Researchers at Yale have identified a protein that triggers loss of immune regulation associated with multiple sclerosis and other diseases.
This discovery, which highlights the role of environmental factors like high salt intake, offers a new target for developing universal autoimmune treatments.
Groundbreaking Discoveries in Autoimmune Research
More than two decades ago, a research team in the lab of David Hafler, a Yale researcher who at the time was at Harvard, discovered a type of T cell in humans that suppresses the immune system; they later found that these so-called regulatory T cells, when defective, are an underlying cause of autoimmune disease, specifically multiple sclerosis (MS). For many years, however, the mechanism behind this dysfunction has remained unclear.
In a new Yale-led study, a team of researchers finds that this loss of immune regulation is triggered by an increase in PRDM1-S, a protein involved in immune function, triggering a dynamic interaction of multiple genetic and environmental factors, including high salt uptake.
The findings, published on August 28 in the journal Science Translational Medicine, also reveal a new target for a universal treatment for human autoimmune disease.
The research was led by Tomokazu Sumida, an assistant professor at Yale School of Medicine (YSM), and Hafler, the William S. and Lois Stiles Edgerly Professor of Neurology and professor of immunobiology at Yale.
Unveiling the Mechanism of MS
“These experiments reveal a key underlying mechanism for the loss of immune regulation in MS and likely other autoimmune diseases,” said Hafler, who is also chair of Yale’s Department of Neurology. “They also add mechanistic insight into how Treg [regulatory T cells] dysfunction occurs in human autoimmune diseases.”
Autoimmune diseases, among the most common disorders of young adults, are known to be affected by genetic and environmental factors, including vitamin D deficiency and fatty acids. In an earlier study, Sumida and Hafler found that high levels of salt also contribute to the development of multiple sclerosis, an autoimmune disease of the central nervous system. Specifically, they observed that high salt induces inflammation in a type of immune cell known as CD4 T cells, while also causing a loss of regulatory T cell function. This, they found, is mediated by a salt-sensitive kinase, or enzyme critical for cell signaling, known as SGK-1.
For the new study, researchers used RNA sequencing to compare gene expression in patients with MS with expression in healthy individuals. In patients with MS, the researchers identified upregulation, or increased expression, of a gene called PRDM1-S (primate-specific transcription factor), also known as BLIMP-1, which is involved in regulating immune function.
New Potential Targets for Autoimmune Treatments
Surprisingly, PRDM1-S induced increased expression of the salt-sensitive SGK-1 enzyme, leading to disruption of regulatory T cells, the researchers found. Moreover, they found similar overexpression of PRDM1-S in other autoimmune diseases, suggesting that it may be a common feature of regulatory T cell dysfunction.
“Based on these insights, we are now developing drugs that can target and decrease expression of PRDM1-S in regulatory T cells,” Sumida said. “And we have initiated collaborations with other Yale researchers using novel computational methods to increase the function of regulatory T cells to develop new approaches that will work across human autoimmune diseases.”
Reference: “An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction” by Tomokazu S. Sumida, Matthew R. Lincoln, Liang He, Yongjin Park, Mineto Ota, Akiko Oguchi, Raku Son, Alice Yi, Helen A. Stillwell, Greta A. Leissa, Keishi Fujio, Yasuhiro Murakawa, Alexander M. Kulminski, Charles B. Epstein, Bradley E. Bernstein, Manolis Kellis and David A. Hafler, 28 August 2024, Science Translational Medicine.
DOI: 10.1126/scitranslmed.adp1720
The study was done with Bradley Bernstein and Manolis Kellis, longtime collaborators of Hafler from the Broad Institute of MIT and Harvard, and several other research institutions.
Other authors from the Yale lab include neurologist Matthew R. Lincoln, and post-graduate research assistants Alice Yi, Helen Stillwell, and Greta Leissa.
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5 Comments
AWESOME…😎
AWESOME RESEARCH FOR MS!!! THANK YOU
This is misleading. Salt was shown to have an effect on cells in tissue culture, not in a human body. There is no evidence here that reducing salt intake would affect MS. The body also has an effective way of balancing sodium and chloride in the body, and eliminating excess amounts.
It is also worth noting that when a there is a correlation between some diseased condition and the appearance of some enzymatic changes, it does not follow that the enzymatic change is the cause of the problem. It could be the body’s way of reacting to and mitigating the problem. Without knowing the cause of an autoimmune disease, you can’t easily tell whether the alterations in the immune system are a response, or are part of the cause. Of course, if you want to develop drugs, you tend to look for a biochemical process that you can alter with a drug. It is assumed that autoimmune disease is a dysfunction of immunity, so any abnormality seems to be part of the problem. But it might actually be part of the body’s way of dealing with it.
Suspiciously, vaccinations are not mentioned as a cause of autoimmune disease, which they are known to be. Blaming salt, which has many important biological functions, is easier than blaming vaccines, which are protected from any criticism by the medical industry. But given that kids these days receive more than 40 vaccinations as infants and toddlers, it is clear that lots of immune sensitizers have been administered to people. These sensitizers are called adjuvants, and they are known to cause autoimmunity. As the article states, “Autoimmune diseases, among the most common disorders of young adults…” It’s not because they eat too much salt.
I appreciate your keen eye as to the limitations of this study. It bothers me greatly that we now have a world where so many limited studies or biased studies are reported or made to sound like fact. I wonder if the old way science methodology was taught has completely been lost.
💯 I am barely alive and mostly bedridden from the covid vaccine. Immediate and debilitating reaction in sept 21. Still being gaslit, dismissed, and ignored by provaxxers and drs, and told I deserve to die by antivaxxers for being coerced and manipulated into getting it. It destroyed every function of my body physically, cognitively, and emotionally.
Also, not disabled enough with all 4 limbs numb most of the time and unable to sit, stand, walk, talk, think, remember, use my hands, etc., and dizzy and flu feeling all the time according to social security. Completely disabled at 42 and no answers or even acknowledgment of my disability. No support system, new ptsd and trauma from starving and being forced to he dependent on others and no one caring what I need at best, or being abusive, neglectful, and controlling at worst. It has been awful.
It caused my immune system and nervous systems to become overactive and dysfunctional and triggered or worsened every genetic condition I had latent symptoms of my whole life or for years as well as every other thing I could possibly have and caused it to happen 20-30 years sooner yet at that severity.
Severe episodes of parkinsons and dementia but don’t fit early onset at all. So many mutations for, eds, parkinsons/fahrs/psp, cmt, osteogenesis imperfecta, hereditary angioedema type 3, just on and on and symptoms or worsensing of all of them.