Cosgrove, Haylee Alexis
(2024)
Toll-Like Receptor 7 in Systemic Lupus Erythematosus: Characterization of Cell-Intrinsic Roles and Regulation by NADPH Oxidase.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Systemic lupus erythematosus is an autoimmune disease characterized by loss of tolerance to self-nucleic acids, followed by immune cell activation and infiltration into nearly every organ system throughout the body. As such, it is a disease that can greatly impact quality of life and remains a major cause of morbidity and mortality across the globe despite recent therapeutic advances. Although many biological pathways have been implicated in disease pathogenesis, the cardinal pathway responsible for breakdown of tolerance in SLE is signaling through the nucleic acid sensing, endosomal toll-like receptors. Specifically, TLR7 has repeatedly been implicated as a driver of SLE in both mice and humans. However, questions remain regarding how TLR7 promotes disease in specific immune cell subsets and how it is regulated. In this dissertation, I define the B cell and CD11c+ dendritic cell intrinsic roles of TLR7 in SLE, demonstrating that B cell intrinsic TLR7 drives severe lupus when lacking regulation by TLR9. I also elucidate global and B-cell intrinsic regulatory relationships between TLR7 and NOX2, another protein implicated in SLE. Finally, I explore the B cell intrinsic mechanisms of NOX2-mediated negative regulation of TLR7 signaling and structure. This work supports the concept of targeting B cell intrinsic TLR7 in lupus to improve outcomes and quality of life for patients.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
16 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
5 January 2024 |
| Approval Date: |
16 September 2024 |
| Submission Date: |
16 January 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
181 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
lupus, systemic lupus erythematosus, TLR7, TLR, toll-like receptor, autoimmunity, autoimmune disease, NADPH oxidase, NOX2 |
| Date Deposited: |
16 Sep 2024 19:04 |
| Last Modified: |
16 Sep 2024 19:04 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45766 |
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