Multiple sclerosis (MS) is thought to be an autoimmune disease with losses of functional CD4+FoxP3+ regulatory T cells allowing activated autoreactive T cells to initiate CNS damage. There have been significant increases in the incidence of autoimmune disease and while we have been successful in elucidating a significant portion of the genetic basis of MS, the environmental contributors remain unknown. In a recent study investigating the role of microbiota and diet in relationship to frequencies of circulating Th17 cells and genetic variation, we noted high intake of a "fast food" diet was associated with Th17 cells. This led to the identification of salt as a possible environmental trigger for autoimmunity by induction of pathogenic Th17 cells. Subsequent preliminary data indicate that high salt impairs the suppressive capacity of human Foxp3+ regulatory T cells through an as yet unknown mechanism. Our data have led us to hypothesize that the chronic high salt intake in western diets, on a genetically susceptible background, may act as a trigger for developing MS by disarming protective Tregs, which function to regulate immune responses. We will investigate this hypothesis by first determining the mechanism for the loss of Treg function observed under high salt conditions. By molecular and functional analyses of Tregs under normal or high salt conditions we will investigate the underlying mechanisms of the effect in vitro. We will also compare RNA and gene expression signatures of Tregs generated under high salt conditions in vitro from healthy controls with Tregs isolated ex vivo from the peripheral blood of patients with MS to determine if there is a "salt-history" of pathogenic Tregs in patients with the disease. We will also investigate whether these RNA and gene expression signatures are driven by the genetic variation we observed from our genome wide association scan studies. The results of these proposed experiments may shed light on a potential environmental cause of MS and provide a novel treatment strategy.

Public Health Relevance

Multiple sclerosis (MS) is an inflammatory autoimmune disease. Although major advancements have guided our understanding of disease pathogenesis, the initial events that trigger disease remain unknown despite the continued rise in incidence of autoimmune diseases. Recent work from our laboratory has identified high salt intake as an environmental trigger that may lead to the development of MS by disarming protective regulatory T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS086434-01
Application #
8658250
Study Section
NST-2 Subcommittee (NST)
Program Officer
Utz, Ursula
Project Start
2013-09-16
Project End
2015-09-15
Budget Start
2013-09-16
Budget End
2014-09-15
Support Year
1
Fiscal Year
2013
Total Cost
$40,108
Indirect Cost
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520