SC Connecticut News

A Yale-led study has uncovered a mechanism that triggers the loss of immune regulation associated with multiple sclerosis (MS) and other autoimmune diseases, identifying a potential target for treatment.

More than two decades ago, a research team in David Hafler's lab discovered regulatory T cells that suppress the immune system. These cells, when defective, were found to be an underlying cause of autoimmune diseases like MS. However, the mechanism behind this dysfunction remained unclear until now.

The new study reveals that this loss of immune regulation is triggered by an increase in PRDM1-S, a protein involved in immune function. This interaction involves multiple genetic and environmental factors, including high salt intake. The findings were published in the journal Science Translational Medicine.

The research was led by Tomokazu Sumida, an assistant professor at Yale School of Medicine (YSM), and Hafler, who holds the William S. and Lois Stiles Edgerly Professorship of Neurology and is also a professor of immunobiology at Yale.

“These experiments reveal a key underlying mechanism for the loss of immune regulation in MS and likely other autoimmune diseases,” said Hafler, who also chairs Yale’s Department of Neurology. “They also add mechanistic insight into how Treg [regulatory T cells] dysfunction occurs in human autoimmune diseases.”

Autoimmune diseases are among the most common disorders affecting young adults and are influenced by genetic and environmental factors such as vitamin D deficiency and fatty acids. In previous research, Sumida and Hafler identified high salt levels as contributing to MS development by inducing inflammation in CD4 T cells while causing regulatory T cell dysfunction through a salt-sensitive kinase known as SGK-1.

In their recent study, researchers used RNA sequencing to compare gene expression between MS patients and healthy individuals. They identified increased expression of PRDM1-S (also known as BLIMP-1), which regulates immune function. This upregulation led to increased expression of SGK-1 enzyme, disrupting regulatory T cells. Similar overexpression was observed in other autoimmune diseases.

“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.”

The study included contributions from Bradley Bernstein and Manolis Kellis from the Broad Institute of MIT and Harvard, along with several other research institutions. Other authors from Yale include neurologist Matthew R. Lincoln and post-graduate research assistants Alice Yi, Helen Stillwell, and Greta Leissa.