Host-Virus Interactions in Hodgkin's Disease

Bryden, Helen (1997) Host-Virus Interactions in Hodgkin's Disease. PhD thesis, University of Glasgow.

Abstract

The pathogenesis of Hodgkin's disease (HD) still poses many questions and this disease is the subject of intense and varied research. There is now little doubt that Epstein-Barr virus (EBV) plays a role in the development of a number of cases, over one third of all HD. The role played by the virus in these cases, however, is as yet not fully understood. The immunopathology of HD is complex. There is a large reactive infiltrate of immune cells, including lymphocytes, histiocytes and eosinophils, with the tumour cells comprising only around 1% of the total tumour mass. However, despite these infiltrating lymphocytes, among them CD8+ CTLs, the Reed-Sternberg (RS) cells are not eliminated, persisting in the lymph nodes and eventually increasing in number if the patient is left untreated. In 1992, at the start of the work of this thesis, little was known about the mechanisms by which RS cells evade immune detection. This phenomenon is of particular interest in EBV-associated HD, where the RS cells are known to harbour latent virus and express several viral latent antigens including EBNA-1 and the latent membrane proteins (LMPs). The LMPs are known to be targets for EBV-specific CTLs, therefore why do such CTLs not recognise or eliminate RS cells expressing these proteins? The answer to this question may fall into one of two broad categories. First, there may be a defect in EBV-specific CTL function in people who develop EBV-associated HD; secondly, there may be a defect in foreign antigen presentation by RS cells that allows these cells to persist and proliferate. The first possibility is investigated in the work presented in chapter 3 of this thesis. EBV-specific CTL responses in the peripheral blood of HD patients were assayed using an in vitro technique. EBV-associated HD cases were compared to other HD cases and to healthy subjects. Although the study was small, the findings suggest that there may be a diminished CTL response in EBV-associated HD which is not seen in the other cases and controls. The second possibility is addressed in chapter 4 of this thesis. It was postulated that people possessing HLA class I antigens known to present epitopes of the LMPs would not develop EBV-associated HD. HLA-A2 was the focus of this study as an epitope of LMP-2 is restricted through this HLA antigen. The results refuted this hypothesis. The possibility that EBV itself may be the cause of the recognition defect rather than the existence of a presentation defect was also investigated. The sequence of a target LMP-2 epitope presented by HLA-A2 was investigated in selected cases and analysed for the presence of mutations which would abolish recognition of the epitope by CTLs. This hypothesis was also refuted by these studies. In conclusion, there must be other mechanisms by which the RS cells evade immune detection.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Ruth Jarrett
• Keywords: Virology
• Date of Award: 1997
• Depositing User: Enlighten Team
• Unique ID: glathesis:1997-75356
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 20:26
• Last Modified: 19 Nov 2019 20:26
• URI: https://theses.gla.ac.uk/id/eprint/75356