March 7, 2013
Autoimmune Diseases Driven By Excessive Intake Of Dietary Salt
Alan McStravick for redOrbit.com - Your Universe Online
Over the previous several years, medical professionals have noted and documented marked increases in the prevalence of autoimmune diseases. An international team of scientists and researchers have come together in an attempt to identify the cause behind the increase in diseases like multiple sclerosis, rheumatoid arthritis, psoriasis and other diseases. What they have learned is that there is a connection between dietary salt intake and autoimmunity. Their results are published in three independent articles in this week´s edition of Nature
"The question we wanted to pursue was: how does the highly pathogenic, pro-inflammatory T cell develop?" said Vijay Kuchroo, co-director of the Center for Infection and Immunity at Brigham and Women's Hospital's (BWH) Biomedical Research Institute and a Broad Institute associate member. Kuchroo is also a professor of neurology at Harvard Medical School (HMS).
"Once we have a more nuanced understanding of the development of the pathogenic Th17 cells, we may be able to pursue ways to regulate them or their function," he said in a statement.
HIGH SALT CONTENT
"These are not diseases of bad genes alone or diseases caused by the environment, but diseases of a bad interaction between genes and the environment," said David Hafler, the Gilbert H. Glaser Professor of Neurology, professor of immunobiology, chair of the Department of Neurology, and senior author of the Yale University paper.
The impetus for the research was brought about by the observation made that eating at fast food restaurants tended to trigger an increase in the production of inflammatory cells. When this production occurs as the result of autoimmunity, healthy tissue is often harmed.
Dominik Mueller, another researcher conducting his study in Germany, along with his colleagues at Yale University, wanted to ascertain whether or not high salt content in a diet might be responsible for the induction of the destructive immune system response.
His research showed that the addition of salt to the diet of laboratory mice was responsible for producing a type of T cell that has already been associated with autoimmune diseases. The lab mice on the salt diets developed a far more severe form of a multiple sclerosis animal model, experimental autoimmune encephalomyelitis.
Multiple sclerosis is an especially insidious disease of the central nervous system. The body´s own immune system will systematically destroy the myelin sheath that surrounds the axons of neurons. This destruction prevents the transduction of signals. When the neuron can no longer receive signals, a variety of neurological deficits and permanent disability can occur. Only recently have researchers theorized that autoreactive Th17 cells are important in the pathogenesis of multiple sclerosis.
"In the presence of elevated salt concentrations this increase can be ten times higher than under usual conditions," Markus Kleinewietfeld and Dominik MÃ¼ller explained. Under the new high salt conditions, the cells undergo further changes in their cytokine profile, resulting in particularly aggressive Th17 cells.
Hafler pointed out, “Humans were genetically selected for conditions in sub-Saharan Africa, where there was no salt. Today, Western diets all have high salt content and that has led to an increase in hypertension and perhaps autoimmune disease as well.”
Hafler also noted that previous measures of salt were typically taken from the blood stream and not in the tissues where immune cells are dispatched to fight an oncoming infection. It is for this reason Hafler believes salt´s role in autoimmunity may have gone undetected.
"We may have been using the wrong concentrations of salt in our experiments for the past half-century," Hafler said in a statement. "Nature did not want immune cells to become turned on in the pipeline, so perhaps blood salt levels are inhibitory."
Patient trials to assess effects of salt on autoimmune diseases are being planned.
"The value in doing an unbiased analysis is that we're able to understand a lot more about the molecular biology at play and put forth a completely novel process," said Aviv Regev, a Broad Institute core member and an associate professor of biology at MIT. Regev is also an Early Career Scientist at Howard Hughes Medical Institute (HHMI) and the director of the Klarman Cell Observatory at the Broad Institute.
Our immune system, as it turns out, must maintain a very delicate and deliberate balance. If our immune system is too lax, we are more susceptible to foreign invaders. If it is too aggressive, we run the risk of being our own worst enemy. These most recent studies have identified part of the molecular circuitry that works to upset our immunity´s equilibrium.
