Sodium Chloride Induced Dysregulation of CD4+CD25+ Regulatory T Cells in Patients

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant): 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.