Degree
Doctor of Philosophy
Program
Microbiology and Immunology
Supervisor
Kerfoot, Steven M.
Abstract
Germinal center (GC) responses are responsible for the protection provided by immunizations but can also drive autoimmunity. B and T cells collaborate in the GC to target the same antigen (Ag) to inform B cell differentiation; however, the properties of Ags differ substantially in autoimmunity and foreign-Ag driven immunity. Currently, it is not well understood how properties of the Ag itself influence the initiation or progression of GC responses, limiting our ability to develop effective vaccinations and predict the progression of autoimmune responses. The purpose of this thesis is to assess how GC responses initiate and progress when immunizing with an autoAg relative to a model foreign-Ag. It was hypothesized that autoreactive GCs would be relatively short-lived and less productive than foreign-Ag driven GCs due to limiting properties of the autoAg. To address this hypothesis, we developed a modular protein expression system to purify large amounts of myelin oligodendrocyte glycoprotein (MOG), a commonly targeted autoAg in Multiple Sclerosis (MS), and streamlined the modification of the MOG protein’s properties. Relative to immunization with a model foreign-Ag, immunization with MOG induces a short-lived GC that collapses early forming a large numbers of memory B cells. Memory B cells generated from the MOG-induced GC are capable of participating in secondary GCs, however, these memory cells are short-lived resulting in a short window in which MOG-specific memory B cells can be engaged. The progression of the MOG-induced GC is then shown to be limited by low T cell Ag-affinity. A possible explanation for how Ag-properties affect GC progression, is that Ag-properties influence how B and T cells communicate with each other. To address this hypothesis, reporters capable of monitoring the activation status of B and T cells were generated although, attempts to generate mice carrying these reporters were unsuccessful. Overall, these results confirm that properties of Ags affect the progression of GC responses and that the MOG-induced GC is limited by properties of the MOG autoAg. These results have important implications for future vaccine design but also gives insight into how autoreactive B cells may expand in MS.
Recommended Citation
Jain, Rajiv William, "Immunization With Recombinant Myelin Oligodendrocyte Glycoprotein Identifies Autoreactive T Cells As A Limiting Factor In Autoreactive Germinal Center Maintenance" (2018). Electronic Thesis and Dissertation Repository. 5809.
https://ir.lib.uwo.ca/etd/5809