Autoimmune diseases are a group of illnesses that occur when the body’s immune system is overactive, attacking its own healthy cells. There are more than 80 types of known autoimmune diseases, impacting as much as 10 percent of the global population, per the Global Autoimmune Institute. These illnesses vary widely in their causes, which can include both genetic and environmental factors. They also differ broadly in their symptoms, which range from mild to life-threatening. Researchers are especially focused on identifying the mechanisms behind the most severe autoimmune diseases, like multiple sclerosis (MS), which has debilitating symptoms like vision loss and reduced motor function. Now, a new Yale-led study has shed light on the molecular mechanism behind the loss of immune function in patients with MS. In the process, it has revealed a new potential target for universal autoimmune disease treatment.
Researchers Build on Prior Understanding of MS Molecular Mechanism
The Yale study was led by Tomokazu Sumida, an assistant professor at Yale School of Medicine, and David Hafler, the William S. and Lois Stiles Edgerly Professor of Neurology and professor of immunobiology at Yale. The study built on prior research conducted in Hafler’s lab — research that included the discovery of a type of T cell in humans that suppresses, or regulates, the immune system. The team found that, when defective, these regulatory T cells can be a major underlying cause of MS. However, the team did not understand the exact molecular mechanism behind the dysfunction. Sumida and Hafler sought to build on those findings.
The duo also aimed to expand upon an earlier study, which found that high levels of salt contribute to the development of MS. During that study, Sumida and Hafler realized that salt induces inflammation in a type of immune cells known as CD4 T cells. Salt also interferes with the function of regulatory T cells. This is largely due to the function of a salt-sensitive enzyme known as SGK-1.
Evaluating MS Molecular Mechanism via Gene Expression
To unlock the mechanism behind MS and other autoimmune diseases, the researchers used RNA sequencing to compare gene expression in patients with MS versus healthy individuals. The difference was clear: Patients with MS had markedly increased expression of a protein called primate-specific transcription factor (PRDM1-S), also known as BLIMP-1, which is known for its role in regulating immune function.
Surprisingly, PRDM1-S also induced increased expression of the SGK-1 enzyme associated with salt absorption, leading to regulatory T cell dysfunction. That expression was not unique to MS patients; the researchers found similar overexpression of PRDM1-S in patients with other, non-MS autoimmune diseases. This suggests that PRDM1-S could be a common feature in many, if not all, conditions associated with 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.”
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Hafler and Sumida’s experiments reveal a key molecular mechanism for the loss of immune regulation in MS — and, likely, other autoimmune diseases as well. Moving forward, researchers may apply these findings to more targeted autoimmune treatments, improving the global understanding of these complicated conditions.
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