Researchers have identified a new mechanism that could contribute to tissue damage and a novel target for drug development.
Our immune system is equipped with numerous defenses aimed at identifying and removing harmful threats. One of its strongest methods of defense is the complement system, which consists of proteins that continuously monitor our bodies for signs of infection or injury. Now, over a century after the complement system was first introduced, scientists at Mass General Brigham have found that a protein called granzyme K (GZMK) triggers tissue damage and inflammation by activating the complement system against our own body tissues. This discovery not only updates our understanding of the complement system but also paves the way for new therapies that could potentially block this damaging process in patients suffering from autoimmune and inflammatory diseases. The results were published in Nature.
“Our discovery of a novel method for activating the complement system, led by an enzyme produced by cells that are prevalent in inflamed tissues, has significant clinical implications,” stated lead author Carlos A. Donado, PhD, an Instructor in Medicine at Harvard Medical School and a postdoctoral fellow at the Brenner lab in the Division of Rheumatology, Inflammation, and Immunity at Brigham and Women’s Hospital, which is part of the Mass General Brigham healthcare system. “Our research points to GZMK as a promising target for therapies that could inhibit complement activation across various diseases. Unlike conventional treatments that indiscriminately inhibit complement activation, targeting this specific pathway could maintain the anti-microbial properties of complement while selectively blocking the harmful activation in chronically inflamed tissues.”
The study, conducted in the lab of Michael Brenner, MD, the E.F. Brigham Professor of Medicine at Harvard Medical School, was inspired by an important observation the Brenner group made: most CD8+ T cells found in the inflamed synovium of rheumatoid arthritis patients—and in affected organs across different inflammatory diseases—produce GZMK, a protein whose function was previously unclear. Interestingly, other research teams have also noted that this same type of cell is highly abundant in diseased tissues of patients with neurodegenerative and cardiovascular diseases, as well as cancer and even among older individuals. Given their widespread presence in inflamed tissues, the researchers suspected that these cells—and GZMK—might have a critical role in promoting inflammatory tissue damage.
To investigate further, they examined the protein sequence of GZMK and compared it with other human proteins to uncover its function. Through a series of experiments, they confirmed that GZMK activates the entire complement cascade, leading to processes that fuel inflammation, attract immune cells, and induce tissue damage.
Their findings also showed that in human rheumatoid arthritis synovium, GZMK is concentrated in areas with significant complement activation. In two separate animal models of rheumatoid arthritis and psoriasiform dermatitis, mice lacking GZMK were notably shielded from disease—showing less arthritis, dermatitis, and complement activation—compared to those with normal GZMK levels. “These results emphasize the crucial role of GZMK-driven complement activation in disease progression and highlight the extensive potential for targeting this pathway across a range of diseases,” noted co-lead author Erin Theisen, MD PhD.
“Our discoveries offer new perspectives on how chronic inflammation may be initiated and maintained in autoimmune and inflammatory diseases,” commented senior author Michael B. Brenner, MD. “In the future, we will continue to examine the effects of this pathway across different diseases and are actively working on developing GZMK inhibitors, hoping to provide new, targeted treatments for patients experiencing autoimmune and inflammatory disorders.”
