Protein triggers juvenile arthritis
Arthritis is often associated with older people, but it can also affect children. Juvenile idiopathic arthritis (JIA), the most common pediatric rheumatological condition, is an antigen-driven autoimmune disease. However, its autoantigens are still unknown.
A study led by researchers at the Albert Einstein College of Medicine and the Children’s Hospital at Montefiore (CHAM) has identified a human protein called transthyretin (TTR) that is reponsible for autoimmune reaction in the joints of Juvenile idiopathic arthritis patients.
According to Laura Santambrogio, M.D., Ph.D., professor of pathology, of microbiology & immunology, and of orthopaedic surgery at Einstein, study leader, "Our findings regarding TTR's involvement in JIA point to a potential treatment - encouraging news for children with this debilitating disease". She said that tafamidis, a drug, might be beneficial for these patients as it targets transthyretin (TTR). Tafamidis was approved in Europe and Japan for treating hereditary amyloidosis, which is also related to TTR. The drug is now undergoing phase III clinical trials in the U.S.
Chronic joint pain, swelling and stiffness are the symptoms which may persist for a few months or a lifetime. However, biologic response modifiers and nonsteroidal anti-inflammatory drugs (NSAIDs) are used to control symptoms of this disorder and helps to prevent complications. Dr. Santambrogio and his research team looked for accumulation of abnormal proteins in the synovial fluid and blood samples of JIA. Researchers at the Children´s Hospital at Montefiore saw a significant increase in 50 patients in TTR and 26 control children had no TTR build-up without JIA. But, some JIA patients also had unusually high levels of antibodies to the TTR protein. To confirm research findings, they further analyzed other 43 patients JIA and statistically significant increase in TTR autoantibodies was observed.
TTR is a molecular chaperone that carries several molecules, including thyroxine and vitamin A, in the blood and cerebrospinal fluid. They found that when proteins accumulate in the jonts, JIA begins. Dr. Santambrogio said, "The TTR protein has a tendency to misfold and then aggregate, which for some reason seems to occur in children with JIA." "And when proteins aggregate, they tend to become more immunogenic."
With the aid of mass spectrometry experiments and other biophysical techniques, they noticed misfolded and aggregated TTR in the synovial fluid in patients of JIA. These proteins was heavily oxidized and brings even further increase to its immunogenicity. Futhermore, abnormal TTR was given to mice and found higher immunogenic response as compared to normal TTR.