Our immune system is armed with an array of defenses designed to detect and eliminate harmful threats. One of its most powerful defense mechanisms is the complement system—a group of proteins that patrols our body, ever vigilant for signs of infection or injury. Now, over 100 years after the complement system was first described, researchers at Mass General Brigham have discovered that a protein known as granzyme K (GZMK) drives tissue damage and inflammation by activating the complement system against our own tissues. Their findings not only reshape the century-old understanding of the complement system but also open new avenues for therapies that could specifically block this harmful pathway in patients with autoimmune and inflammatory diseases. Results are published in Nature .
"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 lead author Carlos A. Donado, PhD, Instructor in Medicine at Harvard Medical School and a postdoctoral fellow in the Brenner lab in the Division of Rheumatology, Inflammation, and Immunity at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system. "Our work highlights GZMK as a promising therapeutic target to inhibit complement activation across multiple diseases. Unlike traditional therapies that broadly inhibit complement activation, hitting this target could preserve the anti-microbial functions of complement, while specifically inhibiting this harmful pathway in chronically inflamed tissues."
The work, carried out in the laboratory of Michael Brenner, MD the E.F. Brigham Professor of Medicine at Harvard Medical School, was driven by a compelling observation the Brenner group had made earlier: the majority of CD8+ T cells in the inflamed synovium of rheumatoid arthritis patients—and in affected organs across various inflammatory diseases—produce GZMK, a protein that had an unclear function. Intriguingly, other research groups have also found this same population of cells to be highly enriched in the diseased 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—might play a fundamental role in driving inflammatory tissue damage.
To explore this, they analyzed the protein sequence of GZMK and compared it to other human proteins to find clues about its function. Through a series of experiments, they demonstrated that GZMK activated the entire complement cascade, producing complexities that drive inflammation, recruit immune cells, and cause tissue damage.
Their research further revealed that in human rheumatoid arthritis synovium, GZMK is enriched in regions exhibiting abundant complement activation. In two independent animal models of rheumatoid arthritis and psoriasiform dermatitis, mice with a genetic deficiency in GZMK were significantly protected from disease—exhibiting reduced arthritis, dermatitis, and complement activation—compared to mice with normal GZMK expression. "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, MD PhD.
"Our findings provide new insights into how chronic inflammation might be triggered and sustained in autoimmune and inflammatory diseases," said senior author Michael B. Brenner, MD. "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."
Authorship: In addition to Donado, Theisen and Brenner, Mass General Brigham authors include Aparna Nathan, Karishma Vijay Rupani, Dominique Jones, Madison L. Fairfield, Soumya Raychaudhuri, and co-senior author A. Helena Jonsson. Additional authors include Fan Zhang, Kellsey P. Johannes, Accelerating Medicines Partnership RA/SLE Network, and Daniel F. Dwyer.
Disclosures: Brenner is a consultant to GSK, Moderna, AbbVie, Third Rock Ventures, 4FO Ventures and consultant to and founder of Mestag Therapeutics. Raychaudhuri is a founder of Mestag Therapeutics, a scientific advisor for Janssen and Pfizer, and a consultant to Gilead and Rheos Medicine. Dwyeris a consultant to Celldex Therapeutics.
Funding: This work was supported by US NIH (R01 AR073290, R01 AR081792, 5T32AR007098-48), Rheumatology Research Foundation grant (889234), NIAMS (K08 AR081412), Rheumatology Research Foundation Investigator Award, and the Dermatology Foundation Career Development Award.
This work was supported by the Accelerating Medicines Partnership® Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP® RA/SLE) Network (AMP) in Rheumatoid Arthritis and Lupus Network. AMP is a public-private partnership (AbbVie Inc., Arthritis Foundation, Bristol-Myers Squibb Company, Foundation for the National Institutes of Health, GlaxoSmithKline, Janssen Research and Development, LLC, Lupus Foundation of America, Lupus Research Alliance, Merck & Co., Inc. Sharp & Dohme Corp., National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Pfizer Inc., Rheumatology Research Foundation, Sanofi and Takeda Pharmaceuticals International, Inc.) created to develop new ways of identifying and validating promising biological targets for diagnostics and drug development Funding was provided through grants from the National 1241 Institutes of Health (UH2-AR067676, UH2-AR067677, UH2-AR067679, UH2-AR067681, UH2-1242 AR067685, UH2- AR067688, UH2-AR067689, UH2-AR067690, UH2-AR067691, UH2-1243 AR067694, and UM2- AR067678).
Paper cited: Donado CA et al. " Granzyme K activates the entire complement pathway " Nature DOI: 10.1038/s41586-025-08713-9
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