similar pro-inflammatory profile was also evident in the periphery and a significant proportion of splenic effector T cells expressed the CCR9 and alpha4beta7 receptors, underlying the abnormal lymphocyte trafficking to this environmental interface in mutant mice. Moreover, deficiency in mucosal B cells and IgA secretion enhanced intestinal permeability and resulted in reduced microbial biodiversity. Fecal transplant into wild-type mice increased host Th1/Th7 mucosal responses, indicating the pathogenic potential of microbiota populating the gut of Rag2^R229Q/R229Q mice. Consistently, administration of broad-spectrum antibiotics significantly limited gut lymphocytic infiltration, and ameliorated both the intestinal and systemic inflammation by diminishing the frequency of Th1/Th17 cells. These results suggest that gut microbiota play a key role in the immune dysregulation distinctive of these conditions.

Supported by grant from the Fondazione Cariplo 2012-0519, by FIR from MIUR RBFR12I3UB_001 and Giovani Ricercatori from Ministero della salute GR-2011-02349759