Genetic mutation offers hope for better rheumatoid arthritis treatments

Research led by York University's Faculty of Health reveals how a specific mutation in a protein called TRAF1 can shut down an overactive immune response, dramatically reducing inflammation in mice. Lead researcher Ali Abdul-Sater says this discovery could pave the way for a new class of drugs to treat rheumatoid arthritis.

Rheumatoid arthritis is a common health condition which can interfere with many aspects of daily life and based on the limited efficacy of current treatments, novel approaches are needed. In this study, we have made a discovery that may pave the way for more effective treatments for rheumatoid arthritis and other inflammatory diseases."

Abdul-Sater, Faculty of Health Associate Professor, York Research Chair with the School of Kinesiology and Health Science

The study is now available online and will be published in the March issue of Journal of Autoimmunity.

Using gene-editing technology, the researchers identified a critical mutation of a protein called TRAF1 and discovered that this mutation dramatically reduces inflammation by disrupting a critical molecular interaction that fuels the immune system into kicking into overdrive.

"TRAF1 plays a central role in immune signaling and is known for its dual roles: it helps amplify inflammatory signaling in some contexts while also acting as a brake to limit overactive responses," says Abdul-Sater. "These opposing roles have made TRAF1 a challenging target for therapeutic intervention – until now."

A single mutation at position valine 196 (V196), the researchers found, selectively blocks TRAF1's interaction with another protein, which dampens a major inflammatory pathway triggered by receptors which are responsible for sensing infection and tissue damage.

"The mutation effectively shuts down a cascade of molecular events that drive excessive inflammation," says Abdul-Sater.

 Rheumatoid arthritis affects one per cent of the population worldwide. In the autoimmune disease, the body starts attacking its own cells, making the joints stiff, swollen and painful. Over time, this can damage joints, cartilage and bone, making everyday tasks difficult.

Typical treatments involve broad immunosuppressants, like steroids, or biologics that inhibit specific cytokines, but these can lose effectiveness over time and can put individuals at greater risk for cancer, infections and other risks, says Abdul-Sater, which is why this discovery is so exciting.

"Such therapies could not only alleviate symptoms but also address the underlying mechanisms of inflammation, benefiting patients who do not respond to existing options."