Hornsby, E. (2010) Development of IL-17A-associated autoimmunity. Doctoral thesis, UCL (University College London).
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Autoimmunity results from a breakdown in tolerance to self-antigens. Interleukin-17A (IL-17A) is a cytokine that has been implicated in the development of certain autoimmune disorders, notably multiple sclerosis and its mouse model experimental autoimmune encephalomyelitis (EAE). In order to further understand mechanisms that lead to the development of autoimmunity, the objectives of this study were to investigate the sequence of immunological events that lead to the development of an autoimmune response and to generate and characterise a reporter mouse for IL-17A. EAE is a well-established model of an autoimmune response directed against selfantigens in the central nervous system and mimics many aspects of the human disease multiple sclerosis. EAE is a CD4 T cell-mediated disease, in that these cells can be used to transfer disease to naïve recipient mice. Following EAE induction, IL-17A-expressing cells were increased in frequency within the CD4 and γδ T cell populations in the draining lymph nodes, with a simultaneous increase in the number of these cell populations in the blood. Disease development was associated with the appearance of IL-17A and IFN-γ-expressing CD4 T cells, as well as IL-17Aexpressing γδ T cells in the spinal cord. EAE induction requires the systemic administration of pertussis toxin for disease development. It was found that pertussis toxin enhanced antigen-specific IL-17A and IFN-γ production in the periphery. An IL-17A reporter mouse was generated in which activation of the IL-17A promoter is reported by expression of Enhanced Yellow Fluorescence Protein (EYFP). In order to generate the mouse, a strain was first generated in which Cre recombinase expression is driven by the IL-17A promoter. This mouse was then crossed with a ROSA-26_EYFP strain in which expression of EYFP in the ubiquitously expressed ROSA-26 locus is usually inhibited by the presence of a LoxP-flanked-transcriptional stop sequence. Expression of Cre recombinase would remove the transcriptional stop sequence, leading to irreversible expression of EYFP in all cells that had activated IL-17A and their progeny. The results from this study suggest that pertussis toxin can amplify antigen-specific cytokine responses in EAE, an effect which could be attributed to enhancing disease pathogenesis. The IL-17A reporter mouse will be an invaluable tool to investigate the generation, lifespan and function of IL-17A-expressing cells in the development of immune responses.
|Title:||Development of IL-17A-associated autoimmunity|
|Open access status:||An open access version is available from UCL Discovery|
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