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Title: An analysis of the immune response to primary Epstein-Barr Virus infection and the association with clinical events
Author: Williams, Hilary J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2005
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Infectious Mononucleosis (IM) is one of the most common serious illnesses in young adults, and is caused by delayed primary infection with Epstein-Barr Virus (EBV). The characteristic clinical features are thought to be due to extensive T cell activation, and cytokine production, but the molecular mechanisms underlying this are unclear. SAP (Surface Lymphocyte Activation Marker (SLAM) associated protein), is mutated in X-linked lymphoproliferative disease (XLP), in which fatal IM occurs, and is a key regulator of lymphocyte activation via signals from cell surface 2B4 (CD244) and SLAM. Our aim was to monitor T cell activation via this SAP/SLAM/CD244 pathway, and analyse whether the scale of activation was related to the severity of clinical features in a cohort of 26 cases of IM. In addition, 10 males with fulminant IM were screened for XLP gene mutations but none were identified. At diagnosis of IM, SAP, CD244 and SLAM were significantly upregulated, compared to controls, on both CD4 and CD8 T cells in peripheral blood (p < 0.01). The expression fell over the course of IM, but CD244 and SLAM remained elevated on CD8 cells at one month post diagnosis. The numbers of lymphocytes expressing CD8, and CD244/CD8 were significantly higher in cases with severe compared to mild sore throat (p < 0.05). Both expression of CD8, and expression of CD244 on CD8 cells correlated positively with increased viral load (p < 0.05). Time is required for this antigen specific immune response to develop. In contrast innate immune responses, such as Natural Killer (NK) cells are thought to be vital early in the infection process. We show that NK cell numbers are significantly elevated at diagnosis of IM compared to controls (p < 0.01) and in the first month following diagnosis. In healthy adults, 2 distinct populations of NK cells have been identified by the density of cell surface expression of CD56; these subsets of CD56bright and CD56dim cells differ in their ability to produce cytokines and lyse target cells. We have identified significant changes in NK cell phenotype and function during IM, with an increase in the proportion of CD56bllght cells, and cells showing an enhanced ability to kill an EBV infected cell line. We suggest that activated T cells expressing CD244 modulate the clinical features of IM, but control of activation is maintained by concurrent increased expression of SAP. However, before this occurs NK cells have a critical role in both eliminating infected B cells and augmenting this antigen specific T cell response via release of immunomodulatory cytokines. The magnitude of the NK cell response may ultimately determine whether primary EBV infection has a subclinical or clinical outcome.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available