The goal of this proposal is to elucidate the role of interferon lambda (IFN?) during central nervous system (CNS) autoimmunity. The most common form of CNS autoimmunity among humans is multiple sclerosis (MS), a disease that affects over 2.5 million people worldwide2,16. MS is a demyelinating autoimmune disease that can cause a variety of neurologic symptoms including extremity weakness, optic neuritis, and ataxia1; it is a major cause of disability in young adults. Due to the young age of onset and continuously progressive nature of the disease, MS is not only a personal burden but also a substantial socioeconomic burden16. Currently, there are approximately one dozen therapeutic options for MS; although effective in reducing relapse frequency and severity, they have numerous side effects and none actually halt disease progression or promote recovery19. This suggests the need for an improved understanding of mechanisms driving chronic disease and to translate this information into new therapeutic strategies for MS. IFN? (interferon lambda or type III IFN) is a class of cytokines closely related to type I IFN; both classes initiate analogous JAK STAT signaling pathways that induce expression of antiviral genes8-10. Type I IFN have been highly studied in CNS autoimmune diseases and play a protective role that is consistent with its use as a therapeutic for MS12,13,31. Very little, however, is known about the role of IFN? in MS. Preliminary data has demonstrated that IFN? may prevent recovery and lead to sustained inflammation in the murine model of CNS autoimmunity, experimental autoimmune encephalomyelitis (EAE). Animals deficient in IFN? signaling demonstrated improved clinical scores, decreased inflammation, and decreased axonal damage during recovery from EAE. This suggests that IFN? may play a critical role in disease maintenance after disease is already initiated. Therefore, the goal of this project is to understand how IFN? modulates immune mediated inflammation and neuronal damage during CNS autoimmunity. The studies outlined in this proposal include experiments to analyze spatiotemporal expression of IFN? and its receptor, to conditionally delete IFN? receptor in a cell specific manner, to analyze in vitro cultures of antigen presenting cells (APCs) and T cells, to examine IFN??s effects on demyelination, and to measure IFN? levels in MS patient samples. Completion of this project will provide insights into the cellular mechanisms underlying CNS autoimmune diseases.

Public Health Relevance

Multiple sclerosis (MS) is a major cause of non-traumatic disability among young adults in the United States16; currently, there are no treatments to halt MS progression or induce recovery19. The goal of this proposal is to understand the mechanisms behind immunomodulatory cues that drive chronic disease and translate these findings into novel therapeutic strategies for MS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Utz, Ursula
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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