New Studies on the Role of Salt in Autoimmunity
Background: The Role of Dietary Salt in Autoimmune Diseases
Autoimmune diseases like MS are defined as inappropriate immune responses to cells and tissues in the body. Much work has been done to identify the types of cells involved in these responses, as well as genetic abnormalities that alter cell behavior. New studies are now looking at the role of environmental and lifestyle factors in driving autoimmune diseases, especially in light of the notable increase in these diseases over the last few decades.
Three studies were published in the prestigious scientific journal Nature examining the effects of salt (NaCl2) on immune activity. Overall the results of their experiments show that increased concentrations of salt lead to the production of a specific type of T cell involved in autoimmunity. This group of T cells, known as Th17 cells, has also been implicated in the development of EAE which is an animal model that mimics MS disease.
Dr. David Hafler, Dr. Markus Kleinewietfeld (Yale University and Broad Institute of MIT and Harvard), Dr. Vijay Kuchroo, Dr. Aviv Regev, Dr. Chuan Wu (Harvard Medical School and Broad Institute of MIT and Harvard), Dr. Regev, Kuchroo and Dr. Nir Yosef (Broad Institute of MIT and Harvard) report on the effects of salt on Th17 cells using a variety of advanced techniques both in cell culture and in animal models.
Dr. Hafler’s team exposed naïve T cells (immune cells which have not yet developed into specific subtypes) to increased salt concentrations. They noticed that this stimulated the naïve cells to become the Th17 cells, which play a major role in autoimmunity. The results demonstrated that the presence of salt led to the expression of molecules that promote inflammation, which is what causes damage in autoimmune diseases like MS. For example, levels of the molecule CCR6 were elevated after the administration of salt; CCR6 is required for Th17 cells to function. The researchers also explored the effects of a high-salt diet in mice which develop MS-like disease. The results showed that a modest increase in salt levels sped up the onset of EAE and increased disease severity.
Dr. Kuchroo’s team observed the effects of salt on a protein called “serum glucocorticoid kinase-1” (SGK1), which a molecule that drives the harmful effects of Th17 cells. The study reports that an increase in salt concentrations led to greater levels of the SGK1 protein, which resulted in an increased expression of molecules that promote the development of Th17 cells. In a follow-up experiment, normal mice as well as mice lacking the SGK1 protein were fed a high salt-diet. After 3 weeks, researchers noticed that mice that did not have SGK1 exhibited lower levels of Th17 cells as well as a reduction in EAE severity.
The final study conducted by Dr. Regev’s team provides evidence on the highly intricate network of signaling molecules that govern the response of the Th17 cells. A key player in this network is IL-17, which has shown to play an important role in high-salt induced autoimmunity as described in the paper from Dr. Kuchroo’s group.
This research collectively illustrates the important role of Th17 cells in autoimmunity. The activity of these cells depends on mechanisms that are governed by a number of signals. Understanding this pathway is key in developing new therapies for autoimmune diseases like MS. The link between Th17 cell activity and salt is a new line of evidence that probes the relationship between autoimmune diseases and environmental factors such as diet. It is important to bear in mind that the clinical and regulatory significance of this work is yet to be determined as these experiments are still being done in a laboratory setting. Further research is required to determine if dietary salt does in fact have an effect on MS disease activity.
Kleinewietfeld M et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature, 2013 Mar 6 [Epub ahead of print]
Wu C et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature, 2013 Mar 6 [Epub ahead of print]
Yosef N et al. Dynamic regulatory network controlling TH17 cell differentiation. Nature, 2013 Mar 6 [Epub ahead of print]