S100B is a member of the S100 calcium binding protein family and is highly expressed within astrocytes in the brain. Elevated levels of S100B are associated with brain and central nervous system disorders, due to the breakdown of the blood brain barrier. Therefore S100B is routinely used as a marker of disease. Traditionally S100B was thought only as a cell breakdown product but increasing evidence suggests that it may play a role in exacerbating inflammation, however this role is not clear. S100B is known to be present within the eye but its role in retinal inflammation has not been investigated. The aim of this project was therefore to examine the role of S100B using the animal model experimental autoimmune uveoretinitis (EAU). This is a well-established model for the sight-threatening human condition posterior endogenous uveoretinitis. In this disease model an autoimmune response is induced leading to retinal inflammation. Using S100B knockout mice, I have shown a significantly reduced level of disease, as determined by clinical and histological grading. Real-time PCR array analysis of diseased matched retinas indicated down regulation of cytokines and chemokines in S100B knockout mice. In vitro experiments on a macrophage cell line confirmed S100B to have a pro-inflammatory effect on macrophages, the main effector cell in EAU, with up-regulation of cytokine and chemokine expression. In particular IL-1β, CCR1 and CCL22 showed a marked increase in gene expression in response to S100B which was confirmed by real-time PCR. Increased protein production of IL-1β (pro-form), CCR1 and CCL22 was also confirmed. S100B inhibited activation of T cells separated from spleens, as shown by reduced CD25+ expression and IL-2 production. IFN-γ and IL-17 production however was not affected. CCL2 and IL-6 are main inflammatory mediators produced by retinal pigment epithelial cells which are known to be elevated during retinal inflammation. S100B promoted CCL2 and IL-6 production in retinal pigment epithelial cells at different concentrations. The work carried out in this thesis provides additional understanding of the actions of extracellular S100B on immune system cells and its potential role in posterior uveitis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:589502 |
| Date | January 2013 |
| Creators | Niven, Jennifer A. |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=202787 |
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