Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). MS is often referred to as an immune mediated disease, where the body's immune system is fooled into attacking myelin within the CNS. The cause of MS is not known. However, viral infections are often associated with the initiation and exacerbations of this disease. How different viruses trigger attacks of MS is still unclear, but at least two hypotheses have been put forth to explain how this could occur. The first hypothesis involves direct infection of the brain by a virus. This viral infection causes inflammation and damage to cells that produce myelin. This damage releases fragments of myelin that are recognized by autoreactive T cells which then are activated within the inflammatory milieu. These T cells that recognize epitopes of myelin proteins then trigger a series of events that result in more inflammation in the CNS and myelin destruction. A second hypothesis involves a virus infection taking place outside of the CNS where the immune response to the virus cross-reacts with CNS myelin or "self." Therefore, T cells have the ability to recognize both the virus as well as myelin. These cells activated by the virus infection that also recognize myelin now ingress into the CNS and cause inflammation and demyelination. We are proposing to test a variation of this second hypothesis. We have evidence that the T cells that are activated following certain kinds of virus infections can recognize virus and myelin. We are proposing to explore how these cells are generated and understand how these T cells can recognize two disparate entities. In our preliminary studies, we find that the T cells that recognize both virus and self have more than one receptor on their surface. T cells normally have one T cell receptor (TCR) that recognizes just virus or self but not both;but, by having more than one receptor, the T cell can be activated by the TCR that recognizes virus and the other TCR targets myelin or self. Relevance: We suspect that there are multiple pathways that lead to the disease we call MS. Our proposal investigates one of these pathways. We are testing the hypothesis that peripheral infections can generate T cells which have specificity to both virus and self. If such cells are able to circumvent regulation and expand, they could initiat autoimmune inflammatory disease. These studies will provide insight into how viral infections could induce T cells that recognize both virus and self and help explain why no single virus has been identified as the causative agent of MS.

Public Health Relevance

Viral infections have been associated with the induction and/or exacerbations of MS. Several hypotheses explain how different pathways lead to the disease we call MS. These include epitope spreading where a persistent viral infection of the CNS generates a sufficient inflammatory environment where self peptides are processed and presented resulting in the expansion of self CNS reactive T cells. Another mechanism, that need not include epitope spreading, involves a persistent viral infection within the CNS resulting in inflammatory demyelinating disease due to the immune response attempting to eliminate infected cells within the CNS. An appealing alternate hypothesis is that peripheral infections (outside of the CNS) can generate cross-reactive T cells that are sufficiently expanded. These T cells then enter the CNS and cause inflammatory demyelinating lesions and MS. These mechanisms are not mutually exclusive and in different individuals probably lead to the disease we call MS. This proposal will study how viral infection in the periphery can generate cross-reactive autoreactive T cells that induce inflammation and demyelination within the CNS.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Utz, Ursula
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Libbey, Jane E; Lane, Thomas E; Fujinami, Robert S (2014) Axonal pathology and demyelination in viral models of multiple sclerosis. Discov Med 18:79-89
Wang, Xiaojie; Cusick, Matthew F; Wang, Yong et al. (2014) Diffusion basis spectrum imaging detects and distinguishes coexisting subclinical inflammation, demyelination and axonal injury in experimental autoimmune encephalomyelitis mice. NMR Biomed 27:843-52
Libbey, Jane E; Cusick, Matthew F; Fujinami, Robert S (2014) Role of pathogens in multiple sclerosis. Int Rev Immunol 33:266-83