Salt may be a risk factor for multiple sclerosis and other autoimmune diseases, study suggests

Courtesy of Alex K. Shalek, Jellert T. Gaublomme, Hongkun Park
Courtesy of Alex K. Shalek, Jellert T. Gaublomme, Hongkun Park
An immune cell lies on a bed of nanowire needles. These microscopic spikes are used to deliver genetic material that can quell gene activity in the cells, allowing scientists to better understand their function.

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 scientists reported Wednesday they 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 developed more severe disease when fed a high salt diet.

The intriguing connection needs further study; no one knows yet whether cutting salt intake will prevent autoimmune diseases. Many of these illnesses—in which the body’s defenses against infections go haywire, attacking itself—have been on the rise.

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But the work illustrates how powerful new biological approaches to probe a seemingly esoteric question—how genes control the behavior of cells—can guide scientists to unexpected insights into the factors that cause human disease. Supported partly by the National Institutes of Health, it 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.

“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 this year 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.”

Americans consume on average nearly fifty percent more salt than is recommended by the nutritionists and government guidelines. But 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 is likely to 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, Dr. Vijay Kuchroo, an immunologist at Brigham and Women’s Hospital, wasn’t thinking about salt. He wanted to better understand TH17 cells, which normally help the body clear infections but can also turn pathogenic, producing proteins that trigger inflammation and are linked to rheumatoid arthritis, psoriasis, and multiple sclerosis. He hoped that understanding those cells in detail could help physicians and researchers sort a needle from a haystack: of the many environmental factors that have changed over the past half century, from diet to lifestyle, which ones might help explain the rise in autoimmune disease?

For example, Type 1 diabetes increased between 2001 and 2009 by 23 percent, 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 cells play in maintaining balance 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.”

They started by taking snapshots of gene activity 18 times over the course of three days as the TH17 cells formed. That gave them a foundation—a way to begin building a circuit diagram of which genes controlled what biochemical processes. They wanted a way to check their circuit diagram, but the immune cells were stubbornly evasive to typical techniques for doing so, by shutting down genes one by one.

Then, Regev attended a symposium and heard Hongkun Park, a Harvard University chemist, talk about an array of tiny silicon wires he had built in the hopes of using them to read the electrical activity of brain cells. Regev rushed up to the podium afterward, excited by the prospect that the thin “nanowires” could be used to puncture cells and inject genetic material that would silence specific genes.

They laid their delicate TH17 cells on a bed of tiny wires coated with the genetic material, a technique Kuchroo compares to a yogi lying on a bed of nails. It worked, allowing the scientists to turn key genes off so they could tweak their cell circuit diagram.

Regev saw that all genes could be grouped into two big networks. One network fired up activity of the immune cells, the other tamped it down. It was, she said, a yin and yang—unless that tension was yanked out of balance.

This diagram allowed the researchers to look for the nodes – the busiest and most critical intersections. 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. They administered salt to immune cells and found that the SGK1 gene became more active, turning them into TH17 cells and ramping up production of an inflammatory protein. They found that mice genetically predisposed to develop a form of multiple sclerosis had more severe disease when they were fed a high-salt diet, and that mice lacking the SGK1 gene 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 see whether they can begin to find any signal that a 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 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. “This adds salt to the list. ... Whether, in humans, it’s going to be important enough to intervene, is something that is being studied right now.”