Granzyme B cleaves tenascin-C to release its C-terminal domain in rheumatoid arthritis
Bibliographic record
Abstract
Rheumatoid arthritis (RA) is a common autoimmune disorder characterized by exacerbated joint inflammation. Despite the well-documented accumulation of the serine protease granzyme B (GzmB) in RA patient biospecimens, little is understood pertaining to its role in pathobiology. In the present study, tenascin-C (TNC) - a large, pro-inflammatory extracellular matrix glycoprotein - was identified as a substrate for GzmB in RA. GzmB cleaves TNC to generate 3 fragments in vitro: a 130 kDa fragment that remains anchored to the matrix and 2 solubilized fragments of 70 and 30 kDa. Mass spectrometry results suggested that the 30 kDa fragment contained the pro-inflammatory TNC C-terminal fibrinogen-like domain. In the synovial fluids of patients with RA, soluble levels of GzmB and TNC were significantly elevated compared with healthy controls. Further, immunoblotting revealed soluble 70 and 30 kDa TNC fragments in the synovial fluids of patients with RA, matching TNC fragment sizes generated by GzmB cleavage in vitro. Granzyme K (GzmK), another serine protease of the granzyme family, also cleaves TNC in vitro; however, the molecular weights of GzmK-generated TNC fragments did not correspond to TNC fragment sizes detected in patients. Our data support that GzmB, but not GzmK, contributes to RA through the cleavage of TNC.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".