The Cogence Clinical Pearls Series

Sodium Drives Autoimmune Tissue Destruction

What the research says…

In this clinical pearl, we review papers from Nature and Frontiers in Physiology. Both point to evidence that sodium drives the maturation of Th17 cells, yielding flares of autoimmune process. Mouse and human T cells exposed to sodium are influenced to turn into Th17 cells. Further, the Th17 cells they turn into “display a highly pathogenic and stable phenotype.”

Application…

This means that, as a practical matter, patients with autoimmune disease may be poor candidates for therapeutic strategies that use sodium. For example, POTS patients for whom this is a concern will need to support their systemic sodium levels through the use of licorice, which diminishes renal clearance of sodium. Supporting systemic / tissue sodium will satisfy the need for support of adequate blood pressure, but without the introduction of significantly higher doses of sodium in the GI tract, where sodium can have a stronger influence on immune response, given the large populations of T cells in the lamina propria of the intestine. It’s important to note that the Frontiers in Physiology paper, a review, describes nine human trials related to RA, MS, and Crohn’s disease. Some have shown a clear association between higher salt intake and worse disease outcomes. Others have not. This suggests that the connection between sodium and Th17 cell-mediated tissue destruction is one of many important factors, and that susceptibility to the influence of sodium may also be variable between patients.

The research…

Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.
Nature. 2013 Apr 25;496(7446):518-22. Kleinewietfeld M, Manzel A, Hafler DA, et al.
(SY: Color and bold added.)

Abstract
There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4(+) helper T cells (TH17 cells) has a pivotal role in autoimmune diseases. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23-TH17 pathway. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.

Could Sodium Chloride be an Environmental Trigger for Immune-Mediated Diseases? An Overview of the Experimental and Clinical Evidence.
Front Physiol. 2018 Apr 24;9:440. Toussirot E, Béreau M, Vauchy C, Saas P.
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Abstract
Immune mediated diseases (IMDs) are complex chronic inflammatory diseases involving genetic and environmental factors. Salt intake has been proposed as a diet factor that can influence the immune response. Indeed, experimental data report the influence of sodium chloride on the differentiation of naive CD4+ T cells into IL-17 secreting T helper (Th) cells (Th17 cells), by a mechanism involving the serum glucocorticoid kinase-1 (SGK1) that promotes the expression of the IL-23 receptor (IL-23R). The IL-23/IL-23R is critical for pathogenic inflammatory Th17 cell differentiation. Experimental data in murine models of arthritis, colitis and encephalomyelitis corroborate these findings. This manuscript reviews the current knowledge on the effects of sodium chloride on innate and adaptive immunity. We also performed a systematic literature review for clinical studies examining the relationships between salt consumption and the development or the activity/severity of the most common IMDs mediated by the IL-23/Th17 pathway, i.e., rheumatoid arthritis (RA), multiple sclerosis (MS), and Crohn’s disease (CD). Nine studies were found, 4 in RA, 4 in MS and 1 in CD. An association was found between developments of anti-citrullinated protein antibody (ACPA) positive RA in smokers and salt intake, but these results were not confirmed in another study. For MS, no association was observed in pediatric subjects while in adult patients, a link was found between salt intake and disease activity. However, this result was not confirmed in another study. These conflicting results highlight the fact that further evaluation in human IMDs is required. Moreover, physicians need to develop clinical trials with diet interventions to evaluate the impact of low salt intake on disease activity/severity of IMDs.