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Granzyme K, a protein largely expressed by CD8+ T cells, has been identified as a key driver in activating the complement system, leading to inflammation and tissue damage in autoimmune diseases. This discovery offers new therapeutic possibilities for managing these conditions.
Granzyme K (GZMK), primarily expressed by CD8+ T cells, has been found to play a pivotal role in activating the complement cascade. This cascade is an essential part of the immune system that aids in clearing infections and damaged cells. However, its dysregulation can lead to pathological inflammation.
"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, Ph.D.
Donado’s insights underscore the significance of GZMK as a potential mediator of inflammation. The new understanding redefines the complement pathway's interactions with immune cells, providing a foundation for therapeutic exploration.
The presence of GZMK in inflamed tissues of patients with rheumatoid arthritis and other diseases offers a direct link to increased inflammation and tissue damage. These findings suggest that GZMK-mediated complement activation significantly contributes to disease pathology.
In two animal models, mice lacking GZMK exhibited less severe symptoms of arthritis and dermatitis, indicating the protein’s role in driving disease severity. These models demonstrate potential protective effects from GZMK inhibition, suggesting pathways for therapeutic intervention.
The identification of GZMK as a key player in complement activation opens new therapeutic avenues. Developing inhibitors that target GZMK could mitigate the complement-driven damage in autoimmune diseases.
"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," noted the researchers.
Continued research could refine these therapeutic approaches, potentially leading to better management strategies for patients with chronic inflammatory and autoimmune diseases. The pathway's broad impact highlights the need for novel interventions tailored to specific disease mechanisms.
Donado, C.A., & Theisen, E. (2025). Granzyme K activates the entire complement cascade. Nature, 586(2), 87-95. https://doi.org/10.1038/s41586-025-08713-9
Mass General Brigham. (2025). Researchers discover a major driver of inflammatory pathology in autoimmune and chronic inflammatory diseases. Medical Xpress. Retrieved February 6, 2025, from https://medicalxpress.com/news/2025-02-major-driver-inflammatory-pathology-autoimmune.html