Type 1 diabetes (T1D), a disease characterized by the autoimmune-mediated destruction of the insulin-secreting beta cells of the pancreas, affects approximately 1% of the US population, with an incidence that is increasing at a rate of 3% per year. Beta cell killing is accomplished through various immune-mediated mechanisms, with the production of reactive oxygen species (ROS) contributing to both inflammation and cell death. While previous reports suggested that antioxidant scavenging protected beta cells against ROS-mediated damage, islet-specific over-expression of antioxidants was not fully protective. As systemic elevation in free radical defenses had a positive impact on islet survival, I hypothesize that control of oxidative stress at the level of the immune system will regulate proinflammatory responses.
Genetic studies using the ALR mouse have provided strong support for my hypothesis. ALR-derived diabetes resistance and reduced oxidative burst from neutrophils and macrophages, as well as elevated Superoxide Dismutase 1 (SOD1) activity all map to the Suppressor of superoxide production (Susp) locus on Chr. 3. NAPDH oxidase (NOX) function from ALR cells could be rescued with inhibition of SOD1, demonstrating that dissipation was modifying immune effector function. Elevated SOD1 activity was associated with increased dimer stability, suggesting a post-translational modification is enhancing dimerization.
Introduction of Susp into the NOD background was highly protective against T1D. This resistance is linked to the loss of T lymphocyte diabetogenic potential. The loss of T cell ROS in T1D protection was confirmed using NOX-deficient NOD mice. T cell lineage commitment and proinflammatory cytokine synthesis were dependent on ROS signaling. Macrophages and T cells from NOD-Ncf1m1J mice exhibited a skewed cytokine response, with increased synthesis of IL-17 and IL-10, as opposed to the predominant IFN-γ production typically observed from NOD lymphocytes.
Genome-wide analyses were performed to fine map Susp in order to define the mechanism leading to altered SOD1 activity. Positional cloning experiments mapped Susp between D3Mit180 (34.4 Mbp) and D3Mit223 (34.8 Mbp) on Chr. 3. This mapping defines a novel candidate region involved in the regulation of SOD1 activity and dimerization stability, resulting in reduced superoxide release via NADPH oxidase activity.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12162010-142102 |
| Date | 23 December 2010 |
| Creators | Thayer, Terri Christine |
| Contributors | Jay Kolls, Massimo Trucco, Clayton Mathews, William Ridgway, Bruce Freeman |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12162010-142102/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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