Sarcoidosis is a multisystem inflammatory disorder of unknown aetiology. The immune pathology is characterised by dysregulated T cell (T<sub>H</sub>1) activity, macrophage activation and granuloma formation, resulting in systemic inflammation, and organ dysfunction. I hypothesised that, as the systemic precursor to the macrophage, altered monocyte activity in sarcoidosis may contribute to the early immune pathology of the disease. In this thesis, I examined their phenotype, four key monocytic functions: cytokine production, suppression of T cell proliferation, phagocytosis and fusion (as a precursor to granulomagenesis); and their gene expression profile compared to monocytes from healthy controls. My data show that the expanded monocyte compartment comprise a greater proportion of the inflammatory (CD14<sup>++</sup>CD16<sup>+</sup>) and patrolling (CD14<sup>+</sup>CD16<sup>++</sup>) subsets, increased TNFα and IL-12 and decreased IL-10 and IL-4 production in sarcoidosis compared with healthy controls. The IL-10 deficit renders the monocytes less able to regulate T cell proliferation or their own fusion to multinucleate giant cells, potentially contributing to T cell expansion and granuloma formation respectively. Additionally, sarcoidosis monocytes are less able to phagocytose inert material. I also showed that previously reported deficiency in invariant NKT cells and low serum vitamin D levels in sarcoidosis may be linked to reduced IL-10 production by monocytes. Vitamin D treatment in vitro restored most of these deficiencies and provides a potential therapeutic method for manipulating monocyte function and disease genesis in sarcoidosis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:665157 |
| Date | January 2014 |
| Creators | Crawshaw, Anjali Priya |
| Contributors | Ho, Ling-Pei ; McMichael, Andrew |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:3378bf46-a494-45a0-b68e-81b37c1dae49 |
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