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dc.contributor.authorMohan, Joanneen
dc.date.accessioned2018-05-14T10:14:44Z
dc.date.available2018-05-14T10:14:44Z
dc.date.issued2005en
dc.identifier.urihttp://hdl.handle.net/1842/29894
dc.description.abstracten
dc.description.abstractTransmissible spongiform encephalopathies (TSEs) are a group of sub-acute infectious neurodegenerative diseases that are characterized by the accumulation in affected tissues ofPrPˢᶜ, an abnormal isoform of the host prion protein (PrPᶜ). After peripheral exposure, TSE infectivity and PrPSᶜ usually accumulate in lymphoid tissues prior to neuroinvasion. Following either oral or intra-peritoneal inoculation follicular dendritic cells (FDCs) are critical for the accumulation of TSE agents within lymphoid tissues and their subsequent neuroinvasion. Studies in mice have shown that exposure through scarified skin is an effective means of transmitting the scrapie agent. Following inoculation via the skin a functional immune system is critical for the transmission of the scrapie agent to the brain as severe combined immunodeficiency (SCID) mice are refractory to infection. However, until now it was not known what components of the immune system are important for scrapie after transmission via the skin. Experiments in this thesis were designed to answer the following questions: firstly does the scrapie agent accumulate within lymphoid tissues after transmission via the skin; secondly what cells are critical for the accumulation and replication of the scrapie agent within lymphoid tissues; and finally how does the scrapie agent reach lymphoid tissues. To answer the first question lymphoid tissues were collected at serial time points after inoculation with the scrapie agent and infectivity titres measured by incubation period assays in indicator mice. Experiments demonstrated that scrapie infectivity first accumulates in the draining lymph node after inoculation via the skin and subsequently spreads to other lymphoid tissues. To address the second aim of this thesis two separate approaches were taken; firstly, a chimeric mouse model was used which had a mismatch in PrP status between FDCs and other bone-marrow derived cells within the lymphoid tissues. This experiment demonstrated that PrPᶜ-expressing FDCs are required for the accumulation of the scrapie agent within the spleen and that the PrP status of bone-marrow derived cells has no effect on scrapie pathogenesis. Secondly, mice were treated with a reagent to dedifferentiate FDCs either prior to or shortly after challenge to determine the role of FDCs in scrapie neuroinvasion. Data presented in this thesis shows that in the absence of FDCs prior to inoculation, disease susceptibility is reduced. Finally it is not known how the scrapie agent is transported from the site of exposure (e.g. the skin) to the draining lymphoid tissue. Previous studies have suggested that dendritic cells are capable of acquiring and transporting PrPSᶜ from the gut lumen to the gut associated lymphoid tissues. Langerhans cells (LCs) are a sub-population of migratory dendritic cells which reside in the epidermis and migrate to the draining lymph node following antigen encounter. Thus, LCs were considered a potential candidate for the transportation of the scrapie agent from the skin to the draining lymphoid tissues. To investigate the role of LCs in the active transportation of the scrapie agent from the skin, mouse models were utilised in which active LC migration was blocked. Experiments demonstrated that the early accumulation of the scrapie agent within the draining lymph node and its subsequent neuroinvasion was not impaired in mice with blocked LC migration, however these experiments did not address steady state LC migration, thus a role for this can not be excluded. Although, in vitro studies in thesis have suggested that LCs have the potential to acquire and degrade the scrapie agent, suggesting that LCs might be involved in impeding the spread of the scrapie agent after inoculation via the skin.en
dc.publisherThe University of Edinburghen
dc.relation.isreferencedbyAlready catalogueden
dc.subjectAnnexe Thesis Digitisation Project 2018 Block 18en
dc.titleImmunobiology of scrapie following transmission via the skinen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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