September 05, 2024

High salt intake may trigger mechanism that contributes to multiple sclerosis

Scientists have identified a novel molecular pathway that may link salt intake to MS risk.

  • Multiple sclerosis (MS) is a chronic autoimmune disease caused by the interaction between environmental factors, such as high dietary salt intake, and genetic risk factors.
  • When regulatory T cells, which are a type of white blood cell that suppress an immune response against the body’s own tissue, malfunction, they can lead to the development of MS and other autoimmune diseases.
  • A new study shows that high sodium levels lead to the upregulation of a molecular pathway involving the SGK-1 and PRDM1-S genes, subsequently causing regulatory T-cell dysfunction.
  • This study thus demonstrates a potential mechanism by which a high-salt diet could increase the risk of autoimmune diseases.

Autoimmune diseases are associated with the dysfunction of regulatory T cells, a type of immune cell that suppresses an immune attack against the body’s own tissue. A recent study published in Science Translational Medicine identified a shared molecular pathway in regulatory T cells that was altered in individuals with multiple sclerosis and other autoimmune diseases, resulting in reduced suppressive function of these immune cells.

The study also found that higher dietary salt intake activates this molecular pathway in regulatory T cells and could potentially explain the previously demonstrated link between high salt consumption and autoimmune diseasesTrusted Source.

The study’s lead author, Dr. Tomokazu Sumida, a professor at Yale School of Medicine, told Medical News Today:

“We previously demonstrated that regulatory T cells are defective in human autoimmune diseases, particularly multiple sclerosis (MS), suggesting they play a critical role in the development of autoimmune diseases, especially MS. In this paper, we uncover the underlying mechanism responsible for the loss of immune regulation in MS, linking both environmental and genetic factors. Additionally, we identify a novel target for the treatment of autoimmune diseases.”

The role of regulatory T cells in autoimmune diseases

Multiple sclerosis is a chronic autoimmune disease that affects nearly 2.8 millionTrusted Source individuals across the globe. During multiple sclerosis, the immune system attacks myelin, the protective sheath that covers nerve fibers. This demyelination process leads to nerve fibers’ damage, inflammation, and symptoms associated with muscle weakness.

Autoimmune diseases, such as MS, are characterized by a malfunction of immune cells, which results in an immune response against the body’s own cells and tissues. These dysfunctional immune cells include regulatory T cells, a type of white blood cell or lymphocyte that helps suppress an autoimmune response.

T cells can be broadly categorized into two groups based on the CD4+ or the CD8+ protein expression. The T cells expressing CD4+ can be further classified as regulatory T cells or conventional T cells.

Conventional T cells activate the immune response against infected or cancerous cells in the body. In contrast, regulatory T cells in the bloodstream suppress the activity of conventional T cells against healthy cells, thus reducing collateral damage.

Similar to other autoimmune diseases, studies have shown that regulatory T cells in multiple sclerosis malfunction, resulting in a decline in their suppressive function. However, the molecular pathways that cause regulatory T-cell dysfunction are poorly understood.

While certain genes predispose individuals to multiple sclerosis, environmental factors, such as high salt intake, also influence susceptibility to this condition. These environmental factors influence the immune response by modulating the expression of immune-related genes.

Further research is needed to understand how environmental factors interact with molecular pathways to modulate the suppressive effects of regulatory T cells.

Alterations in gene expression in regulatory T cells

CD4+ T cells can be categorized as naive or memory cells. Memory cells develop from activated T cells after the initial infection and help produce a more robust response during a future infection. In the case of memory regulatory T cells, these cells help suppress excessive activation of helper T-cells during a subsequent infection.

Autoimmune diseases, such as multiple sclerosis, involve the loss of suppressive function of the memory regulatory T cells. As a result, the researchers focused on memory regulatory T cells in the present study.

To gain further insight into the mechanisms underlying multiple sclerosis, the present study compared the differences in the expression of genes in regulatory memory T cells from individuals with multiple sclerosis and healthy controls.

The researchers found that the PR domain zinc finger protein 1 (PRDM1) gene was one of the most overexpressed genes in both regulatory memory T cells and conventional memory T cells in multiple sclerosis.

A decline in the expression of the ID3 gene accompanied the higher expression of the PRDM1 gene. The ID3 gene maintains FOXP3 expression, which is necessary for maintaining the suppressive function of regulatory T cells.

