Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.705620
Title: The impact of the synovial environment and GM-CSF on the myeloid compartment in rheumatoid arthritis
Author: Kidger, Simone Verina
ISNI:       0000 0004 6060 8958
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2017
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Thesis embargoed until 17 Mar 2019
Access from Institution:
Abstract:
The synovial environment in rheumatoid arthritis (RA) is a milieu of Damage Associated Molecular Patterns (DAMPs), cytokines and immune complexes, which can modulate the activation or polarisation of myeloid cells. GM-CSF, which is a pivotal myeloid cell growth factor, is also a pro-inflammatory cytokine that drives aspects of RA immunopathogenesis. Inhibition of GM-CSF signalling has been successful in both mouse models and in clinical trials for RA, however, the specific effect of GM-CSF on myeloid cells in a synovial setting is not well understood. The aim of this thesis was to investigate the impact of the synovial environment and GM-CSF on myeloid cells in RA. GM-CSF stimulation induced monocytes to secrete substantial amounts of the chemokine CCL17. However, this induction of CCL17 was significantly inhibitedupon co-stimulation with RA synovial fluid, but not osteoarthritis (OA) synovial fluid, whilst the expression of other chemokines was unaffected. TLR ligands also inhibited GM-CSF driven CCL17, however, through the use of MyD88/TRIF knockout mouse monocytes, we found RA synovial fluid inhibition of CCL17 was TLR-independent. Small Immune Complexes and IFNα also had the capacity to inhibit GM-CSF induction of CCL17, suggesting multiple mechanisms within the RA synovial fluid to prevent this induction. Despite the consistency of RA synovial fluid causing inhibition of the GM-CSF signalling pathway in comparison to OA synovial fluid, there were no distinct effects on macrophage polarisation. The RA synovial environment has more of an impact on monocyte activation in comparison to macrophage polarisation, as synovial fluid from other arthropathies had the comparable effects on macrophage phenotypes. This thesis concludes that RA synovial fluid contains several factors that inhibit GM-CSF induction of CCL17. This suggests a regulatory mechanism, preventing the excessive secretion of CCL17 by monocytes, thereby preventing exacerbation of immunopathogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.705620  DOI: Not available
Keywords: QR180 Immunology
Share: