The Role of Type I Interferons in TLR7-Mediated Lupus and UVB-Induced Immune Cell Responses
dc.contributor.author | Wolf-Fortune, Sonya | |
dc.date.accessioned | 2019-10-01T18:25:14Z | |
dc.date.available | NO_RESTRICTION | |
dc.date.available | 2019-10-01T18:25:14Z | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/151513 | |
dc.description.abstract | Systemic Lupus Erythematosus (SLE) is an autoimmune disease that affects up to .02% of the US population and nearly 90% of patients are women. These SLE patients experience devastating organ damage mediated by autoantibody production, immune complex deposition, and elevated production of type I interferons (IFNs). SLE disease activity occurs in a series of flares that incrementally damage kidneys, skin, liver and other organs. Type I IFNs are purported to be important cytokines in the development of SLE, but their role in TLR7- mediated lupus development and UVB induced immune response has not been well understood. This thesis addresses two main questions: 1) What role do type I IFNs play in TLR7 –mediated lupus development. To investigate the role of cutaneous TLR7 signaling and IFN production in lupus flare development, we used a lupus-prone murine model NZM 2328 (NZB/W derived congenic strain) and iNZM (knockout of the α-chain on the IFNα/β receptor). In order to induce lupus flare, mice were treated on the ear with R848 (TLR 7 agonist). Importantly, we show that both NZM and iNZM mice exhibit a decline in survival after 3 to 4 weeks with R848 but not vehicle treatment. This TLR 7 cutaneous stimulation resulted in development of splenomegaly and liver inflammation in a type I IFN-dependent manner. Interestingly, development of autoantibody production in the LN occurred in the absence of type I IFN signaling. Upregulation of IL-1β, ccl2 and renal infiltration of dendritic cells also occurred in a type I IFN-independent manner. Though upregulation of IL-1β occurred, knockout of IL-1β in NZM mice did not show to be protective. These data suggest induction of both type I IFN dependent and independent lupus phenotypes downstream of TLR 7 cutaneous stimulation. 2) What role do type I IFNs play in UVB-induced immune response in lupus-prone mice In order to examine UVB responses, eight-to-ten-week-old female wild-type (BALB/c), lupus-prone (NZM2328) and iNZM mice (lack a functional type I IFN receptor on NZM2328 background) were treated on their dorsal skin with 100mJ/cm2 of UVB for 5 consecutive days. We demonstrated elevated expression of type I IFNs in lupus vs. healthy skin following UVB exposure. Further, we show that UVB treatment led to skewed T cell activation in the dLN of lupus-prone mice through type I IFNs suppression of T regulatory cells. In addition, type I IFNs increased inflammation in lupus compared to healthy skin through regulating the recruitment of differential DC populations and inducing macrophage activation. We also identified that CD103+CDllb- DCs migrate into the dLN of lupus-prone mice in a type I IFN dependent manner. These data suggest type I IFNs prime lupus skin for increased inflammatory response. Thus, we propose that type I IFNs are important for UVB-induced inflammation through regulation of the innate and adaptive immune response in lupus-prone mice and may be an effective target for prevention of UVB- induced cutaneous inflammation. | |
dc.language.iso | en_US | |
dc.subject | Systemic Lupus Erythematosus | |
dc.subject | type I interferons | |
dc.subject | TLR7 | |
dc.subject | UVB | |
dc.title | The Role of Type I Interferons in TLR7-Mediated Lupus and UVB-Induced Immune Cell Responses | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Immunology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.contributor.committeemember | Kahlenberg, J Michelle | |
dc.contributor.committeemember | Raghavan, Malini | |
dc.contributor.committeemember | Cascalho, Marilia I | |
dc.contributor.committeemember | Fox, David A | |
dc.contributor.committeemember | Grigorova, Irina L | |
dc.contributor.committeemember | Knight, Jason Scott | |
dc.subject.hlbsecondlevel | Microbiology and Immunology | |
dc.subject.hlbtoplevel | Health Sciences | |
dc.description.bitstreamurl | https://deepblue.lib.umich.edu/bitstream/2027.42/151513/1/sonwolf_1.pdf | |
dc.identifier.orcid | 0000-0003-3626-9274 | |
dc.identifier.name-orcid | Wolf-Fortune, Sonya; 0000-0003-3626-9274 | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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