dc.creator | Fuseini, Hubaida | |
dc.date.accessioned | 2020-08-22T00:23:18Z | |
dc.date.available | 2019-09-29 | |
dc.date.issued | 2019-04-02 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-04022019-104249 | |
dc.identifier.uri | http://hdl.handle.net/1803/11949 | |
dc.description.abstract | Severe asthma is a significant health care concern, with patients having poorer asthma control, poorer lung function, and increased health care costs compared to milder asthma phenotypes. A sexual dimorphism also exists in severe asthma, and as adults, women are twice as likely as men to have severe asthma. Increased type 2 cytokines and/or IL-17A, leading to increased airway eosinophil and neutrophils, respectively, are associated with asthma. Previous studies showed that ovarian hormones increased while testosterone decreased type 2 OR IL-17A-mediated inflammatory responses. However, the mechanisms by which sex hormones mediated dual type 2 cytokines and IL-17A inflammatory responses remained unclear. We hypothesized that during dual type 2 and IL-17A mediated airway inflammation, ovarian hormones promote inflammation by increasing cytokine expression of type 2 cytokines and IL-17A while testosterone attenuates inflammation by decreasing cell numbers of type 2 and IL-17A secreting cells. To test our hypothesis, we utilized a house dust mite (HDM) model of airway inflammation in hormonally intact or deficient female and male mice and determined how sex hormones affected total numbers and cytokine expression from CD4+ T helper cell subsets important for type 2 inflammation (Th2 cells) or IL-17A-mediated inflammation (Th17 cells). Ovarian hormones increased and testosterone decreased HDM-induced IL-13+Th2 cells and IL-17A+ Th17 cells, but through different mechanisms. Subsequent studies using ERα and AR deficient mice determined that ERα signaling increased IL-23R surface expression on Th17 cells, leading to increased IL-17A protein expression. However, AR signaling intrinsically decreased total numbers of IL-17A+ Th17 cells in the lung and decreased Il23r mRNA and IL-17A protein expression in Th17 cells. Combined, these findings showed that sex hormones signaling regulates type 2 and IL-17A-mediated airway inflammation and IL-17A expression in Th17 cells, providing potential mechanisms for the increased prevalence of asthma in women compared to men. | |
dc.format.mimetype | application/pdf | |
dc.subject | type 2 | |
dc.subject | testosterone | |
dc.subject | ovarian hormones | |
dc.subject | estrogen receptor alpha | |
dc.subject | asthma | |
dc.subject | androgen receptor | |
dc.subject | IL-17A | |
dc.title | The Role of Ovarian Hormones and Testosterone on Type 2
and IL-17A-Mediated Airway inflammation | |
dc.type | dissertation | |
dc.contributor.committeeMember | Amy S. Major | |
dc.contributor.committeeMember | Robert J. Matusik | |
dc.contributor.committeeMember | R. Stokes Peebles | |
dc.contributor.committeeMember | Dawn C. Newcomb | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Microbiology and Immunology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2019-09-29 | |
local.embargo.lift | 2019-09-29 | |
dc.contributor.committeeChair | Jeffrey C. Rathmell | |