Thayer, Terri Christine
(2010)
CRITICAL ROLE OF SUPEROXIDE PRODUCTION IN THE PATHOGENESIS OF AUTOIMMUNE DIABETES.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
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Details
Item Type: |
University of Pittsburgh ETD
|
Status: |
Unpublished |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID  |
---|
Thayer, Terri Christine | tes32@pitt.edu | TES32 | |
|
ETD Committee: |
Title | Member | Email Address | Pitt Username | ORCID |
---|
Committee Chair | Mathews, Clayton | | | | Committee Member | Freeman, Bruce | freerad@pitt.edu | FREERAD | | Committee Member | Kolls, Jay | | | | Committee Member | Trucco, Massimo | nonemnt@pitt.edu | NONEMNT | | Committee Member | Ridgway, William | | | |
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Date: |
23 December 2010 |
Date Type: |
Completion |
Defense Date: |
13 October 2010 |
Approval Date: |
23 December 2010 |
Submission Date: |
16 December 2010 |
Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
Institution: |
University of Pittsburgh |
Schools and Programs: |
School of Medicine > Immunology |
Degree: |
PhD - Doctor of Philosophy |
Thesis Type: |
Doctoral Dissertation |
Refereed: |
Yes |
Uncontrolled Keywords: |
autoimmune diabetes; genetics; reactive oxygen species; superoxide dismutase |
Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-12162010-142102/, etd-12162010-142102 |
Date Deposited: |
10 Nov 2011 20:11 |
Last Modified: |
15 Nov 2016 13:54 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/10398 |
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