Environmental Factors Mediating Autoimmunity

Multiple sclerosis (MS) is an autoimmune disease characterized by autoreactive CD4+ T cells initiating CNS damage through recognition of myelin antigen. Although the Hafler Lab has recently been successful in elucidating a significant portion of the genetic basis of MS, the associated environmental triggers remain unknown. These genetic investigations demonstrate that MS strongly clusters with other autoimmune diseases, consistent with the long-standing hypothesis of an autoimmune attack on CNS myelin as the underlying disease etiology. While significant proportions of the population carry these common genetic variants, it is the accumulated frequencies of disease-associated variants that dictate heightened and dysregulated immune responses thought to be mediated both by functional losses of CD4+CD25highCD127lowFoxP3+ regulatory T cells (Treg) and heightened Th17 pro-inflammatory responses leading to disease risk by shifting immune homeostasis. Rather than labeling MS as simply a genetic disease, it can instead be modeled as an unfavorable interaction between genes and environment. A number of potential environmental triggers have been identified, including smoking, Vitamin D intake, infections and gut microbiota. However, none of these factors appear to explain increases in autoimmune disease incidence and prevalence at a rate of 5-7% of the population per year in the Western world.

In a recent pilot study investigating the role of microbiota and diet to frequencies of circulating Th17 cells and genetic variation as assessed by the ImmunoChip, it was noted that high intake of a “fast food” diet was statistically associated with high frequencies of Th17 cells. An unexpected result, the lab pursued investigations between high salt and fat enriched diets on Th17 cells. These results were recently published and revealed that slightly higher physiologic salt concentrations have direct effects on the induction of Th17 cells with initiation of an inflammatory signature in vitro and a high salt diet worsens experimental autoimmune encephalomyelitis (EAE), the murine model of MS, implicating a direct effect of salt on CD4+ T lymphocytes. Given these remarkable findings, the lab is now actively pursuing investigations to further understand the changes taking place in the Th17 subset secondary to high salt, and the potential means by which high salt may disarm the regulatory immune axis and shift the gut microbiome.