Investigation of toll-like receptor tolerance in the regulation of inflammation

Inflammation is a complex and highly organised immune response to microbes and tissue injury. Recognition of noxious stimuli by pathogen recognition receptor families including Toll-like receptors results in the expression of hundreds of genes that encode cytokines, chemokines, antimicrobials and regulators of inflammation. Regulation of TLR activation responses is controlled by TLR tolerance which induces a global change in the cellular transcriptional expression profile resulting in gene specific suppression and induction of transcription. In this thesis the plasticity of TLR receptor tolerance is investigated using an in vivo, transcriptomics and functional approach to determine the plasticity of TLR tolerance in the regulation of inflammation. Firstly, using mice deficient in the negative regulator of TLR gene transcription, Bcl-3 (Bcl-3-/-) in a model of intestinal inflammation, we investigated the role of Bcl-3 in the regulation of intestinal inflammatory responses. Our data revealed a novel role for Bcl-3 in the regulation of epithelial cell proliferation and regeneration during intestinal inflammation. Furthermore this data revealed that increased Bcl-3 expression contributes to the development of inflammatory bowel disease (IBD). Secondly, we demonstrate that lipopolysaccharide tolerance is transient and recovery from LPS tolerance results in polarisation of macrophages to a previously un-described hybrid state (RM). In addition, we identified that RM cells have a unique transcriptional profile with suppression and induction of genes specific to this polarisation state. Furthermore, using a functional approach to characterise the outcomes of TLR tolerance plasticity, we demonstrate that cytokine transcription is uncoupled from cytokine secretion in macrophages following recovery from LPS tolerance. Here we demonstrate a novel mechanism of regulation of TLR tolerance through suppression of cytokine secretion in macrophages. We show that TNF-α is alternatively trafficked towards a degradative intracellular compartment. These studies demonstrate that TLR tolerance is a complex immunological response with the plasticity of this state playing an important role in the regulation of inflammation.

"Ladyes, damesels, and jantilwomen": female autonomy and authority in Sir Thomas Malory's Morte Darthur

Popular medieval English romances were composed and received within the social consciousness of a distinctly patriarchal culture. This study examines the way in which the dynamic of these texts is significantly influenced by the consequences of female endeavour, in the context of an autonomous feminine presence in both the real and imagined worlds of medieval England, and the authority with which this is presented in various narratives, with a particular focus on Sir Thomas Malory’s Morte Darthur. Chapter One of this study establishes the social and economic positioning of the female in fifteenth-century England, and her capacity for literary engagement; I will then apply this model of female autonomy and authority to a wider discussion of texts contemporary with Malory in Chapters Two and Three, in anticipation of a more detailed study of Le Morte Darthur in Chapters Four and Five. My research explores the female presence and influence in these texts according to certain types: namely the lover, the victim, the ruler, and the temptress. In the case of Malory, the crux of my observations centres on the paradox of the capacity for power in perceived vulnerability, incorporating the presentation of women in this patriarchal culture as being vulnerable and in need of protection, while simultaneously acting as a significant threat to chivalric society by manipulating this apparent fragility, to the detriment of the chivalric knight. In this sense, women can be perceived as being an architect of the romance world, while simultaneously acting as its saboteur. In essence, this study offers an innovative interpretation of female autonomy and authority in medieval romance, presenting an exploration of the physical, intellectual, and emotional placement of women in both the historical and literary worlds of fifteenth-century England, while examining the implications of female conduct on Malory’s Arthurian society.

Counterstories: who counts as lesbian?

Coming out midlife is a profound and life‐changing experience—it is an experience of self‐shattering that entails the destabilisation of identity, and of family relationships. Entailing a displacement from social insider to outsider, it is a difficult, but also exhilarating, journey of self, and sexual, discovery. This thesis is an examination of the experiences of nine women who undertook that journey. This dissertation is very much a search for understanding—for understanding how one can be lesbian, and how one can not have known, following a lifetime of heterosexual identification—as well as a search for why those questions arise in the first place. I argue that the experience of coming out midlife exposes the fundamental ambiguity of sexuality; and has a significance that ranges beyond the particularity of the participants’ experiences and speaks to the limitations of the hegemonic sexual paradigm itself. Using the theoretical lens of three diverse conceptual approaches—the dynamic systems theory of sexual fluidity; liminality; and narrative identity—to illuminate their transition, I argue that the event of coming out midlife should be viewed not merely as an atypical experience, but rather we should ask what such events can tell us about women’s sexuality in particular, and the sexual paradigm more generally. I argue that women who come out midlife challenge those dominant discourses of sexuality that would entail that women who come out midlife were either in denial of their “true” sexuality throughout their adult lives; or that they are not really lesbian now. The experiences of the women I interviewed demonstrate the inadequacy of the sexual paradigm as a framework within which to understand and research the complexity of human sexuality; they also challenge hegemonic understandings of sexuality as innate and immutable. In this thesis, I explore that challenge.