Introduction: While many studies on rheumatoid arthritis have focused on the active phase of the disease, the events that lead to the development of autoimmunity remain poorly defined. We have developed a model of breach of self tolerance, where a Th1 response to irrelevant antigen (OVA) results in arthropathy associated with spontaneous induction of autoreactive T and B cell responses, which allows the investigation of the immnologival events that lead to the development of autoreactivity. Employing this model the role of Th17 cells, a a subset of IL-17 producing CD4+ T important in autoimmunity, was investigated in the development of autoimmunity. In addition, the relative ability of Th1 and Th17 polarised populations in supporting B cell responses was analysed. Finally, in this thesis the role of sterile damage regulation in the development of autoimmunity was assesed, by investigating the role of Siglec-G, a molecule involved in DAMP-signalling regulation, in this process. Results: Transfer of OVA specific Th17 cells induced similar levels of inflammation as Th1 cells, and could induce a breach of self tolerance as demonstrated by CII specific T and B cell responses. While the CII specific T cells in the Th1 recipients produced IFNγ and not IL-17, surprisingly the CII T cell responses in the Th17 recipients were predominantly IFNγ producers. Whereas the transferred OVA specific Th1 population retained its phenotype, the transferred Th17 population displayed significantly reduced IL-17 production. However, cells polarised under Th17 conditions expanded in a higher degree and persisted for longer time in response to immunisation. This resulted in a higher ability of Th17 polarised population in supporting B cell responses. Finally in this thesis, preliminaty data for a role of Siglec-G in the development of autoimmunity were presented, as Siglec-G deficient mice were protected from the development of autoreactive B cell responses. Conclusion: The results of this thesis suggest that the developing autoimmuniy in both Th1 and Th17 models is mediated by Th1 cells. These studies highlight the plasticity of transferred cell populations in vivo, and support the use of blocking and fate-mapping studies to definitively address how auto-reactive responses develop.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:559926 |
| Date | January 2011 |
| Creators | Patakas, Agapitos |
| Publisher | University of Glasgow |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://theses.gla.ac.uk/2867/ |
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