Novel therapeutic targets in uveitis
File(s)
Author(s)
Tempest-Roe, Shenzhen Makahn
Type
Thesis
Abstract
Autoimmune posterior uveitis is a potentially blinding ocular disorder characterized by inflammation of the choroid and retina. Etiology is unknown and is assumed to be autoimmune and proposed to involve activation of autoreactive retinal-peptide specific T-cells, blood-retinal barrier breakdown, further leukocyte recruitment and ensuing ocular inflammation. The P2X7 receptor is a transmembrane purinergic receptor activated by high concentrations of ATP. Expression is ubiquitous with highest expression in immune cells. Stimulation results in the production and release of pro-inflammatory cytokines and potentiates leukocyte recruitment. Differences in mechanisms of P2X7 regulation in macrophages, dendritic cells and T cells were explored in vitro. Dendritic cells and macrophages have been proposed to release IL-1β through the NLRP3 inflammasome, requiring TLR4 stimulation followed by P2X7 stimulation. Dendritic cells were found to release IL-1β with TLR4 stimulation only, unlike macrophages which required additional P2X7 stimulus. Potential mechanisms of P2X7 regulation were explored, and it was found that T cells and not macrophages or dendritic cells exhibited significantly potentiated P2X7 mediated dye uptake upon lipid raft disruption. These results suggested a role for lipid rafts in P2X7 regulation in T cells. In vivo experiments utilized animal models of anterior, posterior and pan-uveitis. Mice deficient in P2X7 were protected against developing severe posterior uveitis, and treatment of mice with established EAU with P2X7 specific antagonist A438079 prevented the development of severe panuveitis. Finally, the role of the spleen tyrosine kinase (SYK) was investigated in murine posterior uveitis. Recent research implicates potential crossover of the P2X7 and SYK signalling pathways. SYK inhibition with the specific inhibitor fostamatinib did not prevent the development of uveitis in mice.
Version
Open Access
Date Issued
2017-03
Date Awarded
2017-12
Advisor
Taylor, Simon
Tam, Frederick
Sponsor
Biotechnology and Biological Sciences Research Council (Great Britain)
GlaxoSmithKline
Grant Number
NN0785_WMIR
Publisher Department
Department of Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)