Autophagy gene polymorphisms influence the interaction of <i>E coli</i> and macrophages in Crohn's disease
Bibliographic record
Abstract
Introduction A well established expression of the proposed defect in innate immunity in Crohn's disease (CD) is the prolonged survival of strains of Escherichia coli in peripheral blood monocytes/macrophages (PBM) from patients with CD compared to those from healthy controls (HC). Altered handling of E coli in CD has been demonstrated in PBM and in-situ in CD by laser dissection of E coli infected macrophages. Several of the gene polymorphisms conferring an increased risk of CD occur in genes involved in bacteria-immune cell interactions. The aim of this study was to determine the influence of these polymorphisms on the interaction of E coli with CD-derived monocyte / macrophages. Methods PBM's and lamina propria macrophages were obtained from 43 and 17 CD patients respectively (mean age 39 years / range 20–70 years). PBM's were challenged with E coli and then the response of these PBM's measured by levels of bacterial killing, using the gentamicin protection assay. Phagocytosis and reactive oxygen radicals (ROR's) production were measured by flow cytometry using the phagotest and phagoburst assays. Cytokine (TNFα, IL10, IL23) production was measured by ELISA. In parallel experiments, TNFα, IL10 and CD163 expression was measured by qRT-PCR in laser dissected E coli laden and unladen lamina proprial macrophages. All patients were genotyped for the three common NOD-2 SNP's (G908R, L1007fs and R702W), and the autophagy related SNP's (ATG16L1 and IRGM). Genotypes and monocyte/macrophage markers were compared. Results Presence of the ATG16L1 risk variant was strongly associated with a reduced E coli induced TNFα expression in CD PBM's (p=0.0017) and increased levels of ROR's on uptake of CD derived E coli (p=0.0027). Presences of IRGM risk variant was associated with increased IL10 expression from PBM's. NOD-2 mutations were not associated with a difference in any variable studied. No genotype altered survival of E coli in PBM at 2 or 4 h after infection or in-situ lamina propria macrophage cytokine expression. Conclusion These results show that defective autophagy modifies the handling of intracellular bacteria in CD but appears unlikely to be the main cause of prolonged bacterial survival. Further studies are needed to elucidate the nature of this innate defect and it's role in CD pathogenesis.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".