CD154–CD40 interactions drive hepatocyte apoptosis in murine fulminant hepatitis†
Bibliographic record
Abstract
The CD154-CD40 interaction is a critical costimulatory pathway modulating the cellular immune response. Moreover, fulminant hepatitis of various etiologies is characterized by a hepatic influx of CD154-expressing T cells and an upregulation of CD40 expression on Kupffer cells and hepatocytes, implicating this pathway in the pathogenesis of fulminant hepatitis. In this study, we used a murine model of fulminant hepatitis induced by concanavalin A (con A) and documented a significant influx of CD154-expressing T cells into the livers of mice treated with con A, in association with markedly increased expression of CD40 restricted mainly to hepatocytes in damaged areas of the liver. Furthermore, con A hepatitis in CD154-deficient mice was significantly attenuated compared with that in wild-type controls and was associated with a decrease in hepatic tumor necrosis factor alpha (TNF-alpha) levels and hepatocyte death. We next determined the role of the CD154-CD40 pathway in hepatocyte death in vitro. These in vitro studies demonstrated that TNF-alpha induces CD40 expression in hepatocytes and that subsequent activation of CD40 results in hepatocyte apoptosis mediated at least in part by enhanced hepatocyte expression of FasL. In conclusion, CD154 stimulation of CD40 plays a central role in hepatocyte death in fulminant hepatitis through direct and indirect pathways that may have direct therapeutic implications in humans. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
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".