PhD Candidate , University of British Columbia
How does Epstein-Barr Virus affect the onset of Multiple Sclerosis?
Multiple Sclerosis (MS) in humans is caused by both genetic and environmental factors. While there are many environmental factors that may impact the development of MS, one factor often associated with the onset of the disease is a history of Infectious Mononucleosis, which is caused by the Epstein Barr Virus (EBV). However, exactly how infection with EBV increases a person’s chances of developing MS is not known. Because Epstein Barr Virus only infects humans, our lab has developed a mouse model to study the relationship between these two diseases. The model, which very closely resembles the onset of MS in human patients, uses γHV-68 (a mouse virus) as an analogue for Epstein Barr Virus, and Experimental Autoimmune Encephalomyelitis (EAE) as an analogue for MS. My project specifically focuses on the impact of γHV-68 on B cells (immune system cells that produce antibodies), where the virus establishes a life-long latency. I have shown that when B cells are infected by γHV-68, they alter the immune system so that EAE symptoms are more acute. This is because infected B cells communicate differently with other immune system cells than non-infected B cells. To better understand the impact of infected B cells on the immune system, I am currently conducting experiments that closely examine the differences in how infected B cells and other immune cells communicate. By isolating and studying the infected cells, we hope to determine which immune processes lead to enhanced symptoms of EAE in mice. In turn, these data will help us better understand the events that lead to the development of MS in human patients and will contribute in the development of new therapies for the treatment and/or cure of MS.
Abstract: The onset of multiple sclerosis (MS) is caused by both genetic and environmental factors. Among the environmental factors, it is believed that previous infection with Epstein-Barr virus (EBV) may contribute in the development of MS. EBV has been associated with other autoimmune diseases, such as systemic lupus erythematous, and cancers like Burkitt's lymphoma. EBV establishes a life-long latency in B cells with occasional reactivation of the virus throughout the individual's life. The role played by B cells in MS pathology has been largely studied, yet is not clearly understood. In MS patients, Rituximab, a novel treatment that targets CD20(+) B cells, has proven to have successful results in diminishing the number of relapses in remitting relapsing MS; however, the mechanism of how this drug acts has not been clearly established. In this review, we analyze the evidence of how B cells latently infected with EBV might be altering the immune system response and helping in the development of MS. We will also discuss how animal models, such as experimental autoimmune encephalomyelitis (EAE) and murine gammaherpesvirus-68 (γHV-68), can be used as powerful tools in the study of the relationship between EBV, MS, and B cells.
Pub.: 19 Nov '15, Pinned: 28 Jun '17
Abstract: Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS), yet EBV's role in MS remains elusive. We utilized murine gamma herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how infection by a virus like EBV could enhance CNS autoimmunity. Mice latently infected with γHV-68 developed more severe EAE including heightened paralysis and mortality. Similar to MS, γHV-68EAE mice developed lesions composed of CD4 and CD8 T cells, macrophages and loss of myelin in the brain 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, whereas a Th17 response was observed in uninfected EAE mice. Clearly, γHV-68 latency polarizes the adaptive immune response, directs a heightened CNS pathology following EAE induction reminiscent of human MS and portrays a novel mechanism by which EBV likely influences MS and other autoimmune diseases.
Pub.: 23 May '12, Pinned: 28 Jun '17
Abstract: Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis (MS) by multiple groups working worldwide. Previously, we reported that when experimental autoimmune encephalomyelitis (EAE) was induced in mice latently infected with murine γ-herpesvirus 68 (γHV-68), the murine homolog to EBV, a disease more reminiscent of MS developed. Specifically, MS-like lesions developed in the brain that included equal numbers of IFN-γ producing CD4(+) and CD8(+) T cells and demyelination, none of which is observed in MOG induced EAE. Herein, we demonstrate that this enhanced disease was dependent on the γHV-68 latent life cycle and was associated with STAT1 and CD40 upregulation on uninfected dendritic cells. Importantly, we also show that, during viral latency, the frequency of regulatory T cells is reduced via a CD40 dependent mechanism and this contributes towards a strong T helper 1 response that resolves in severe EAE disease pathology. Latent γ-herpesvirus infection established a long-lasting impact that enhances subsequent adaptive autoimmune responses.
Pub.: 12 Sep '15, Pinned: 28 Jun '17
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