Regulation of Autoimmunity and Inflammation by microRNAs and Environmental Factors

Sammanfattning: Tolerance is crucial for maintaining immunological balance and avoid autoimmune diseases like type 1 diabetes and the inflammatory bowel disease, ulcerative colitis (UC). In Study I, we have investigated the regulatory role of a class of noncoding RNAs, the miRNAs, during thymocyte development of the where central tolerance is established. We used the non-obese diabetic mouse (NOD) which is spontaneously developing T1D and have been described to have defects in the T cell maturation. By studying the apoptosis response of NOD lymphocytes (which activates similar cell-cycle checkpoints and apoptosis pathways as during thymocyte maturation) we showed differential expression of the miRNA-34a/b/c gene family, miR-125 and miR-155 in the DNA damage response between NOD and wild-type mice. We believe that these differentially expressed miRNAs may contribute to defect p53 expression in NOD thymocytes after DNA damage, which we also demonstrated in this study. In Study II, we studied the importance of global canonical miRNA regulation in the NOD mice for the development of T1D development by deleting Dicer1 (an enzyme needed for miRNA maturation) early in thymocyte development. We showed that these NOD.Lck-Cre Dicer KO mice had phenotype alterations including markedly decreased amount of αβ CD4+ and CD8+ T cells in the secondary lymph nodes but not a similarly large decrease in nTregs. No difference in diabetes incidence between female NOD.Lck-Cre Dicer KO mice and control littermates could be found as a result of these phenotypic changes but surprisingly a significant increase in the male mice diabetes incidence. In Study III, we investigated whether the maternal intestinal microbiota is an environmental factor influencing T1D development in the offspring. By modulating the intestinal gut microbiota with antibiotics during pregnancy of NOD mice we showed decreased diversity and a persistent modulation of the intestinal microbial pattern in the offspring. Possibly resulting in the immunological alterations of CD8+ and CD4+CD25+ T cell frequencies in the mesenteric lymph nodes respectively Peyer’s patches, which we demonstrated. The diabetes incidence seems to have increased in the offspring to treated mothers at 20 weeks of age but the effect was not persistent. In study IV, the relationship between the global intestinal microbiota and the immune system was investigated in the dextran sulfate sodium induced UC mouse model. We demonstrated changes in the colonic intestinal microbiota pattern and immunological alterations of different populations of T cells, dendritic cells and natural killer cells after UC induction.