This project aims to integrate knowledge of genetic susceptibility, immune cell function, and environmental modifiers in determining risk for type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse model. Similar to human T1D, disease risk in the NOD mouse is polygenic and has been mapped to multiple Idd loci. We have fine-mapped the Idd4.1 locus and identified Nlrp1b as its candidate gene. We report an alternatively spliced isoform in the diabetes-resistant Nrlp1b allele, resulting in a truncated NLRP1b protein that is unable to activate release of IL-1β. In another aspect of this project, we have characterized the critical contribution to T1D pathogenesis by γδ T cells. We report that CD27- γδT cells infiltrate islets of pre-diabetic NOD mice. Adoptive transfer of T1D to lymphocyte-deficient NOD.SCID recipients was potentiated when CD27- γδ T cells were transferred, compared to transfer of αβ T cells alone. Antibody-mediated blockade of IL-17 prevented T1D transfer in this setting. Moreover, introgression of genetic Tcrd deficiency onto the NOD background provided robust T1D protection. Finally, we report novel relationships between the gut microbiome, host sex hormones and metabolism, and T1D pathogenesis in the NOD mouse. Using germ-free, specific pathogen free, and microbiome-transplanted NOD mice, we show that colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipients’ microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and endowed robust T1D protection. Collectively, the data presented in this thesis describe a novel genetic lesion involved in T1D risk and its immunological consequences, demonstrate a potent role for IL-17-producing γδ T cells in NOD mouse model, and uncover a novel relationship between the gut microbiome, host hormonal and metabolic phenotypes, and autoimmunity risk.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/65517 |
| Date | 20 June 2014 |
| Creators | Markle, Janet |
| Contributors | Danska, Jayne |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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