Interactions between the immune system and the nervous system are currently underappreciated, assumed to play minor mechanistic roles in disease pathogenesis. In contrast, our laboratory has demonstrated the importance of this relationship with significant impact, initially in Type 1 Diabetes (T1D). The experiments presented here build on our previous work to provide insights into the etiology of Multiple Sclerosis (MS) and Type 2 Diabetes (T2D).
Transient Receptor Potential Vanilloid-1 (TRPV1) is an ion channel expressed on peripheral sensory afferent neurons that fundamentally control T1D pathogenesis. Here we show that mice with genetic ablation of TRPV1 are protected from EAE progression, attributable to reduced central nervous system (CNS) leukocyte passage. The pathogenic role of TRPV1 in permeabilizing the blood-CNS barriers may also translate to MS, as patients with progressive disease show a significant mutation bias within the TRPV1 gene.
We were simultaneously intrigued by the growing worldwide obesity epidemic, and we observed that obese mice develop more severe EAE compared to lean mice. This was mechanistically linked to an expansion of TH17 cells, driven by sustained rises of IL-6 in obese mice. This research implies new therapeutic opportunities for the many obese patients with diverse autoimmune diseases.
Finally, the immune system, obesity, and T2D are functionally linked, and we contributed to research that uncovered a large presence of immune cells in adipose tissue that drive insulin resistance. Manipulation of T cells and B cells affects local inflammation as well as whole-body insulin resistance and glucose homeostasis. Intriguingly, auto-antibodies in insulin resistant individuals are specific for a number of unique proteins, including glial fibrillary acidic protein (GFAP), initially shown by our laboratory to play a key role in T1D progression. We further characterized the autoimmune and neuronal progression elements that steer disease pathogenesis, and observed that administration of a vaccine containing GFAP is able to dramatically reduce weight gain and insulin resistance in mice.
The data presented in this thesis provide a number of novel, mechanistic observations linking the immune and nervous systems in disease, and implies several potential avenues for treatment.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/43706 |
| Date | 14 January 2014 |
| Creators | Paltser, Geoffrey |
| Contributors | Dosch, Hans-Michael |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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