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T cell responses in the pathogenesis of cholestatic liver disease

The cholestatic liver diseases include Primary Biliary Cirrhosis (PBC) and Primary Sclerosing Cholangitis (PSC). The aetiologies of PBC and PSC are not yet known but it is thought that there are both inherited and environmental factors associated with pathogenesis. In this thesis, I set out to explore the immunologic and virologic basis of cholestatic liver diseases. In recent years a novel human betaretrovirus has been proposed as an antigenic target in PBC. Using separate T cell assays, I analysed responses to both autoantigens and foreign antigens in parallel, backed up with a molecular approach. I have shown that although there is definite evidence of prior encounter with HBRV peptides at the immunologic level the virus is not closely associated with the pathogenesis of PBC. I have shown that there are links between the composition of the cellular infiltrate and the histologic scores as well as the clinical status. In PBC, the accumulation of CD8+ cells in particular correlates with liver fibrosis stage and Foxp3 cells may have an influence on portal and lobular inflammation. In PSC, the frequency of T helper cells and B cells correlate with alkaline phosphatase and liver stage. This may indicate a closer relationship between tissue histochemistry results and fibrosis and clinical markers in PSC than in PBC and may not simply be a result of portal tract inflammation but be associated with disease pathogenesis. The quality of life tool PBC-40 showed similar results to the original Newcastle cohort. Fatigue is the symptom with the greatest apparent impact and there was no association found between symptoms and biological parameters of disease activity and severity. In PSC, there was a negative correlation between the average CD8 count per infiltrate and the emotional and social domain suggesting alterations in CD8 liver cell counts may have an influence on human behaviour or vice versa. Overall these data provide new insight into the pathogenesis of both PBC and PSC, and provide new avenues for immunologic analysis of these diseases in future.

Identiferoai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:564278
Date January 2010
CreatorsWorthington, Joy
ContributorsKlenerman, Paul
PublisherUniversity of Oxford
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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