The PRDM1 gene encodes the B lymphocyte–induced maturation protein–1 (BLIMP1), a protein that regulates the function of regulatory T cells and helps prevent an autoimmune responseTrusted Source. The BLIMP1 protein exists in two different forms in humans, including the original full-length form and a truncated form, BLIMP1-S.

BLIMP1-S is encoded by PRDM1-S and involves a different transcription start site and promoter region than the longer PRDM1-L that encodes the full-length version of the protein. The expression of these two forms of PRDM1 varies among immune cells, with regulatory T cells expressing higher levels of PRDM1-S than PRDM1-L in healthy individuals.

In the present study, the researchers found that the expression of the shorter PRDM1-S transcript was elevated to a greater extent in memory regulatory T cells from individuals with multiple sclerosis than in healthy controls. There was also a modest increase in PRDM1-L transcript levels in memory regulatory T cells from multiple sclerosis individuals.

BLIMP1-S-mediated pathway

BLIMP1-S tends to suppress the expression of BLIMP1, but the ratio of PRDM1-S to PRDM-L did not differ in regulatory T cells from MS and healthy controls. Hence, the researchers examined other pathways through which elevated PRDM1-S expression could potentially influence regulatory T cell function in multiple sclerosis.

The researchers found that the expression of serum and glucocorticoid-regulated kinase 1 (SGK-1) was positively correlated with PRDM1-S expression in memory-regulatory T cells. Subsequent experiments suggested that the BLIMP1-S protein directly regulated the expression of SGK-1.

Previous studiesTrusted Source have shown that the SGK-1 gene is associated with the dysfunction of regulatory T cells. In the present study, the researchers found that the overexpression of PRDM1-S, but not PRDM1-L, in regulatory T cells led to an increase in SGK-1 expression.

The overexpression of PRDM1-S also reduced the suppressive effect of regulatory T cells. Reducing the expression of the SGK-1 gene by knockdown ameliorated the impact of PRDM-1 S overexpression on impaired suppressive function of memory regulatory T cells. This suggests that PRDM1-S upregulation led to a decline in suppressive function of memory regulatory T cells in multiple sclerosis, and these effects of PRDM1-S were mediated via the SGK-1 gene.

Notably, the increase in PRDM1-S and SGK-1 expression was also observed in regulatory T cells from individuals with other autoimmune diseases, including systemic lupus erythematosus(SLE).

In other words, the PRDM1-S/SGK-1 pathway could be a common molecular mechanism underlying regulatory T-cell dysfunction in autoimmune diseases.

High salt diet and autoimmunity

Studies have shown that SGK-1 inhibitsTrusted Source the transcription factor FOXO1, subsequently leading to regulatory T-cell dysfunctionTrusted Source. High dietary salt intake is associated with an increased risk of autoimmune diseasesTrusted Source, including multiple sclerosis.

Moreover, studies have shownTrusted Source that exposure to high sodium concentrations, such as those associated with consuming a high-salt diet, can interfere with the suppressive function of regulatory T cells by inducing the activation of SGK1.

In the present study, the researchers found that exposure to high sodium concentrations in vitro led to increased expression of PRDM1-S. Further evidence suggested that increased salt intake led to the activation of the PRDM1/SGK-1 pathway in regulatory T cells, contributing to their dysfunction.

What this means for treating MS

While the study shows that the PRDM1-S/SGK-1 pathway is upregulated in multiple sclerosis and potentially contributes to the dysfunction of regulatory T cells in this condition, the role of other pathways cannot be ruled out.

Moreover, experiments that block the PRDM1-S/SGK-1 pathway are needed to determine whether this pathway plays a causal role in multiple sclerosis.

Lastly, the experiments in the present study were conducted using regulatory T cells isolated from blood samples, and these results need to be validated in clinical trials.

“Targeting the PRDM1-S/SGK1 axis in susceptible MS patients has the potential to halt and prevent disease onset and progression. This approach could also lead to the development of new cellular markers to stratify patients and guide treatment options, ultimately aiding in the design of more effective therapies for MS,” Sumida said.

“Another direction for future research is exploring the role of PRDM1-S in other cell types, which has been minimally studied. Given its association with lymphoma pathology and Epstein-Barr Virus (EBV) infection, we aim to investigate its function not only in the context of autoimmunity but also in viral infections and cancer progression,” he added.

https://www.medicalnewstoday.com/articles/high-salt-intake-may-trigger-mechanism-contributes-multiple-sclerosis#High-salt-diet-and-autoimmunity

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