Rheumatoid arthritis, affecting 0.47% of the population in 2019, is an inflammatory condition that affects the joints. They are gradually destroyed, which can lead to a disability. This disease is characterized by “production of auto-antibodies directed against the synovial membrane of the joints”, according health insurance. Clearly, the immune system is deregulated and attacks the body. This autoimmunity is at the root of various disorders, such as Crohn’s disease, type 1 diabetes and celiac disease.
Rheumatoid arthritis: a complex of two proteins promotes the autoimmune response
To combat these conditions, it is essential to determine the mechanisms underlying their pathogenesis. This is why the Japanese team carried out an experiment on mice, namely a kind of bats, suffering from rheumatoid arthritis. As part of a study published in the journal Science Immunology, it repressed the expression of the COMMD3 protein as soon as the animals presented the first symptoms. After this intervention, disease progression stopped, indicating that the complex of two proteins, named COMMD3 and COMMD8, promotes the autoimmune response.
“Deletion of the COMMD3 protein leads to the degradation of COMMD8 and, consequently, the disappearance of the COMMD3/8 complex. (…) The number of cells producing antibodies decreased, suggesting that the COMMD3/8 complex plays a role important in the autoimmune response, confirmed Taiichiro Shirai, senior research author, in a statement.
Celastrol, a powerful protein complex inhibitor
After identifying this protein complex that promotes the progression of rheumatoid arthritis, researchers set out to find a compound that might interfere with the formation of the complex. “Our chemical screening identified celastrol as the most potent inhibitor of the COMMD3/8 complex,” said Kazuhiro Suzuki, co-author of the work. Celastrol is an extract from the root and bark of a plant used in Chinese medicine. The latter is called “Lei gong teng (Tripterygium wilfordii)” and nicknamed “divine thunder vine”. It is known for its anti-inflammatory properties. “However, its mechanism of action has not been fully elucidated,” the authors said.
In their study, the scientists administered a treatment consisting of celastrol to the mice at the onset of the disease. According to the results, celastrol binds to the COMMD3 protein and prevents the formation of the COMMD3/8 complex, thereby impairing the antibody response and blocking the progression of rheumatoid arthritis in bats.
According to the authors, the COMMD3/8 complex is a promising therapeutic target for autoimmune diseases, as it is central to the pathogenesis of rheumatoid arthritis and the progression of autoimmunity in general. As for celastrol, it is “a particularly exciting avenue for the development of treatments for rheumatoid arthritis and other autoimmune diseases in the future”.