A team from Scripps Research has found a molecular cause of a group of rare autoimmune disorders. The discovery was published yesterday in Nature Communications.
The National Institutes of Health estimates that more than 20 million Americans suffer from autoimmune disorders. They include rheumatoid arthritis, psoriasis, inflammatory bowel disease, multiple sclerosis, lupus, type 1 diabetes, and many more. There are very few safe and effective treatments for such disorders, largely because so little is understood about how they arise and persist.
The same is true for a rare autoimmune disease called Singleton-Merton syndrome (SMS). Patients with SMS develop serious bone, heart, muscle, and skin problems starting in early childhood, largely due to chronic inflammation from an overactive immune system. The scientists’ aim was to understand how two mutations in a gene called RIG-I that are linked to SMS end up triggering the autoimmunity.
Most viruses have genes made of RNA, a close chemical cousin of DNA. RIG-I works as an early-warning detector of viral RNA that is capable of triggering a broad antiviral immune response. The scientists showed that mutations in RIG-I cause the sensor protein to activate even when it encounters non-viral “self” RNA.
RIG-I is a big protein with flexible elements and is thus hard to study with standard techniques. But Griffin has helped pioneer the use of an advanced technology called hydrogen–deuterium exchange mass spectrometry (HDX-MS), which enables scientists to analyze the structures and dynamics of just such proteins. He and his team applied HDX-MS to normal and mutant RIG-I to determine how these mutations contribute to autoimmunity.
RIG-I has a particular segment that it keeps mostly covered. When RIG-I encounters and recognizes viral RNA, this segment is supposed to briefly swing open so it can bind to another protein called MAVS, an event that triggers the immune response. Using HDX-MS, Griffin and colleagues found that both SMS-linked mutations cause this key segment of RIG-I to become stuck open, making it easier to trigger an immune response.
The scientists are now using their data to try to find a way to target mutant RIG-I, block its inappropriate signaling, and thus alleviate the autoimmunity it causes.