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Title: Pathogenic immune responses in spondyloarthritis
Author: Al-Mossawi, Mohammad Hussein
ISNI:       0000 0004 6497 4111
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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Immune dysfunction in spondyloarthritis (SpA) causes significant morbidity to a large number of patients. An understanding of the underlying pathological processes involved in causing the disease is essential for the development and better targeting of therapies. I have shown for the first time in patients with SpA an overall expansion of peripheral blood and synovial fluid T cells producing GM-CSF and an expansion of GM-CSF positive Th17 cells. In addition, I have shown GM-CSF to be a major effector cytokine of joint-derived innate lymphoid cells. Surface phenotyping and transcriptional analysis of the IL-17A/GM-CSF double positive cells showed that whilst they are related to classic Th17 cells, they also have a uniquely activated transcriptional profile. Additionally, I have shown IL-7 to be a promoter of GM-CSF production by CD4 T lymphocytes in vitro. However, my data shows that polymorphisms of the IL7R, which have been shown to be associated with AS in genome-wide association studies, play a functional role through cell surface expression of the IL7R on CD14 monocytes. This genotypic expression of the IL7R on monocytes is only seen after activation with LPS or TNFa. I further show CD14 monocytes expressing IL7R to be present in SpA joints. My data shows that ROR?t, the master transcription factor of Th17 cells, can be therapeutically targeted using small molecule inhibitors in-vitro. These inhibitors lead to a specific suppression of both polyfunctional and IL-17A single positive Th17 cells. The work in this thesis has highlighted several areas of novel immune biology with potential therapeutic applications in SpA and across the spectrum of related inflammatory diseases.
Supervisor: Bowness, Paul ; Powrie, Fiona Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available