It is well known that a strong immune system is a definite advantage in combating various diseases. However, sometimes the immune system can fail and attack our own body. This autoimmunity is the cause of several disorders, including rheumatoid arthritis, Crohn’s disease, type 1 diabetes, and celiac disease. To combat these pathologies, it is crucial to determine the mechanisms underlying their pathogenesis.
In a study published in Science Immunology, Osaka University researchers address this knowledge gap by identifying a protein complex that promotes the progression of rheumatoid arthritis. This complex comprises two proteins, designated COMMD3 and COMMD8. The research team also found that celastrol, an extract from the root of a medicinal plant colloquially called “Thunder God Vine,” is a potent inhibitor of the COMMD3/8 complex.
“We had previously shown that the COMMD3/8 complex potentiates humoral immune responses, but its role in autoimmune diseases remained unclear,” says lead author Kazuhiro Suzuki. The team generated a mouse model in which the expression of COMMD3 can be turned off.
“The deletion of COMMD3 results in the degradation of COMMD8 and consequently the disappearance of the COMMD3/8 complex,” explains Taiichiro Shirai, lead author of the study. The absence of the COMMD3/8 complex led to an altered humoral immune response. “The number of cells that produce antibodies decreased, suggesting that the COMMD3/8 complex has an important role in the autoimmune response,” says Shirai.
Celastrol, a clue for new treatments against arthritis
The researchers then used a mouse model of rheumatoid arthritis. They suppressed COMMD3 expression as soon as the mice showed the first symptoms of arthritis. By doing so, the progression of the disease was halted, indicating that the COMMD3/8 complex promotes the autoimmune response.
“Having established the importance of the complex in autoimmunity, we set out to identify a compound that could interfere with complex formation,” explains Kazuhiro Suzuki. “Our chemical analysis identified celastrol as the most potent inhibitor of the COMMD3/8 complex.”
Celastrol is an active compound from Tripterygium wilfordii, a medicinal herb known to have anti-inflammatory properties, although its mechanism of action has not yet been fully explained. The study showed that celastrol binds to COMMD3 covalently and prevents the formation of the COMMD3/8 complex, thereby affecting the antibody response and blocking the progression of rheumatoid arthritis in the mouse model.
Given that the COMMD3/8 complex is central to the pathogenesis of rheumatoid arthritis and the progression of autoimmunity in general, it is a promising therapeutic target for autoimmune diseases, and celastrol is a particularly exciting lead for developing anti-arthritis treatments. rheumatoid and other autoimmune diseases in the future.
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