Scientists Identify New Driver of Inflammation Implicated in Autoimmune Diseases

Unlike existing therapies that broadly inhibit complement activation, Donado explained, targeting GZMK offers a more precise approach — one that could selectively dampen harmful inflammation in chronically inflamed tissues while preserving the complement system’s essential antimicrobial functions.

The work, carried out in the laboratory of Michael Brenner, the HMS Elizabeth Fay Brigham Professor of Medicine at Brigham and Women’s, was driven by a tantalizing observation made earlier by researchers in the lab: The majority of immune CD8⁺ T cells in the joints of patients with rheumatoid arthritis produced GZMK. Furthermore, these GZMK-secreting immune cells were also elevated in the inflamed tissues of individuals with a wide range of chronic inflammatory diseases.

Intriguingly, other research groups have also found this same population of GZMK-producing immune cells to be highly enriched in the tissues of patients with neurodegenerative and cardiovascular diseases, cancer, and even in aging individuals. Given their widespread abundance in inflamed tissues, the research team suspected that these cells — and GZMK — may be key drivers of tissue-damaging inflammation.

To define the function of GZMK, the researchers analyzed its structure and found a striking similarity to known complement-activating proteins. Through a series of experiments, the team demonstrated that GZMK activates the entire complement cascade, producing molecules that drive inflammation, recruit immune cells, and cause tissue damage. Their research further revealed that in the joints of patients with rheumatoid arthritis, GZMK was abundant in areas where the complement system is very active.

Next, the researchers studied two groups of mice — one of them with rheumatoid arthritis and one with psoriasiform dermatitis, an inflammatory skin condition — that were also deficient in GZMK. Both groups had far milder forms of these diseases. The animals exhibited fewer and milder symptoms of arthritis and of dermatitis, and less complement activation, compared with mice with intact GZMK.

“These findings underscore the pivotal role of GZMK-mediated complement activation in driving disease and highlight the broad translational potential of targeting this pathway across multiple disease states,” said co-lead author Erin Theisen, HMS instructor in dermatology and a postdoctoral fellow at Brigham and Women’s.

The findings provide new insights into how chronic inflammation may be triggered and sustained in autoimmune and inflammatory diseases, said Brenner, senior author on the study and director of the Human Immunology Center at Brigham and Women’s.

“Moving forward, we will continue to investigate the impact of this pathway across various diseases and are actively working on developing inhibitors to target GZMK, with the hope of offering new, targeted treatments for patients suffering from autoimmune and inflammatory conditions.”

Adapted from a Mass General Brigham news release.