Phenotypic characterization of mice carrying a <i>PTPN22</i> single nucleotide polymorphism associated with autoimmunity in humans (47.13)
Bibliographic record
Abstract
Abstract Type 1 diabetes (T1D) is a strongly heritable autoimmune disease due to the destruction of pancreatic β-cells by self-reactive T-cells. The third strongest genetic locus for T1D involves a single-nucleotide polymorphism (SNP) causing an arginine(R) to triptophan(W) substitution at codon 620 (620R>W) in PTPN22, the gene encoding the tyrosine phosphatase LYP, an important negative regulator of T-cell receptor (TCR) activation. However, the cellular effects of the 620R>W risk allele remain controversial, as different studies report either a gain or a loss of function in its ability to inhibit TCR signaling. To study this variant in an animal model, we created a knock-in mouse by introducing the 620R>W substitution in, the murine LYP orthologue, PEP encoded by Ptpn22. The knock-in analyzed on the autoimmune-resistant C57Bl/6 background showed a mild but significant increase in CD4+ helper T-cell activation and proliferation upon weak TCR activation. Conversely, upon strong TCR stimulation, the tendency seemed to be reversed as the 620W allele showed a slightly decreased responsiveness compared to the 620R allele. Phenotypic analysis of other immune cellular compartments, including memory T cells, showed no significant difference between genotypes. There was no evidence of autoimmunity in this genetic background. This dependence of allelic effect on the strength of the TCR signal may reconcile previous observations and indicate a complex role of R620>W in autoimmunity.
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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 | 0.001 |
| 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) | 0.006 | 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".