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.
Researchers led by Mariano Garcia-Blanco, MD, PhD, 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.
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."
Mariano Garcia-Blanco, MD, PhD, Chair of UVA's Department of Microbiology, Immunology and Cancer Biology
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."
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.
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." 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.
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.
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.
"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. "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."
The researchers have published their findings in the scientific journal eLife. The team consisted of Minato Hirano, Gaddiel Galarza-Muñoz, Chloe Nagasawa, Geraldine Schott, Liuyang Wang, Alejandro L. Antonia, Vaibhav Jain, Xiaoying Yu, Steven G. Widen, Farren B.S. Briggs, Simon G. Gregory, Dennis C. Ko, W. Samuel Fagg, Shelton S. Bradrick and Garcia-Blanco. Garcia-Blanco acknowledges he has a financial interest in Autoimmunity BioSolutions a company that is developing novel therapies for autoimmune diseases; a full list of the other authors' disclosures is included in the paper.
The research was supported by the National Institutes of Health, grants R01 CA204806, F32 NS087899, KL2 TR001441-07, R21AI133305 and P01 AI150585; Uehara Foundation Fellowship and McLaughlin Postdoctoral Fund; Duke Neurology startup and Stone family funds; Duke Molecular Genetics and Microbiology startup funds; and University of Texas Medical Branch startup funds.
Hirano, M., et al. (2023) The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate. eLife. doi.org/10.7554/eLife.76927.