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The Role of Early Life Commensals & Peripheral Regulatory T Cells in Preventing Type 1 Diabetes in the NOD Mouse Model / Sarah K Maddux.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Maddux, Sarah K., author.
- Language:
- English
- Subjects (All):
- Immunology.
- Microbiology.
- Cellular biology.
- Immunology--Penn dissertations.
- Penn dissertations--Immunology.
- Local Subjects:
- Immunology.
- Microbiology.
- Cellular biology.
- Immunology--Penn dissertations.
- Penn dissertations--Immunology.
- Physical Description:
- 1 online resource (201 pages)
- Contained In:
- Dissertations Abstracts International 84-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Ann Arbor : ProQuest Dissertations & Theses, 2022
- Language Note:
- English
- Summary:
- Type 1 diabetes (T1D) is an autoimmune disease in which the immune system destroys the insulin producing β-cells in the pancreatic islets, leaving a person unable to control blood sugar levels. There are clear genetic factors that impact incidence of disease, especially MHC-II haplotype, which account for about 50% of heritable risk. There are haplotypes that make people highly susceptible to T1D while others are dominantly protective. However, the underlying mechanisms of these increased and decreased risks are largely unknown. While genetic risks for T1D clearly exist, there has also been a significant increase in incidence of the disease in the last century, approximately 1 - 3% per year in recent decades. This increase indicates that there are also important environmental factors that affect T1D risk. One such factor is the microbiota as various microbial factors and species have been associated with increased or decreased T1D incidence in humans. However, the mechanism of microbiota-derived risk or protection is also largely a mystery. In this study, I investigated the mechanism of protection provided by both a protective gene and a protective microbe. I found that Tregs may contribute to T1D protection conferred by expression of an MHC-II I-E transgene in non-obese diabetic (NOD) mice, a spontaneous mouse model of T1D. I also investigated the effects of a diabetes preventing microbe, Akkermansia muciniphila on immune development and found that it induced peripheral regulatory T cells (Tregs) and strong antibody responses in pre-weaning NOD mice but had no effect on Tregs in adult NOD mice. In NOD mice colonized with a gnotobiotic community designed to represent the early life microbiota, PedsCom, I also found that A. muciniphila enhanced antibody responses to two other commensals, Staphylococcus sciuri and Staphylococcus xylosus, which is a novel function observed for a commensal microbe. Collectively, this body of work provides a better understanding of how genetic and microbial factors provide protection from T1D through the function of Tregs and introduces a novel commensal to commensal interaction that may have yet unexplored impacts on host health.
- Notes:
- Source: Dissertations Abstracts International, Volume: 84-08, Section: B.
- Advisors: Silverman, Michael A.; Committee members: Oliver, Paula; Henao-Mejia, Jorge; Levy, Maayan; Eisenlohr, Lawrence.
- Department: Immunology.
- Ph.D. University of Pennsylvania 2022.
- Local Notes:
- School code: 0175
- ISBN:
- 9798374412567
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
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