Abstract O.27: The Role Of CD40L And CD40 In The Pathogenesis Of Kawasaki Disease
Bibliographic record
Abstract
Kawasaki Disease (KD) is characterized by acute, systemic inflammation followed by a persistent immune response localized to the coronary arteries. Lactobacillus Casei Cell Wall Extract (LCWE) contains among its active ingredients a superantigen (SAg) that induces coronary arteritis in mice. LCWE induces massive immune activation followed by apoptosis or anergy. Previous work has shown that co-stimulatory signals can rescue a subset of SAg-reactive T-cells from apoptosis. CD40-CD40L (ligand) are members of the TNF superfamily which play a role in T-cell co-stimulation. Moreover, genome wide association studies have implicated CD40/CD40L as candidate genes in the pathogenesis of KD. We hypothesize that co-stimulation via the CD40 pathway regulates survival of SAg-reactive T-cells during disease development. Using thymidine proliferation assay and flow cytometry we show that activation of CD40 signaling via agonistic anti-CD40 antibody or recombinant soluble CD40L (rsCD40L) upregulates CD86 (ligand responsible for CD28 signaling) expression, reduces active-caspase-3 expression, indicating decreased cell death and promotes lymphocyte proliferation, Additionally, using CD28 deficient mice we show that lymphocytes do not proliferate in response to SAg plus CD40 stimulation indicating that CD28 is the intermediary that mediates the proliferative effects of CD40 activation. Furthermore, platelets, which are markedly elevated in KD, produce approximately 90% of the soluble CD40L in the circulation. We show that activated platelets (CD62P+) express CD40L and promotes cell survival as evidenced by enhanced lymphocyte proliferation. Likewise, the absence of CD40L negates the proliferative effects of platelet mediated proliferation. Lastly, to determine the role of CD40 stimulation on in vivo development of KD, LCWE was injected into B6 and CD40L deficient mice. We show that inflammation in the coronary arteries does not develop in the absence of CD40L. Therefore, CD40L plays a critical role in immune activation via upregulation of CD86 on antigen presenting cells leading to enhanced co-stimulation and T-cell survival.
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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) | 0.008 | 0.004 |
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".