Abstract 156: Deletion of the Lymphocyte Adaptor Protein LNK Promotes Aortic Dissection
Bibliographic record
Abstract
Background: The immune response plays a key role in the development of aortic dissection. In particular, interferon gamma (IFNγ), produced by the T cell subsets, Th1 (CD4 + ) and Tc1 (CD8 + ), is elevated in human aortic dissection samples. Interestingly, a polymorphism in the gene SH2B3 that encodes LNK has been associated with several cardiovascular diseases in humans. LNK is an intracellular adaptor protein that has been shown to negatively regulate T cell activation and cytokine signaling. We hypothesized that LNK deficiency promotes aortic dissection through enhanced Th1/Tc1 responses. Methods: Angiotensin II (Ang II; 1000 ng/kg/min) was infused for 14 days into LNK -/- or WT mice in the absence or presence of an initial intraperitoneal injection of saline equal to 10% of their body weight. Kaplan-Meier survival curves were generated and flow cytometry, RT-PCR, histology were used to assess aortic inflammation and remodeling. Naïve CD4 + T cells from WT and LNK -/- mice were polarized ex vivo with Th1 polarizing cytokines and expression of IFNγ and T-bet were evaluated. Results: LNK -/- mice infused with Ang II exhibited an accelerated rate of aortic dissection or rupture compared to WT mice and this was exacerbated by saline injection prior to Ang II infusion (Figure). LNK -/- mice treated with salt plus Ang II exhibited increased aortic inflammation compared to WT mice. Aortic expression of IFNγ, T-bet and MMP9 were increased, while the expression of the procollagens type I and III were reduced in LNK -/- mice compared to WT mice. Ex vivo, naïve CD4 + T cells from LNK -/- mice expressed more T-bet and IFNγ compared to corresponding naïve T cells from WT mice when cultured under Th1 polarizing conditions. Conclusion: Loss of LNK enhances the Th1/Tc1 responses and promotes adverse aortic remodeling leading to development of aortic dissection and rupture. Targeting LNK and the Th1/Tc1 cell subsets could be a potential therapeutic strategy for the management of aortic dissection.
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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) | 0.005 | 0.002 |
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".