OP02 The role of PTPN2 SNP in the pathogenesis of fibrosis in Crohn’s disease
Bibliographic record
Abstract
We identified altered IL-6-induced Jak1-dependent STAT3 phosphorylation in human ileal subepithelial myofibroblasts (SEMF) of patients with stricturing Crohn’s disease. This resulted in co-localisation of pSTAT3(Y705) to Rab5+ signalling endosomes along with pIGF-I receptors that jointly mediated excess collagen I production and proliferation in SEMF of strictures. PTPN2 gene variants occur in patients with Crohn’s disease with rs7234029 associated with apparent ‘loss-of-function’ and with stricturing disease. In other cells, PTPN2 targets Jak and STAT3. However, whether expression of rs7234029 in fibrostenotic Crohn’s disease is associated with altered phosphatase activity, increased STAT3 phosphorylation, and excess extracellular matrix deposition has not been studied yet. Primary cultures of SEMF isolated from ileum of patients with Montreal B2 Crohn’s disease were naïve, transfected with wtPTPN2, or were used for CRISPR/Cas9-mediated PTPN2 gene deletion. Rs7234029 haplotype was determined in each subject by genotyping assay. Increased basal pSTAT3, pErk1/2, collagen I production and proliferation in SEMF of strictured ileum were normalised by inhibition of STAT3 phosphorylation or expression of dominant negative STAT3 (Y705F). Despite a 3-fold increase in PTPN2 protein in strictured SEMF in these cells, levels of STAT3 phosphorylation were also increased suggesting a loss-of-phosphatase function had occurred. Phosphatase function was restored by expression of wtPTPN2 and resulted in lowered levels of pSTAT3 (Y705). This notion regarding PTPN2 was also confirmed in normal SEMF where CRISP/Cas9 mediated PTPN2 gene deletion resulted in a 4-fold increase in pSTAT3 (Y705) levels. The haplotype rs7234029 was significantly detected in Montreal B2 Crohn’s disease compared with other phenotypes. A loss of PTPN2 function associated with rs7234029 in SEMF of patients with fibrostenotic Crohn’s disease leads to increased phosphorylation of pSTAT3 (Y705), and results in the excess collagen I production and proliferation that occur in these patients’ strictures.
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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) | 0.000 | 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 0.000 |
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".