Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Cameron, Lisa

Abstract

Women are more likely to have severe asthma than men. Recent data suggest this could be due to women having more circulating CD4+CRTh2+ T cells (Th2 cells). Glucocorticosteroids (GC)s are the main therapy for asthma as they inhibit cytokine production and eliminate inflammatory cells by apoptosis. The current study examined whether the female sex hormone estrogen influences the anti-inflammatory action of GC. Experiments show that ER⍺ agonist reduced GC-induced apoptosis of primary Th2 cells and enhanced GC-mediated transcriptional activation of the proximal CRTh2 promoter. Genetic variation within CRTh2 is associated with asthma and allergic phenotypes. Using constructs representing the single nucleotide polymorphism CRTh2-6388G>A, ER⍺ agonist enhanced GC-induced activity of the A but not the G allele. Collectively, these data suggest that in vivo Th2 cells may exhibit sex and genotype specific response to GC and that some of these effects are pro-inflammatory.

Summary for Lay Audience

Throughout the world, asthma places a large financial burden on the health care system. Genetic and environmental factors both play a role in the development of this disorder. Glucocorticosteroids (GC)s are the main treatment for asthma because of their anti- inflammatory action. Despite being effective in most patients, in severe asthmatics GC therapy fails to control asthma symptoms. Less understood is that GCs can also promote expression of some immune genes such as CRTh2 (chemoattractant receptor-homologous molecule expressed on Th2 cells), which supports the survival of Th2 cells. Women are more likely to be diagnosed with severe asthma and were recently shown to have more circulating Th2 cells than men. This may be due to estrogen influencing Th2 differentiation or the effect of GC on Th2 cells. On this basis, it was hypothesized that estrogen reduces the ability of GC to trigger Th2 cell death, that this occurs by enhancing GC-mediated increase in CRTh2 expressing cells, and that the outcome of this cross-talk is altered by genetic variation in CRTh2. Results revealed that the ability of GC to induce Th2 cell death was dampened by co-treatment was estrogen. Though the mechanism of enhanced survival was not confirmed to be due to increased expression of CRTh2, results do show that GC activated CRTh2 transcription and this effect was enhanced by co-treatment with an estrogen receptor agonist. Analysis of the CRTh2 gene variant CRTh2-6388G>A showed that estrogen enhanced the ability of GC to induce transcriptional activation of the CRTh2-6388A allele. This study suggests that combined exposure to GC and estrogen, an environment found in women taking GC for their asthma, increases Th2 cell survival. If this occurs in vivo, this cross-talk may explain why women have more Th2 cells and asthma severity than men. Transcriptional activation of CRTh2 was induced by GC and estrogen in a genotype specific manner. Ultimately, these results suggest that precision medicine for asthma therapy should consider both sex and CRTh2 genetics.

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