Abstract 57: Costimulation Mediated T-cell Survival Excerbates Kawasaki Disease
Bibliographic record
Abstract
Introduction: Kawasaki Disease (KD) is a multi-system vasculitis leading to coronary artery damage. Previous work has shown that co-stimulatory signals can rescue a subset of superantigen (SAg) reactive T-cells from apoptosis and one of the major pathways responsible for delivery of this co-stimulatory signal is CD28 signaling on T-cells. Lactobacillus casei cell wall extract (LCWE) contains a SAg among its active ingredients, leading to induction of coronary arteritis in mice that closely resembles human KD. Methods: Flow cytometry was used to measure the expression of pro-survival molecules and markers of apoptosis. In vivo studies were performed with C57BL/6 mice (4-5 weeks) injected i.p. with either LCWE, or LCWE and anti-4-1BB or Isotype control antibody. Cardiac tissue isolated, processed, stained and scored as per protocol. Gene expression analysis in KD patients was performed using the Illumina HumanHT-12v4. Results: Despite the fact that SAg-activated T-cells undergo apoptosis and are deleted, T-cells persist and are central to ongoing inflammation in affected arteries. Stimulation of CD28 leads to upregulation of pro-survival molecules cFLIP and BCLxL and reduction of caspase 3-annexinV double positive cells (markers of apoptosis) after SAg-stimulation, as detected by flow cytometry. In animals co-injected with anti-4-1BB (co-stimulation agonist), the incidence of coronary arteritis was dramatically increased to 94% compared to 54% with LCWE alone. Analysis of gene expression profile from 171 children with KD show elevated levels of molecules specific to the CD28 signaling cascade through Grb2, and VAV1 leading to the upregulation of Rac1 and CDC42, together with upregulation of pro-survival molecules cFLIP, MCL1 and NAIP. Interestingly, increased expression of cell survival molecules was associated with IVIG failure, with statistically significant elevation of NAIP and CDC42 and a trend towards increased expression for cFLIP and MCL, in IVIG non-responders compared to responders. Conclusions: Enhanced co-stimulation contributes to T-cell survival after SAg-stimulation leading to persistent coronary artery inflammation and poor treatment response in KD.
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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 | 0.000 | 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) | 0.011 | 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; 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".