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HomeHealth"Mutational Tsunami: The Unseen Catalyst Behind Infection-Driven Autoimmune Disorders"

“Mutational Tsunami: The Unseen Catalyst Behind Infection-Driven Autoimmune Disorders”

Researchers have discovered how chronic hepatitis C infection can lead to autoimmune diseases, paving the way for new treatment strategies.

A team of scientists at the Garvan Institute of Medical Research has unveiled how a viral infection can trigger autoimmune diseases, challenging a long-held belief and providing an exciting new direction for developing therapies for these conditions.

The findings, published today in the journal Immunity, center on the hepatitis C virus (HCV), which impacts approximately 58 million individuals globally. The study demonstrates its involvement in inducing a serious autoimmune condition known as cryoglobulinemic vasculitis in up to 15% of cases, where antibodies attack blood vessels, causing potential damage to various organs in the body.

Previously, researchers thought that this autoimmune reaction happened because the viral proteins resembled the body’s own proteins, thus misleading the immune system into attacking both. However, the Garvan team discovered that the true trigger lies in mutations found in ‘rogue clone’ B cells.

“This finding fundamentally alters our comprehension of how infections can lead to autoimmune disorders,” states Professor Chris Goodnow, head of the Immunogenomics Lab at Garvan and co-senior author of the study. “By identifying these rogue clones, we can enhance our strategies for targeting them, which could revolutionize the treatment of autoimmune diseases in affected patients.”

Viral Infection Creates a ‘Perfect Storm’ of Mutations

Employing advanced single-cell analysis and genome sequencing, the researchers examined the immune cells in the blood of four patients experiencing HCV-related cryoglobulinemic vasculitis. They pinpointed the specific rogue clone B cells that were abundant and producing harmful autoantibodies.

“The prevailing theory suggested that B cells designed to recognize the foreign virus became confused and turned against the body – a concept known as molecular mimicry. Our research revealed that during a chronic hepatitis C infection, antibodies on the virus’s surface form clusters that continuously stimulate B cells to mutate,” explains lead author Dr. Clara Young. “This ongoing mutation ultimately results in the emergence of rogue clones responsible for cryoglobulinemic vasculitis.”

“Our study indicates that three types of genetic mutations are necessary for developing the autoimmune disease,” adds Dr. Dan Suan, co-senior author and Clinical Director of the Hope Research Program at Garvan. “Two of these mutations naturally occur in B cells, but the continuous presence of chronic viral particles that cannot be eliminated leads to ongoing stimulation. The third mutation, linked with blood cancer development, occurs randomly over time. This combination of mutations allows these cells to amass sufficient numbers to incite the autoimmune disease.”

New Avenues for Autoimmune Disease Treatments

“This research opens up fresh avenues for anticipating and preventing autoimmune complications,” asserts Professor Goodnow. “By grasping this structural mechanism, we can potentially create targeted therapies that inhibit these antibody formations from inciting autoimmune reactions.”

“While our focus has been on HCV, the implications of these discoveries extend to other autoimmune complications linked with infections,” states Dr. Young. The findings hold significance for other infection-related autoimmune conditions, such as Guillain-Barré syndrome and multiple sclerosis, which are also associated with various bacterial and viral infections.

“Mutations in B cells are part of their typical development, and understanding how they contribute to autoimmunity represents a major advancement in our goal to tackle the root causes of autoimmune diseases instead of merely alleviating symptoms,” explains Dr. Suan.

This research received support from the Bill and Patricia Ritchie Foundation, Croall Foundation, John Brown Cook Foundation, and Miss Lyn Unsworth.

Chris Goodnow holds The Bill and Patricia Ritchie Foundation Chair at the Garvan Institute and is a Professor at the Cellular Genomics Futures Institute and School of Biomedical Sciences at UNSW Sydney.

Dr. Dan Suan serves as a Senior Research Fellow and Clinical Director of the Hope Research Program at the Garvan Institute.

Dr. Clara Young is a Research Fellow at the Garvan Institute and a Conjoint Lecturer at St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney.