The Molecular Process That Causes MS and Autoimmune Diseases

A human immune system suppressor known as “regulatory T cells” was first identified more than 20 years ago by a research team working in the lab of Yale researcher David Hafler, who was at Harvard at the time. The team went on to discover that the malfunction of these cells can lead to autoimmune diseases, including multiple sclerosis (MS). However, the precise mechanism behind this malfunction has remained a mystery for a long time.

A recent Yale-led study reveals that this lack of immune modulation is caused by an increase in PRDM1-S, a protein implicated in immune function, which triggers a dynamic interplay of numerous genetic and environmental variables, including excessive salt intake.

The results, which appear in the journal Science Translational Medicine, also identify a novel target for a universal therapy for human autoimmune disease.

The study was directed 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 Immunobiology at Yale.

These experiments reveal a key underlying mechanism for the loss of immune regulation in MS and likely other autoimmune diseases. They also add mechanistic insight into how Treg [regulatory T cells] dysfunction occurs in human autoimmune diseases.”

David Hafler, Chair, Department of Neurology, Yale University

Autoimmune diseases, one of the most frequent conditions in young people, are known to be influenced by hereditary and environmental variables such as vitamin D deficiency and fatty acids. In a previous study, Sumida and Hafler discovered that elevated salt levels lead to the development of multiple sclerosis, a central nervous system autoimmune disease.

They discovered that excessive salt levels cause inflammation in a kind of immune cell known as CD4 T cells, as well as a lack of regulatory T cell activity. They discovered that SGK-1, a salt-sensitive kinase or enzyme crucial for cell signaling, is responsible for this.

In the new study, gene expression in MS patients was compared to expression in healthy persons using RNA sequencing. Researchers found that a gene known as PRDM1-S (primate-specific transcription factor), also referred to as BLIMP-1 and involved in immune function, was expressed more frequently or upregulated in MS patients.

The researchers discovered that PRDM1-S unexpectedly enhanced the expression of the salt-sensitive SGK-1 enzyme, which disrupted regulatory T cells. Furthermore, they discovered that PRDM1-S was overexpressed in various autoimmune diseases, indicating that this could be a common characteristic 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. 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.”

Tomokazu Sumida, Assistant Professor, School of Medicine, Yale University