“We wanted to understand how the body gets the right kinds of immune cells in the right amount, and how it keeps those cells at the right activity level so that they are not too active but also not underactive," said Regev.
The team, in conducting their research on Th17 development, understood the volatility of immune cells from the outset. These cells are able to change and evolve over time. For this reason, the team took 18 different snapshots of the cells over three days. This allowed them to observe the cells as they grew from naive cells into the more specialized Th17 cells. The snapshots also enabled them to use computational algorithms to understand the molecular changes that occurred as each cell matured.
To further understand the Th17 cells, the researchers would need to test their model by silencing genes one-by-one. They believed this would help to reveal the most important points in the network and untangle their biological meaning. But silencing the genes was going to require a non-traditional approach.
"This was a real challenge," said Kuchroo. "Every time we tried to downregulate a gene with existing technologies, the cell would change. We didn't know if we were looking at the right thing. We needed a new technology — something that could have a dramatic but precise effect."
Harvard professor and Broad associate member Hongkun Park and his lab in the departments of chemistry and chemical biology and of physics seemed an unlikely ally in this study. His lab, however, had been working on a computer-chip-like structure meant to interact with brain cells. Co-first authors Alex Shalek and Jellert Gaublomme had developed a bed of silicon nanowires designed to pierce cells.
"We learned that we could use these needles to deliver molecules into cells in a minimally invasive fashion," said Park. "And as Vijay and Aviv taught me, there are lots of things that this allows you to do that you could not do before. It's been an eye-opening experience."
This new technology allowed the research teams to slowly separate key components of the network, piece by piece, by deleting each of the key genes required in the development of Th17 cells.
This process showed the team that the Th17 cells are governed by two independent networks that are seemingly at odds with one another. The first network operates to positively regulate the cells, prompting them to increase in overall number. The second network behaves in such a way as to promote the opposite effect.
"It's a system in perfect tension," said Regev. "It both suppresses and promotes Th17 cell creation, keeping the cells at equilibrium."
As the team worked to silence genes in the Th17 cell, one gene in particular stood out. SGK1, important in the development of Th17, was found to cease immune cell production when turned off in mice.
There had been no previous study of SGK1 in T cells, but it has been found in cells in the gut and in kidneys, where it is instrumental in the absorption of salt. It was due to the discovery of SGK1 and its integral role in Th17 development that researchers turned their attentions to the connection between salt and autoimmunity.
"It's not just salt, of course," Kuchroo said. "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."
"One important question is: how can one think of these results in the context of human health?" said Regev. "It's premature to say, 'You shouldn't eat salt because you'll get an 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."
With a fuller understanding of the immune cell circuitry and related data, the teams plan to follow up on potential drug targets. Kuchroo, referencing the published works in this week´s Nature, states these findings were only possible because of the interdisciplinary team that was brought together by shared questions of cell circuitry.
"We often work in isolation in our areas of expertise, but this is the kind of work I could not have done in my own lab, and that Hongkun and Aviv could not have done in their respective labs," said Kuchroo. "We needed this unique combination of tools and technologies to come together around this problem. Looking forward, we'll need the tools and intellect of different disciplines in order to solve big problems in biology and medicine."
The German contingent of researchers and scientists hope to continue the study of Th17 cells further, looking into psoriasis. According to researcher Jens Titze, the skin also plays a key role in salt storage. This additional salt storage could affect the immune system, as well. “It would be interesting to find out if patients with psoriasis can alleviate their symptoms by reducing their salt intake.”
Kleinewietfeld pointed out, “The development of autoimmune diseases is a very complex process which depends on many genetic and environmental factors. Therefore, only further studies under less extreme conditions can show the extent to which increased salt intake actually contributes to the development of autoimmune diseases.”
Hafler, however, is not waiting with his own patients.
"I already recommend that my patients use a low-salt, low-fat diet," he said.