A healthy immune system is a finely balanced system: too little
activity and we fall prey to disease, too much, and it attacks our own
tissue, triggering autoimmune diseases like multiple sclerosis. Now
three studies published online this week in Nature suggest the
amount of salt we eat may influence this balance by indirectly encouraging the overproduction of immune cells.
In the three studies the researchers focused on a group of immune cells known as T cells because they play an important role in clearing disease-causing pathogens and also in autoimmune disease. They were particularly interested in how T cells develop.
However, Th17 cells have also been implicated in diseases like multiple sclerosis, psoriasis, rheumatoid arthritis, and ankylosing spondylitis. Treatments for some of these diseases, such as psoriasis, involve manipulating T cell function.
Until now, scientists have struggled to pinpoint the molecular machinery behind the overproduction of TH17 cells, partly because the usual way of activating native immune cells in the lab, such as RNA interference (RNAi) to manipulate genes, either harms them or disturbs their development.
Regev got the idea for the new approach after attending a lecture given by co-author, Hongkun Park, a physicist at Harvard University, also in Cambridge, on how to use silicone nanowires to disarm single genes in cells without disturbing the way the cells operate.
She says in a report by Nature NEWS that without such a model they would probably have been only "guessing in the dark".
Co-author Vijay Kuchroo, an immunologist at Brigham and Women's Hospital in Boston, Massachusetts, says in a statement that until they got the new technology using the nanowires, every time they downregulated a gene (with the previous technology), the cell would change.
The team identified and validated 39 "regulatory factors" altogether, uncovering the most important points in the network and untangling their biological meaning.
They conclude that their findings highlight "novel drug targets for controlling TH17 cell differentiation".
One protein in particular grabbed their attention, SGK1 (short for serum glucocorticoid kinase 1), a well-studied signaling protein that had not been described in T cells before, but is known to regulate how salt is absorbed in cells of the gut and in kidneys.
By manipulating salt levels in cultured mouse cells, the researchers found SGK1 expression was stronger the more salt there was, causing more TH17 cells to be produced.
Kuchroo says:
"If you incrementally increase salt, you get generation after generation of these TH17 cells."
Hafler says this was easy to do, "you just add salt".
They also found that mice fed with a high-salt diet developed a more severe form of experimental autoimmune encephalomyelitis (EAE), "in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells".
EAE is an animal model of brain inflammation that is used to study autoimmune disease in the lab.
Hafler and colleagues conclude that " ... increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells".
In their studies they had to induce autoimmune disease, the salt played an additional role. And there are other factors too, as Kuchroo explains:
"It's not just salt, of course. We have this genetic architecture - genes that have been linked to various forms of autoimmune diseases, and predispose a person to developing autoimmune diseases. But we also suspect that environmental factors - infection, smoking, and lack of sunlight and Vitamin D - may play a role."
"Salt could be one more thing on the list of predisposing environmental factors that may promote the development of autoimmunity," says Kuchroo.
Regev also says it is far too early to say people shouldn't eat salt because it leads to autoimmune disease.
"We're putting forth an interesting hypothesis - a connection between salt and autoimmunity - that now must be tested through careful epidemiological studies in humans," she explains.
Hafler adds, "As a physician, I'm very cautious."
He says people should be on a low-salt diet anyway, for general health reasons.
The researchers now plan to apply the new model and build on the results to identify and follow up on potential drug targets.
Support for the research came from the National Human Genome Research Institute, the National Institutes of Health, National Multiple Sclerosis Society, the Klarman Cell Observatory, Guthy Jackson Foundation, and the Austrian Science Fund.
A study published in 2012 finds that the the prevalence and incidence of autoimmune diseases is on the rise in the US and researchers at the Center for Disease Control and Prevention are unsure why.
In the three studies the researchers focused on a group of immune cells known as T cells because they play an important role in clearing disease-causing pathogens and also in autoimmune disease. They were particularly interested in how T cells develop.
