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DC Field | Value | Language |
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dc.contributor.author | Ridgley, Laura Alice | - |
dc.date.accessioned | 2019-08-02T08:24:31Z | - |
dc.date.available | 2019-08-02T08:24:31Z | - |
dc.date.issued | 2018 | - |
dc.identifier.uri | http://theses.ncl.ac.uk/jspui/handle/10443/4401 | - |
dc.description | PhD Thesis | en_US |
dc.description.abstract | Background A 12-gene signature in CD4+ T-cells had discriminatory utility for early rheumatoid arthritis (RA) patients compared with disease controls. This signature is enriched for STAT-3 target genes whose expression correlates with paired circulating IL-6. I hypothesise that pre-exposure of CD4+ T-cells to IL-6 mediates STAT-3 activation and aberrant effector function following T-cell receptor (TCR) stimulation, providing a mechanism of antigen non-specific immune dysfunction in early RA. Methods A model for cytokine pre-exposure was developed, in which naïve (CD45RA+) and antigen experienced (CD45RA-) CD4+ T-cells from healthy human donors were cultured with IL-6 and equimolar soluble IL-6R for 3 days, before being washed and stimulated with anti-CD3 and anti-CD28 for 6 days. RNA was extracted at multiple experimental time-points and global gene expression profiling undertaken. Phenotype and proliferation were assessed by flow cytometry, measuring cell surface markers and proliferation dyes. Whether the observed consequences of IL-6 pre-exposure reflected transcriptional and phenotypic characteristics of CD4+ T-cells isolated from patients with early RA was explored. Results The effects of IL-6 pre-exposure were seen most prominently in naïve CD4+ T-cells, potentially related to IL-6 receptor expression. Pre-exposure of healthy control naïve CD4+ T-cells to physiological levels of IL-6 caused significant STAT-3 target gene induction, mirroring genes previously found to distinguish RA patients from disease controls. Following TCR-stimulation, a distinctive set of genes differentially expressed in IL-6 pre-exposed cells were associated with to cell proliferation and survival. This is consistent with altered effector phenotype of IL-6 preexposed cells characterised by dose-dependent enhancement in activation and proliferative capacity. CD4+ T-cells from early RA patients showed no difference in proliferation compared to healthy controls, although our group has observed that a higher proportion are committed to the cell cycle as measured by ki67 expression. Conclusion These findings highlight that cytokine “pre-priming” during the early disease state may have consequences for naïve CD4+ T-cell effector function, impacting the transition to disease chronicity in early RA. | en_US |
dc.description.sponsorship | Arthritis Research UK | en_US |
dc.language.iso | en | en_US |
dc.publisher | Newcastle University | en_US |
dc.title | Cytokine mediated CD4+ T-cell dysregulation in early rheumatoid arthritis | en_US |
dc.type | Thesis | en_US |
Appears in Collections: | Institute of Cellular Medicine |
Files in This Item:
File | Description | Size | Format | |
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Ridgley C 2018.pdf | Thesis | 21.14 MB | Adobe PDF | View/Open |
dspacelicence.pdf | Licence | 43.82 kB | Adobe PDF | View/Open |
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