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.
No comments:
Post a Comment