The human immune system has a formidable arsenal of defenses to detect and eliminate threats. One of its most powerful guardians is the complement immune system - a dynamic network of proteins that tirelessly patrols our body, looking ever vigilantly for signs of infection or injury. In the presence of danger, these proteins spring into action, unleashing a cascade of inflammatory signals that mobilizes the body's defenses to neutralize the threats.
- By HALEY BRIDGER | Mass General Brigham
Now, more than 100 years after the complement system was first described, Harvard Medical School researchers at Brigham and Women's Hospital have discovered a novel mechanism by which this critical defense system can misfire and turn against the body's own tissues - a protein called granzyme K (GZMK), whose role up until now had remained unclear.
The findings, published Feb. 6 in Nature and enabled in part by federal funding, show that GZMK drives tissue damage and inflammation by activating the complement system against the body's own tissues - in stark contrast with this system's well-established role in host defense.
The team also found that GZMK is produced by a special group of immune cells abundant in the inflamed tissues of patients with a wide range of inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and lupus.
The research, which was conducted in mice and human tissue samples, augments the current understanding of this part of immunity, opening new avenues for targeted therapies that could specifically block this harmful pathway in patients with inflammatory diseases.
"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 study lead author Carlos Donado, HMS instructor in medicine and a postdoctoral fellow in the Brenner lab in the Division of Rheumatology, Inflammation, and Immunity at Brigham and Women's. "Our work highlights GZMK as a promising therapeutic target to inhibit complement activation across multiple diseases."
