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The role of gammaherpesviruses in the development of autoimmunity

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dc.contributor.author Casiraghi, Costanza
dc.date.accessioned 2012-10-02T16:40:33Z
dc.date.available 2012-10-02T16:40:33Z
dc.date.copyright 2012 en_US
dc.date.issued 2012-10-02
dc.identifier.uri http://hdl.handle.net/2429/43320
dc.description.abstract The development of autoimmune diseases is thought to involve both genetic and environmental factors. Epstein-Barr virus (EBV) has been associated with the development of both multiple sclerosis (MS) and systemic lupus erythematosus (SLE). My research projects aimed at identifying the mechanism that this virus is exploiting to cause autoimmunity. In the first project, the role of EBV infection of the blood brain barrier (BBB) as a trigger of MS was investigated. EBV was found to be able to infect human primary endothelial cells isolated from the BBB. EBV infected brain endothelial cells upregulated pro-inflammatory mediators and supported increased immune cell adhesion. These results suggest that EBV has the ability of increasing the BBB permeability. EBV latency and reactivation in endothelial cells could lead to initial inflammation and infiltration of the first wave of autoreactive immune cells during MS initiation. The second and third research project were aimed at developing a mouse model to study the interactions between latent gammaherpesvirus infection and the host’s immune system that may lead to autoimmunity. The role of murine gamma herpesvirus 68 (γHV-68), the murine equivalent to EBV, was analyzed in the experimental autoimmune encephalomyelitis (EAE) model, an experimentally induced model to study MS, and in the New Zealand Black and White (NZBW) model, a spontaneous SLE mouse model. Mice latently infected with γHV-68 developed more severe EAE that mirrored human MS more closely than EAE in uninfected mice. γHV-68 EAE mice developed lesions composed of CD4 and CD8 T cells, loss of myelin in the brain parenchyma and spinal cord. Further, T cells from the CNS of γHV-68 EAE mice were primarily Th1, producing heightened levels of IFN-γ and T-bet accompanied by IL-17 suppression and decreased regulatory T cells frequencies. γHV-68 NZBW mice exhibited a similar Th1 skewed response and they produced different types of autoantibodies, if compared to uninfected NZBW mice. Clearly, gammaherpesvirus latency polarizes the adaptive immune response in both mouse models, directs a heightened brain pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases. en_US
dc.language.iso eng en_US
dc.publisher University of British Columbia en
dc.title The role of gammaherpesviruses in the development of autoimmunity en_US
dc.type Electronic Thesis or Dissertation en
dc.degree.name Doctor of Philosophy - PhD en_US
dc.degree.discipline Microbiology and Immunology en_US
dc.degree.grantor University of British Columbia en
dc.date.graduation 2012-11 en_US
dc.degree.campus UBCV en_US
dc.description.scholarlevel Graduate en


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