March 7, 2013
(The New York Times News Service) -- What started as a detailed study of the inner workings of one kind of immune cell has led two teams of researchers from New England to a surprising insight: a high-salt diet may increase risk of autoimmune diseases, such as multiple sclerosis and psoriasis.
The intriguing connection, reported Wednesday, is an important step in identifying dietary and other environmental causes of these disorders at a time when many of them have been on the rise.
Americans on average consume nearly 50 percent more salt than recommended, and salty diets have long been linked to problems such as high blood pressure.
The findings raise the possibility that cutting salt intake could protect against autoimmune diseases, which occur when the body's defenses against infections go haywire and attack itself -- but far more research is needed to make that determination.
The scientists found an enzyme that, when exposed to salt, causes a regular immune cell to transform into a pathogenic one, spewing out inflammatory proteins that have been linked to autoimmune illnesses. Mice genetically prone to develop a form of multiple sclerosis had more severe disease when fed a high-salt diet, the researchers reported.
"I was quite elated when I saw this work," said Dr. Lawrence Steinman, a professor of neurology at Stanford University, who was not involved in the research described in a trio of papers published Wednesday in the journal Nature. Steinman plans to launch a trial of a drug for MS patients that targets a different but related process involved in salt regulation. "I'm such a strong believer that salt matters that I'm pushing this into the clinic."
The work illustrates how powerful new biological approaches to investigate a seemingly esoteric question -- how genes control the behavior of cells -- can guide scientists to unexpected insights into the factors that cause common human disease. The work, supported partly by the National Institutes of Health, is the kind of fundamental laboratory research whose funding scientists say is imperiled by the across-the-board federal spending cuts that began last week.
Several outside researchers cautioned that although there are already good health arguments for lowering salt intake, the connection between salt and autoiummune disease needs more research to prove whether it holds true in the human body -- and is an important trigger.
Daniel Cua, a senior principal scientist at Merck Research Laboratories in Palo Alto, Calif., called the studies "remarkable," but added that the diseases are complex and salt may be
just one of many risk factors.
"People have different genetic predispositions to various diseases, including autoimmune disease," Cua said. "If you genetically have a very high susceptibility to autoimmune disease, it may be by reducing salt, you're taking away that one" risk.
Three and a half years ago, Vijay Kuchroo, an immunologist at Brigham and Women's Hospital, was not thinking about salt. He wanted to better understand TH17 cells, which normally help the body clear infections, but can also turn pathogenic. He hoped to help physicians and researchers sort a needle from a haystack: of the many environmental factors that have changed during the past half-century, from diet to lifestyle, which ones might help explain the rise in autoimmune diseases?
One common autoimmune disorder, Type 1 diabetes, increased 23 percent between 2001 and 2009, according to the American Diabetes Association. The incidence of psoriasis nearly doubled between 1970 and 2000. Pediatric multiple sclerosis, Kuchroo said, was virtually unheard of 20 years ago, and now more and more cases are being reported.
He began talking with computational biologist Aviv Regev at the Broad Institute in Cambridge, an expert in studying cells' molecular circuitry. Would her approach, he wondered, provide insight into the complicated role that the TH17 cells play in the immune system?
"It's like a Rube Goldberg machine -- a zillion different places where things are controlled, and if any one of those breaks down, it can increase your risk of autoimmune disease," Regev said. "In order to know what goes wrong, you have to know how it normally functions."
Researchers mapped the relationships between hundreds of genes and the factors that regulate them within the cell, and identified important ones.
A gene called SGK1 kept popping up, and a little research showed that the gene was usually active in the gut and the kidney, where it helped regulate salt absorption.
The researchers were intrigued, and eventually found that mice genetically predisposed to develop a form of multiple sclerosis had more severe disease when they were fed a high-salt diet. Mice lacking the SGK1 gene that also were fed a high-salt diet had less severe disease.
A team from Yale University did experiments on human immune cells and mice, and found the same connection.
The Brigham and Broad scientists will collaborate with Swedish researchers who have access to detailed observational data of human health and diet, to look for evidence that salt plays an important role in autoimmune disease. But outside scientists said that perhaps most exciting is the approach the Boston-area team used, which could provide scientists with hints about where to look when trying to understand other diseases that have a complex combination of genetic and environmental causes.
"We're all on a hunt for environmental factors. And the problem is there are too many, so we have lots and lots of them," said Dr. Noel Rose, director of the Johns Hopkins Center for Autoimmune Disease Research.
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