TH17 Cells Have Been Implicated In a Number of Autoimmune Diseases
Previous research has suggested that some types of autoimmunity may be tied to overproduction of a type of immune cell called TH17, a type of helper T cell that protects against pathogens.However, Th17 cells have also been implicated in diseases like multiple sclerosis, psoriasis, rheumatoid arthritis, and ankylosing spondylitis. Treatments for some of these diseases, such as psoriasis, involve manipulating T cell function.
Until now, scientists have struggled to pinpoint the molecular machinery behind the overproduction of TH17 cells, partly because the usual way of activating native immune cells in the lab, such as RNA interference (RNAi) to manipulate genes, either harms them or disturbs their development.
First Study: Using Nanowires to Manipulate Genes in TH17 Cells
But, by using a new method based on nanowires to manipulate genes in immune cells without altering the cells' functions, the authors of the first study, led by Aviv Regev, a biologist at the Massachusetts Institute of Technology, in Cambridge, in the US, were able "systematically" to assemble and validate a model of how TH17 cells are controlled in mice.Regev got the idea for the new approach after attending a lecture given by co-author, Hongkun Park, a physicist at Harvard University, also in Cambridge, on how to use silicone nanowires to disarm single genes in cells without disturbing the way the cells operate.
She says in a report by Nature NEWS that without such a model they would probably have been only "guessing in the dark".
Co-author Vijay Kuchroo, an immunologist at Brigham and Women's Hospital in Boston, Massachusetts, says in a statement that until they got the new technology using the nanowires, every time they downregulated a gene (with the previous technology), the cell would change.
The team identified and validated 39 "regulatory factors" altogether, uncovering the most important points in the network and untangling their biological meaning.
They conclude that their findings highlight "novel drug targets for controlling TH17 cell differentiation".
Second Study: Discovering Key Role of SGK1 Signal
In the second study, Regev and another team, this time led by Kuchroo, took snapshots of how immune cells were produced over a three day period.One protein in particular grabbed their attention, SGK1 (short for serum glucocorticoid kinase 1), a well-studied signaling protein that had not been described in T cells before, but is known to regulate how salt is absorbed in cells of the gut and in kidneys.
By manipulating salt levels in cultured mouse cells, the researchers found SGK1 expression was stronger the more salt there was, causing more TH17 cells to be produced.
Kuchroo says:
"If you incrementally increase salt, you get generation after generation of these TH17 cells."
Third Study: Confirming Findings in Mouse and Human Cells
In the third study, researchers led by David Hafler, a neurologist at Yale University in New Haven, Connecticut, confirmed the findings in mouse and human cells.Hafler says this was easy to do, "you just add salt".
They also found that mice fed with a high-salt diet developed a more severe form of experimental autoimmune encephalomyelitis (EAE), "in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells".
EAE is an animal model of brain inflammation that is used to study autoimmune disease in the lab.
Hafler and colleagues conclude that " ... increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells".
Implications
The researchers do not wish people to go away from these findings assuming that high salt diets alone cause autoimmune diseases.In their studies they had to induce autoimmune disease, the salt played an additional role. And there are other factors too, as Kuchroo explains:
"It's not just salt, of course. We have this genetic architecture - genes that have been linked to various forms of autoimmune diseases, and predispose a person to developing autoimmune diseases. But we also suspect that environmental factors - infection, smoking, and lack of sunlight and Vitamin D - may play a role."
"Salt could be one more thing on the list of predisposing environmental factors that may promote the development of autoimmunity," says Kuchroo.
Regev also says it is far too early to say people shouldn't eat salt because it leads to autoimmune disease.
"We're putting forth an interesting hypothesis - a connection between salt and autoimmunity - that now must be tested through careful epidemiological studies in humans," she explains.
Hafler adds, "As a physician, I'm very cautious."
He says people should be on a low-salt diet anyway, for general health reasons.
The researchers now plan to apply the new model and build on the results to identify and follow up on potential drug targets.
Support for the research came from the National Human Genome Research Institute, the National Institutes of Health, National Multiple Sclerosis Society, the Klarman Cell Observatory, Guthy Jackson Foundation, and the Austrian Science Fund.
A study published in 2012 finds that the the prevalence and incidence of autoimmune diseases is on the rise in the US and researchers at the Center for Disease Control and Prevention are unsure why.
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