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Hubaida Fuseini, Ph.D.

Department: Pathology, Microbiology & Immunology, 2019

Faculty Mentor: Dawn Newcomb, Ph.D.

Dissertation Title: The Role of Ovarian Hormones and Testosterone on Type 2 and IL-17A-Mediated Airway inflammation

Dissertation AbstractSevere 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.