Scleroderma is a chronic autoimmune connective tissue disease of unknown etiology characterized by excessive fibrosis and is broadly divided into two clinical entities: localized scleroderma (LSc) and systemic sclerosis (SSc). SSc is a multi-system disease resulting in both skin and visceral organ fibrosis. The more benign disorder, LSc is for the most part self-limited with the disease pathology being confined to the skin and subcutaneous tissues. Proposed factors involved in the pathogenesis of these disorders include endothelial cell injury and dysfunction, immunological alterations and inflammatory activation, and abnormal ECM production by activated fibroblasts. However, the initiating mechanisms that leads to these changes remains largely unknown. This thesis examines the hypothesis that the transcriptional expression at the edge and centre of expanding LSc plaques could represent the metabolic changes involved in the different stages of disease. The major finding of this thesis was the identification of two panels of genes that showed significant changes in expression between LSc patients and healthy controls irrespective of whether the sample was taken from a diseased or clinically unaffected area of the patient. The first panel consisted of inflammatory genes including those genes characteristic of the Thl response and those induced by NF-KB. The Thl response was supported by an increased infiltration of CD4+ T cells in the LSc patients. The second panel consisted of a subset of array identified genes (scleroderma Signature) in SSc patients. Of interest, WIF1 was down regulated in both disorders and showed a gradual decrease in expression across the clinically different areas of the LSc patients. Both panels of genes showed the biggest changes of expression at the edge of the plaque suggesting their involvement in the initiating events of the disease. These results suggest that, like SSc, the underlying pathology of LSc is related to systemic changes in genes controlling amongst others, immunological and inflammatory responses. This information not only sheds light on the mechanisms involved in the initiation and progression of scleroderma, but could also contribute to the creation of a diagnostic test for the early detection of sufferers of this rare, but important disease.
| Identifer | oai:union.ndltd.org:ADTP/258470 |
| Date | January 2008 |
| Creators | Gold, Wendy Anne, Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. Clinical School - St Vincent's Hospital |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Gold Wendy Anne., http://unsworks.unsw.edu.au/copyright |
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