International study: Excess dietary salt may drive the development of autoimmune diseases

(Press-News.org) Increased dietary salt intake can induce a group of aggressive immune cells that are involved in triggering and sustaining autoimmune diseases. This is the result of a study conducted by Dr. Markus Kleinewietfeld, Prof. David Hafler (both Yale University, New Haven and the Broad Institute of the Massachusetts Institute of Technology, MIT, and Harvard University, USA), PD Dr. Ralf Linker (Dept. of Neurology, University Hospital Erlangen), Professor Jens Titze (Vanderbilt University and Friedrich-Alexander-Universität Erlangen-Nürnberg, FAU, University of Erlangen-Nuremberg) and Professor Dominik N. Müller (Experimental and Clinical Research Center, ECRC, a joint cooperation between the Max-Delbrück Center for Molecular Medicine, MDC, Berlin, and the Charité – Universitätsmedizin Berlin and FAU) (Nature, doi: http://dx.doi.org/10.1038/nature11868)*. In autoimmune diseases, the immune system attacks healthy tissue instead of fighting pathogens.

In recent decades scientists have observed a steady rise in the incidence of autoimmune diseases in the Western world. Since this increase cannot be explained solely by genetic factors, researchers hypothesize that the sharp increase in these diseases is linked to environmental factors. Among the suspected culprits are changes in lifestyle and dietary habits in developed countries, where highly processed food and fast food are often on the daily menu. These foods tend to have substantially higher salt content than home-cooked meals. This study is the first to indicate that excess salt intake may be one of the environmental factors driving the increased incidence of autoimmune diseases.

A few years ago Jens Titze showed that excess dietary salt (sodium chloride) accumulates in tissue and can affect macrophages (a type of scavenger cells) of the immune system. Independent of this study, Markus Kleinewietfeld and David Hafler observed changes in CD4 positive T helper cells (Th) in humans, which were associated with specific dietary habits. The question arose whether salt might drive these changes and thus can also have an impact on other immune cells. Helper T cells are alerted of imminent danger by the cytokines of other cells of the immune system. They activate and "help" other effector cells to fight dangerous pathogens and to clear infections. A specific subset of T helper cells produces the cytokine interleukin 17 and is therefore called Th17 for short. Evidence is mounting that Th17 cells, apart from fighting infections, play a pivotal role in the pathogenesis of autoimmune diseases.

Salt dramatically boosts the induction of aggressive Th17 immune cells In cell culture experiments the researchers showed that increased sodium chloride can lead to a dramatic induction of Th17 cells in a specific cytokine milieu. "In the presence of elevated salt concentrations this increase can be ten times higher than under usual conditions," Markus Kleinewietfeld and Dominik Müller explained. Under the new high salt conditions, the cells undergo further changes in their cytokine profile, resulting in particularly aggressive Th17 cells.

In mice, increased dietary salt intake resulted in a more severe form of experimental autoimmune encephalomyelitis, a model for multiple sclerosis. Multiple sclerosis is an autoimmune disease of the central nervous system in which the body's own immune system destroys the insulating myelin sheath around the axons of neurons and thus prevents the transduction of signals, which can lead to a variety of neurological deficits and permanent disability. Recently, researchers postulated that autoreactive Th17 cells play a pivotal role in the pathogenesis of multiple sclerosis.

Interestingly, according to the researchers, the number of pro-inflammatory Th17 cells in the nervous system of the mice increased dramatically under a high salt diet. The researchers showed that the high salt diet accelerated the development of helper T cells into pathogenic Th17 cells. The researchers also conducted a closer examination of these effects in cell culture experiments and showed that the increased induction of aggressive Th17 cells is regulated by salt on the molecular level. "These findings are an important contribution to the understanding of multiple sclerosis and may offer new targets for a better treatment of the disease, for which at present there is no known cure," said Ralf Linker, who as head of the Neuroimmunology Section and Attending Physician at the Department of Neurology, University Hospital Erlangen, seeks to utilize new laboratory findings for the benefit of patients.

Besides multiple sclerosis, Dominik Müller and his colleagues want to study psoriasis, another autoimmune disease with strong Th17 components. The skin, as Jens Titze recently discovered, also plays a key role in salt storage and affects the immune system. "It would be interesting to find out if patients with psoriasis can alleviate their symptoms by reducing their salt intake," the researchers said. "However, the development of autoimmune diseases is a very complex process which depends on many genetic and environmental factors," the immunologist Markus Kleinewietfeld said. "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."

### *Sodium Chloride Drives Autoimmune Disease by the Induction of Pathogenic Th17 Cells

Markus Kleinewietfeld1, 2*, Arndt Manzel3, 4, Jens Titze5, 6, Heda Kvakan7, 8, Nir Yosef2, Ralf A. Linker3, Dominik N. Muller7,9+, David A. Hafler1, 2*+

1Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, United States, 2Broad Institute of MIT and Harvard, Cambridge, MA, United States, 3Department of Neurology University of Erlangen-Nuremberg, Germany, 4International Graduate School for Neuroscience, Ruhr-University Bochum, Germany, 5Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, United States. 6Interdisciplinary Center for Clinical Research and Department for Nephrology and Hypertension, University of Erlangen-Nuremberg, Germany. 7Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine Berlin, Germany, 8Helios Klinikum Berlin-Buch, Germany, 9Nikolaus-Fiebiger-Center for Molecular Medicine, University Erlangen-Nuremberg, Germany * corresponding authors +these authors contributed equally to the work

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PD Dr. Ralf Linker
Neuroimmunology Section
Department of Neurology
University Hospital Erlangen
Schwabachanlage 6
D-91054 Erlangen
Phone: +49 (0)9131 - 85-32187
Fax: +49 (0)9131 - 85-36597
e-mail: Ralf.Linker@uk-erlangen.de Further information: http://www.mdc-berlin.de/en/news/archive/2012/20120907-skin_and_immune_system_influence_salt_stor/index.html