INVESTIGATING HOW HOST-MICROBE INTERACTIONS INFLUENCE THE PROGRESSION OF TYPE 1 DIABETES
Date
2024-11-25
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Abstract
The global prevalence of allergies and autoimmune diseases, such as type 1 diabetes (T1D), has increased significantly over the past 50 years. Epidemiological evidence points to the gut microbiome as being one of the strongest drivers of increased disease incidence. Recent research has described associations between microbiome signatures and disease incidence through the induction of immune responses, however the underlying mechanisms by which the gut microbiome influences T1D progression remains largely unknown. Using gnotobiotic mouse models, this thesis aims to explore the role of host-microbe interactions in T1D development. One way in which the microbiome can modulate autoimmunity is through molecular mimicry. Previous work in the lab identified BacINT36-44, which will be referred to as Integrase, expressed by a commensal strain of Bacteroides as a bonafide molecular mimic to the islet autoantigen, IGRP206-214. Here, we further explored how Integrase expression by bacterial species in the gut influences antigen-specific immune responses in the T1D susceptible non-obese diabetic mouse model. Although microbial Integrase expression did not influence disease incidence in monocolonized mice, antigen-specific T cells were found to significantly modulate microbiome composition in specific-pathogen free mice. Additional analysis suggested that these changes were specific to Integrase expressing species. Integrase expression within the commensal gut microbiome also induced the expansion of antigen specific T cells both locally, within the gastrointestinal associated lymphoid tissue, and systemically, in the spleen. In addition, we sought to further investigate how the transfer of maternal antibodies influences T1D development in the offspring. It is widely accepted that the transfer of maternal antibodies during breast feeding shapes immune responses in the offspring. Thus, we explored how the transfer of maternal antibodies influences immune maturation in response to the microbiome. Together, this thesis reveals how the gut microbiome influences T1D, how molecular mimicry between gut microbes and self-antigens can shape antigen-specific immune responses, and the pathogenic role of maternal antibodies in non-obese diabetic mice.
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gut microbiome, Type 1 Diabetes, Immunology, Maternal Antibodies, Molecular Mimicry
Citation
Abbott, S. (2024). Investigating how host-microbe interactions influence the progression of type 1 diabetes (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.