‘Important discovery’ shows how complement cascade drives systemic inflammation
A protein known as granzyme K was recently shown to be a driver of inflammation by activating the complement system in human tissue, a discovery that could reshape the treatment of many rheumatic and autoimmune diseases.
“We are still learning a lot about what drives inflammation in autoimmune and rheumatic disease,” Michael B. Brenner, MD, Elizabeth Fay Brigham professor of medicine at Harvard Medical School, and director of the Human Immunology Center at Brigham and Women's Hospital, told Healio. “This is a very novel and potentially important discovery.
“We think we have so many therapeutic options already, but more targets are being discovered every day,” he added. “For this discovery, it is important to consider that if you block granzyme K, it could have widespread use across many diseases. One important part of this discovery is that blocking granzyme K specifically would leave intact other complement pathways that are necessary to fight infection. This could be an approach where the therapeutic balance could have a favorable side effect tolerability.”
In a paper published in Nature, Brenner and colleagues noted that previous research demonstrated that the majority of CD8+ T cells in the synovium of patients with rheumatoid arthritis express the protein granzyme K. An abundance of granzyme K CD8+ T cells was also observed in inflamed organs in inflammatory bowel disease, lupus nephritis and other diseases.
In the current study, the researchers observed that granzyme K cleaves C2 and C4. Moreover, fragments of C4b and C2b form a C3 convertase that cleaves C3, enabling assembly of a C5 convertase that cleaves C5.
In short, this protein activates the full complement cascade.
Looking specifically at RA synovium, the researchers observed that granzyme K is enriched in regions where the complement cascade is activated. Moreover, fibroblasts produce complement proteins that serve as substrates for complement activation that is mediated by granzyme K. They found that knocking out granzyme K resulted in abrogation of both arthritis and psoriasiform dermatitis in mouse models.
From these findings, the researchers concluded that granzyme K-mediated complement activation may contribute to inflammatory processes in RA and other diseases under the rheumatology umbrella.
Healio sat down with Brenner to discuss the earlier work that fueled their research, the role of the complement cascade in RA and how these findings might lead to therapeutic interventions.
Healio: Could you give some background on why you looked at the complement system in the first place?
Brenner: Complement is an ancient system driving inflammation and host defense in humans. Importantly, there are three different ways complement can get activated.
In the classical pathway it is activated by antibodies, so it is an antigen driven pathway. In the lectin pathway, carbohydrate epitopes on microbes are recognized. The third is the alternative pathway, which is an amplifier of those two pathways.
When complement gets activated, it releases anaphylatoxins C3a and C5a that are potent chemotactic agents. They recruit leukocytes into lesions and also activate cells that express C3a and C5a receptors. The later components of complement activation can result in the membrane attack complex that can lyse target cells.
Healio: Your findings show that when granzyme K acts on the complement system, it not only drives inflammation, but also recruits immune cells and causes tissue damage. How does that occur?
Brenner: All of these complement activities are designed to control microbes in host defense, but in autoimmune diseases activated complement can drive inflammation and tissue injury in the absence of infection.
It has been assumed that whenever you have autoantibodies, such as in lupus, RA, the vasculitides and other autoimmune diseases, that the antibodies drive the classical pathway. But now that we know another pathway exists, it is possible that granzyme K may be driving a lot of the complement activation.
Healio: Why did you choose RA and psoriasis, and not other diseases, to conduct your modeling?
Brenner: We first discovered granzyme K in RA. We were doing what we call disease reconstruction. We conducted single-cell RNA sequencing in the peripheral end organs in RA and lupus. The intention was to ignore what was known already and to go in with no preconceptions.
Of course, we found a lot of T cells, and we expected to find a lot of CD4 T cells. But what we discovered was that there were almost as many CD8 T cells as there were CD4 T cells in the synovium of RA. We wondered what they were doing there. Normally, you expect to find CD8 T cells that are cytotoxic T cells, the ones that express granzyme B and kill virally infected and cancer cells. But only about 10% to 15% were typical cytotoxic T cells. The rest expressed granzyme K.
The function of these cells was not known.
Healio: Could you talk about how granzyme K activates the complement system?
Brenner: There are three pathways of complement activation. Each of those three pathways has a unique enzyme that initiates the complement cascade. We found that granzyme K works differently from other proteases. It is independent because it comes from CD8 T cells in the tissue and it is a distinct protease. Because it generates both C3 and C5 convertases, it is capable of activating the entire cascade.
Since granzyme K CD8 T cells are present in large numbers in many other rheumatic and autoimmune diseases, it is possible that blocking it could be effective against many other diseases.
Healio: Do these findings need to be validated by other studies or models? Do you plan on taking those next steps in research, or will you leave it up to other groups?
Brenner: In a way, our competition has already confirmed it for us. Since our research went public, another paper was published in Nature that showed the granzyme K cleaving complement in nasal polyps. So, that validated and confirmed our findings.
Healio: If these findings are validated, how do you go about acting on them? Will medications be necessary to act on granzyme K, or the complement system, or both? Or some other approach?
Brenner: We already know that you can make antibodies and small molecules that will block the activity of other proteases, so we assume this can also be accomplished to block granzyme K.
There has already been significant interest from pharma and biotech, so it is likely that we will see future progress in developing therapeutics to target granzyme K in RA and likely other autoimmune and rheumatic diseases.
References:
Donado CA, et al. Nature. 2025;doi:10.1038/s41586-025-08713-9.
For more information:
Michael B. Brenner, MD, can be reached at rheumatology@healio.com.
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