Granzyme K’s Role in Complement System Activation

Researchers at Mass General Brigham have made a significant discovery about the complement system, a crucial component of our immune defense. They found that a protein called granzyme K (GZMK) activates the complement system against our own tissues, leading to tissue damage and inflammation. This finding, published in Nature, challenges the century-old understanding of the complement system and offers potential new therapeutic approaches for autoimmune and inflammatory diseases.

The research team, led by Carlos A. Donado and Michael Brenner, focused on GZMK after observing its abundance in inflamed tissues across various diseases. Through a series of experiments, they demonstrated that GZMK activates the entire complement cascade, driving inflammation and tissue damage.

In human rheumatoid arthritis synovium, GZMK was found to be enriched in areas with high complement activation. Animal studies showed that mice lacking GZMK were significantly protected from rheumatoid arthritis and psoriasiform dermatitis, exhibiting reduced disease symptoms and complement activation.

"Our discovery of a new way of activating the complement system, driven by an enzyme produced by cells that are abundant in inflamed tissues, has important clinical implications," said Donado. He emphasized that targeting GZMK could potentially inhibit complement activation across multiple diseases while preserving the system's anti-microbial functions.

The research team is now investigating the impact of this pathway across various diseases and working on developing GZMK inhibitors. Brenner stated, "Our findings provide new insights into how chronic inflammation might be triggered and sustained in autoimmune and inflammatory diseases."