Identification of a critical risk factor for multiple sclerosis

Loss of FOXP3 expression in DDX39B-depleted T cells. (A) RNA abundance changes between control (NTC) and DDX39B-depleted (Sh3) CD4+ T cells from two healthy individuals (Donor 1 and Donor 4) identified by RNAseq. Data points for DDX39B (cyan) and FOXP3 (magenta) are indicated. (B) Examples of MS susceptibility genes differentially expressed upon DDX39B knockdown. The heat map shows expression of five genes between control (NTC) and DDX39B depleted (Sh3) CD4+ T cells. (C) Enrichment analysis of MS susceptibility genes in DEGs following DDX39B depletion. Resampling 100,000 times resulted in a distribution of the number of genes that overlap by chance, with 23 being the most common result. The observed overlap of 41 (Magenta arrow) demonstrates substantial enrichment (empirical p=0.00013). (D) Levels of DDX39B RNA and FOXP3 RNA, normalized to EEF1A1 RNA levels, after DDX39B depletion in CD4+ T cells and levels of DDX39B and FOXP3 protein relative to Tubulin after DDX39B depletion in CD4+ T cells. Connected dots indicate samples from the same donor. In all figures the error bars indicate standard deviation. *: p<0.05, **: p<0.01, ***: p<0.001 and ****: p<0.0001. Credit: eLife (2023). DOI: 10.7554/eLife.76927

University of Virginia School of Medicine scientists have discovered a key determinant of our risk for multiple sclerosis (MS), advancing efforts to prevent and better treat the disease.n

Researchers led by Mariano Garcia-Blanco, MD, Ph.D., chair of UVA’s Department of Microbiology, Immunology and Cancer Biology, identified a series of processes in our cells that suppresses our risk for developing multiple sclerosis. At the head of these processes, the scientists found, is a gene that acts as a master controller for many other genes important in our susceptibility to MS and in the proper functioning of our immune systems.n

“It is remarkable that a protein that unwinds RNA is a central player in how we recognize our cells as our own, not to be confused with invading pathogens,” Garcia-Blanco said. He noted that the new understanding could help lead to better, more targeted treatments: “While there are effective treatments for multiple sclerosis and other autoimmune diseases, most of these lead to general suppression of the immune system and makes patients susceptible to infections or incapable of responding well to vaccines.”n

Understanding multiple sclerosis

Multiple sclerosis is a potentially disabling autoimmune disorder in which the immune system begins to attack the sheath-like coverings that protect our nerves. The damage interrupts the nerves’ ability to transmit communications through the body. This leads to symptoms such as muscle weakness and stiffness, spasms, fatigue, numbness and difficulty moving. The disease is estimated to affect nearly a million Americans and almost 3 million people worldwide.n

The new work from Garcia-Blanco and his collaborators sheds important light on how our immune systems are calibrated to prevent MS and identifies several key places where things might go wrong. For example, the researchers conclude that the master gene they identified, DDX39B, is an “important guardian of immune tolerance.”n

This means that it helps keeps the body’s immune response working at the appropriate levels, so that the immune system doesn’t begin to attack the body’s own cells?as is the case in MS and other autoimmune diseases.n

This master gene, the researchers found, directs the activity of another gene critical in the production of important immune cells called T regulatory cells (Tregs) previously linked to MS. This second gene, FOXP3, is already known to play a critical role in autoimmune disorders.n

These new insights into how the immune system functions, or should function, help doctors and scientists better understand the underlying causes of multiple sclerosis and give them attractive targets in their efforts to develop new treatments and preventive measures.n

“In cases of autoimmune diseases, we would want to activate DDX39B with small-molecule agonists, for which there is strong pre-clinical precedent,” said Chloe Nagasawa, a graduate student with Garcia-Blanco and second author of the new scientific paper outlining the findings.n

“Multiple sclerosis takes a massive toll on patients and society, affecting disproportionately young women, and to date there is no cure. We believe that basic understanding of molecular mechanisms underpinning immune tolerance will open paths to truly targeted therapy.”n

The researchers have published their findings in the scientific journal eLife.

More information:
Minato Hirano et al, The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate, eLife (2023). DOI: 10.7554/eLife.76927

Journal information: eLife n