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Title: The role of the autoimmune regulator gene (AIRE) in peripheral T cells
Author: Adamson, Karen A.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2004
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Mutations of the autoimmune regulator gene (AIRE) lead to the development of the multiple organ specific autoimmune disease, autoimmune polyendocrine syndrome type 1 (APS1). Aire is known to have a role in central tolerance through regulating the expression of self-antigens in the thymus. Prevention of autoimmune disease also relies on peripheral control of any autoreactive T cells which do exit the thymus, however, the role of Aire in the maintenance of these mechanisms, if any, is unknown. Thus, the hypothesis of this thesis was that lack of functional Aire affects peripheral T cell function and that Aire plays a role in peripheral tolerance in addition. Initially, the disease phenotype and genotype of APS1 patients in the UK was determined. The phenotype of the peripheral lymphocytes of a small number of thee patients was determined through assessment of cell surface markers by flow cytometry. The ability of these cells to proliferate when stimulated through the T cell receptor was then assessed, this revealed a trend to a higher maximal proliferative response in patients compared to controls. Cytokine production in response to T cell stimulation showed a trend to a decrease in IFN-γ and TNF-α in patients compared to controls. The tissue and cellular distribution of Aire in mice was characterised and Aire was found to be expressed in tissues of the immune system along with a number of other tissues, where its expression was predominantly limited to epithelial cells. Given the cellular distribution of Aire, i.e. within speckles in the nucleus, its interaction with nuclear proteins investigated. Aire was found to interact with paraspeckle protein 1. The role of Aire in CD4+ T cells was then investigated. Aire was found to be up-regulated upon activation thought the T cell receptor, at the mRNA and protein level. This up-regulation of Aire could be abrogated by inhibiting signalling through Notch, a developmental gene pathway which may play a role in peripheral tolerance. Thus, it is possible that Aire may be regulated by a component of the Notch signalling pathway, or alternatively by precursor common to both pathways.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available