Multiple Sclerosis is a neurological disorder characterized by inflammatory infiltrates, axonal damage, and plaques of demyelination located throughout the central nervous system (CNS). The specific locations of these plaques vary among patients and have profound effects on clinical symptoms, disease course and severity. The mechanisms determining where inflammation occurs are not well understood. MS has been studied for decades using an animal model referred to as Experimental Autoimmune Encephalomyelitis (EAE). Our lab has recently developed a new EAE model in which we are able to study the mechanisms responsible for regional localization of inflammation. By transferring myelin-specific T cells comprised of different ratios of TH1 (IFN-3-secreting) and TH17 (IL-17-secreting) cells into mice, we are able to induce inflammation preferentially in the brain or spinal cord. Historically, the CNS milieu has been considered as a whole, rather than viewing the brain and spinal cord as two distinct environments. Based on the above finding, we hypothesize that the CNS is actually made up of distinct microenvironments, which vary in their response to TH1 and TH17 cells, and that this may contribute to the varying patterns of inflammation seen in MS patients. To investigate this, we propose the following aims: 1) Determine whether differential inflammatory responses are elicited when myelin antigen is presented to TH1 and TH17 cells by cells residing in the brain versus the spinal cord;2) Define the specific role of IL-17 and IFN-3 in inflammation in the brain and spinal cord;and 3) Characterize differences in survival patterns of T cells between the brain or spinal cord and identify factors contributing to these patterns. These goals will enhance our understanding of the mechanisms that lead to different patterns of inflammation in the CNS and lead to improvements in current therapies for this disease.

Public Health Relevance

Multiple Sclerosis is an immune-mediated, demyelinating disease of the central nervous system (CNS) affecting over a million individuals worldwide. The specific sites of inflammation within the CNS and responses to therapies vary between patients. Understanding the mechanisms responsible for different inflammatory patterns will allow for better, more specific treatments of this debilitating disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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NST-2 Subcommittee (NST)
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Utz, Ursula
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University of Washington
Schools of Medicine
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Simmons, Sarah B; Liggitt, Denny; Goverman, Joan M (2014) Cytokine-regulated neutrophil recruitment is required for brain but not spinal cord inflammation during experimental autoimmune encephalomyelitis. J Immunol 193:555-63
Simmons, Sarah B; Pierson, Emily R; Lee, Sarah Y et al. (2013) Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol 34:410-22
Pierson, Emily; Simmons, Sarah B; Castelli, Luca et al. (2012) Mechanisms regulating regional localization of inflammation during CNS autoimmunity. Immunol Rev 248:205-15