Gut dysbiosis breaks immunological tolerance toward the central nervous system during young adulthood

• Published in: The Journal of immunology (1950) 2017-05, Vol.198 (1_Supplement), p.125-125.31
• Main Authors: Yadav, Sudhir Kumar, Boppana, Sridhar, Ito, Naoko, Mindur, John E, Mathay, Martin T, Patel, Ankoor, Dhib-Jalbut, Suhayl, Ito, Kouichi
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.198.Supp.125.31

Multiple sclerosis (MS) is an immune mediated disease targeting the central nervous system (CNS) mainly in young adults, and a breakage of immune tolerance to CNS antigens has been suggested to initiate CNS autoimmunity. Recent studies have suggested that gut microbiota affects the development of autoimmune diseases and alterations in the gut microbiota, termed gut dysbiosis, are associated with MS. However, it is still unknown how gut dysbiosis affects the onset and/or progression of CNS autoimmunity. In this study, we investigated the effects of gut dysbiosis on the development of CNS autoimmunity in humanized transgenic mice expressing the MS- associated HLA-DR gene, DR2a, and the T cell receptor (TCR) gene specific for MBP87-99/DR2a that were derived from an MS patient. We show here that the induction of gut dysbiosis triggers the development of spontaneous experimental autoimmune encephalomyelitis (EAE) during adolescence and early adulthood, while increase in immunological tolerance with aging suppresses the disease onset after late young adulthood. Furthermore, gut dysbiosis induces the expression of complement C3 and production of the anaphylatoxin C3a, and down-regulates the expression of the Foxp3 gene in Tregs and anergy-related E3-ubiquitin ligase genes in CD4+CD25− T cells. Consequently, gut dysbiosis was able to trigger the development of encephalitogenic T cells and promote the induction of EAE during the young adulthood age-window. This data suggests that gut dysbiosis increases the risk for CNS autoimmunity in young adulthood through the up-regulation of the complement C3 gene and down-regulation of Foxp3 and E3-ubiquitin ligase genes.