Gene Mutation Study Sheds Light on Autoimmune Disease Development

Researchers say they have discovered how a gene mutation can lead to diseases that occur when the immune system attacks the body by mistake. Understanding how these mechanisms work could help scientists to develop new treatments for autoimmune diseases such as Lupus and neurodegenerative conditions, including Motor Neurone Disease, according to the researchers, who published their study (“The RNA-Editing Enzyme ADAR1 Controls Innate Immune Responses to RNA”) in Cell Reports.

The team found that a mutation in the ADAR1 gene causes a defect in an alarm system in cells that normally protects the body from viruses and other infections. This means that the alarm system is tripped by the cell’s own molecules, causing the immune system to attack. Some viruses encode their genetic material using RNA, which is also produced by our own cells when the genes encoded in our DNA are translated into proteins.

Detecting foreign RNA inside a cell, such as from a virus, is the first warning sign of an infection. A group led by the University of Edinburgh has uncovered a system that helps the body to differentiate between normal RNA and RNA from foreign organisms. They found that ADAR1 adds a distinct chemical signature to the cell’s own RNA molecules to stop them from setting off an immune response. Virus RNA molecules lack this and so are detected by the cell’s alarm system.

“Aberrant immune responses in Adar1 mutant mouse embryo fibroblasts are dramatically reduced by restoring the expression of editing-active cytoplasmic ADARs,” wrote the investigators. “We propose that inosine in cellular RNA inhibits antiviral inflammatory and interferon responses by altering RLR interactions.”

Defects in the cell’s ability to modify its RNA could lead to the triggering of immune responses against the cell itself when there is no infection present, the scientists say.

Mutations in the ADAR1 gene have been linked to a rare autoimmune disease called Aicardi-Goutieres Syndrome. The disease affects the brain and skin and most people who are affected have significant intellectual and physical problems. The syndrome usually takes hold in early childhood and is so rare that it is not known how many people are affected. However the disease shows significant resemblances to the much more common and less severe Lupus.

“Our findings provide fresh insights into the way cells distinguish our own genetic material from that of disease-causing agents, such as viruses,” said Liam Keegan of the MRC Human Genetics Unit at the University of Edinburgh.


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