[Truncated abstract] The cornea plays a major role in the refraction of light and thus the maintenance of its transparency is critical for optimal vision. Infection or trauma can initiate a host inflammatory response, which can cause edema of the collagenous stroma. This tissue edema compromises vision by disrupting the regular arrangement of the corneal stromal lamellae, whose organization is critical to its refractive properties. Until recently, it was the accepted dogma that the cornea was an immune privileged tissue owing in part to its avascular nature and paucity of resident macrophages and dendritic cells (DCs) in the central region of the cornea. However, recent studies have identified heterogenous populations of macrophages and DCs in both the corneal stroma and epithelium. Despite the recognition of the existence of these cells in the cornea, very little is known about their biological role. The overall purpose of the experiments described in this thesis is to characterise corneal macrophages and DCs in homeostatic conditions and investigate their role in the initiation of inflammatory responses to bacterial ligands that induce corneal inflammation and contribute to the severity and resolution of bacterial keratitis. Experiments described in this thesis utilized a range of transgenic, knock-out and bone marrow (BM) chimeric mice to address the immunological function and characterization of BM-derived cells in the mouse cornea. Of particular importance was the use of Cx3cr1 transgenic mice, which contain an enhanced green fluorescent protein (eGFP) encoding cassette knocked into the Cx3cr1 gene that disrupts its expression but facilitates GFP expression under the control of the Cx3cr1 promoter. ... This highlights a novel functional role for corneal BM-derived cells in the recognition and initiation of inflammatory responses to LPS. Finally, a novel observation of a potential mechanism by which DC in the cornea communicate with neighbouring DCs via fine membrane extensions was identified in both chimeric and wild-type mice. These membrane nanotubes, found exclusively on MHC class II+ cells in the corneal stroma, significantly increased in density in the central cornea under inflammatory conditions, suggesting a role for these cell protrusions in the immune response. These data represent the first ever description of nanotubes in vivo, the only previous evidence of their presence being in vitro studies. In summary, the data presented in this thesis supports a role for Cx3cr1 in the homing of DCs to the normal corneal epithelium and also suggests that Cx3cr1-deficiency may influence the ability of corneal macrophages and DCs to respond to bacteria. In addition, the thesis supports a role for resident corneal macrophages and DCs in the initiation of immune responses following challenge with LPS, which is possibly supported by a newly discovered system of membrane nanotubes. A greater understanding of the biology of the resident corneal immune cells could lead to the development of potential therapies aimed at targeting macrophages and DCs as a means of regulating potentially harmful inflammatory responses in the cornea.
| Identifer | oai:union.ndltd.org:ADTP/202497 |
| Date | January 2008 |
| Creators | Chinnery, Holly Rose |
| Publisher | University of Western Australia. School of Anatomy and Human Biology, University of Western Australia. Faculty of Life and Physical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Holly Rose Chinnery, http://www.itpo.uwa.edu.au/UWA-Computer-And-Software-Use-Regulations.html |
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