The pathophysiology of eosinophilic esophagitis: Altered mechanisms of antigen detection in the esophagus

Recently, a chronic idiopathic disease of the esophagus has emerged, which is now known as eosinophilic esophagitis (EoE). Incomplete knowledge regarding the pathogenesis of EoE has limited treatment options. EoE is known to be a Th2-type immune-mediated disorder. Based on previous studies in both patients and experimental models, it is possible that an abnormal reaction to antigen mediates the pathophysiology of EoE. In this thesis, symptoms and signs unique to EoE were identified by an age-matched, case-controlled study of 326 patients with EoE and gastroesophageal reflux disease. The molecular mechanisms involved in antigen detection in the esophagus, in relation to EoE were then investigated. Esophageal epithelial cells were found, for the first time, to be capable of acting as non-professional antigen presenting cells, with the ability to engulf, process and present antigen on MHC class II to T helper lymphocytes. Antigen presentation by esophageal epithelial cells was induced by interferon-γ, which is increased in biopsies from patients with EoE. Next, it was discovered that esophageal epithelial cell lines expressed functional toll-like receptor (TLR) 2 and TLR3, but in esophageal mucosal biopsies only infiltrating immune cells (including eosinophils) expressed TLR2 and TLR3. Finally, the potential involvement of IgE in the pathogenesis of esophageal inflammation was investigated. IgE in the esophagus was found to be present on mast cells, which are increased in density in the esophageal mucosae of patients with EoE and especially those with a history of atopy. Mechanisms of antigen detection may mediate the pathophysiology of EoE in the esophagus through antigen presentation by epithelial cells, detection by TLRs on immune cells and detection through IgE on mucosal mast cells. Together, these findings demonstrate that mechanisms of antigen detection may actually contribute to the pathophysiology of EoE. Through increased understanding of the mechanisms of EoE, the results of this thesis may contribute to future therapy.

AUSTRALIA’S STRATEGIC CULTURE: An investigation of the concept of strategic culture and its application to the Australian case

The notion that each state in the international system approaches matters of war and peace somewhat differently because they each possess a unique strategic culture is not a new or obscure one – but it nevertheless remains controversial. While some scholars dismiss the utility or practicality of examining states’ cultures when seeking to explain or predict those states’ patterns of strategic decision-making, even amongst those who accept that we should pay attention to cultural differences between states when carrying out strategic analysis there remains a frustratingly eclectic range of offerings from scholars regarding how best to do so. In short, significant uncertainty remains regarding both whether strategic culture should be used as an analytical tool and, if it is so utilized, how one should go about doing so. This thesis therefore explores the concept of strategic culture in great detail, both theoretical and empirical. The opening three chapters examine why the more traditional rationalist/materialistic theories should not exclusively dominate strategic analysis, then the various existing strategic cultural offerings are considered and critiqued and, finally, a new conceptual model for strategic cultural analysis is proposed which draws from the hitherto largely neglected psychological and sociological literature. Both of these fields, it is submitted in Chapter 3, have spent more time and effort developing ways of understanding and analyzing culture than the field of IR has to date, and therefore the models and methods debated and developed in these fields should, it is argued, be ‘imported’ into IR to drive further strategic cultural research. The thesis then moves in the following six chapters to consider Australia’s strategic culture. The purpose of this part of the thesis is two-fold: first, it illustrates how the model offered in Chapter 3 works and, by implication, suggests how scholars may go about applying it to other cases. Second, and perhaps more importantly, the latter six chapters explore the twists and turns of Australia’s substantive strategic decision-making over the course of the last century or more, thereby explaining how Australia’s strategic history can be understood from a cultural perspective.