The discovery of multiple sclerosis identifies the key factor that determines the risk

By | June 8, 2023

The discovery of multiple sclerosis identifies the key factor that determines the risk

image: Mariano Garcia-Blanco, MD, PhD, chair of the department of microbiology, immunology and cancer biology at the University of Virginia School of Medicine, has identified a number of processes in our cells that suppress our risk of developing sclerosis multiple.
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Credit: Courtesy of Mariano Garcia-Blanco, PhD

Scientists at the University of Virginia School of Medicine have discovered a key determinant of our risk for multiple sclerosis (SM), promoting efforts to better prevent and treat the disease.

Researchers led by Mariano Garcia-Blanco, MD, PhD, chair of UVA’s Department of Microbiology, Immunology and Cancer Biology, have identified a number of processes in our cells that suppress our risk of developing multiple sclerosis. At the head of these processes, the scientists discovered, is a gene that serves as the master controller for many other genes important for our susceptibility to MS and for the proper functioning of our immune system.

“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: ‘Although there are effective treatments for multiple sclerosis and other autoimmune diseases, most of them lead to overall suppression of the immune system and make patients susceptible to infections. or unable to respond well to vaccines”.

Understanding multiple sclerosis

Multiple sclerosis is a potentially disabling autoimmune disease in which the immune system begins attacking the sheath-like coverings that protect our nerves. The damage disrupts the ability of nerves to transmit communications throughout 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 one million Americans and nearly 3 million people worldwide.

The new work by Garcia-Blanco and her collaborators sheds important light on how our immune systems are calibrated to prevent MS and identifies several key points where things could go wrong. For example, the researchers conclude that the main gene they identified, DDX39B, is an “important guardian of immune tolerance”. This means that it helps keep the body’s immune response functioning at the proper levels, so that the immune system doesn’t start attacking the body’s cells, as is the case with MS and other autoimmune diseases.

This master gene, the researchers found, directs the activity of another gene crucial in the production of important immune cells called regulatory T cells (Tregs) previously linked to MS. This second gene FOXP3it is already known to play a critical role in autoimmune diseases.

These new insights into how the immune system works, or should work, help doctors and scientists better understand the underlying causes of multiple sclerosis and provide them with compelling targets in their efforts to develop new treatments and preventative measures.

“In cases of autoimmune diseases, we would like to activate DDX39B with small molecule agonists, for which there is a strong preclinical precedent,” said Chloe Nagasawa, a graduate student with Garcia-Blanco and second author of the new scientific paper outlining the findings. “Multiple sclerosis has a huge impact on patients and society, disproportionately affecting young women, and to date there is no cure. We believe that basic understanding of the molecular mechanisms underlying immune tolerance will pave the way for truly targeted therapy.”

Published results

The researchers published their findings in the scientific journal and Life. 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 BS Briggs, Simon G. Gregory, Dennis C. Ko, W. Samuel Fagg, Shelton S. Bradrick and Garcia-Blanco. Garcia-Blanco acknowledges having a financial interest in Autoimmunity BioSolutions, a company developing new therapies for autoimmune diseases; a complete list of the other authors’ revelations is included in the document.

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; startup Duke Neurology and Stone family funds; startup funds Duke Molecular Genetics and Microbiology; and University of Texas Medical Branch startup funds.

To keep up to date with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

MORE FROM THE GARCIA-BLANCO WORKSHOP: How mosquito saliva can weaken our defenses against the deadly dengue virus.

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