Innate immunity and inflammation in cystic fibrosis lung disease
Bibliographic record
Abstract
Inflammatory lung disease is the major life-limiting factor of cystic fibrosis (CF) and occurs through a self-sustaining cycle of airway obstruction, infection and inflammation. Although there is no consensus regarding the pathways responsible for the excessive inflammation, reducing lung-damaging pro-inflammatory responses are likely to be beneficial for CF patients. Using CF (IB3-1) and non-CF control (C38) respiratory cells, the host-pathogen interaction between the airway epithelium and the common CF pathogens P. aeruginosa and B. cepacia was investigated. Using purified Toll-like receptor (TLR) ligands and different knock-out strains of P. aeruginosa, TLR5 was identified as the receptor mediating much of the increased inflammatory response to CF pathogens. To validate TLR5 as an anti-inflammatory target, the disease modifying effects of the functionally relevant TLR5 c.1174C>T single nucleotide polymorphism (rs5744168) was analysed in approximately 80% of Canada’s CF population. rs5744168 encodes a premature stop codon and the T allele is associated with 45.5 – 76.3% reduction in flagellin responsiveness. CF patients carrying rs5744168 (CT or TT) had a significantly higher body mass index than CF patients homozygous for the common allele (CC) (p=0.044); however, similar improvements in lung function associated with the T allele were not statistically significant. Since TLR5 mediates much of the excessive inflammation to P. aeruginosa, it is of interest to understand the mechanisms underlying this dysregulated immune response. By combining gene expression arrays with network analyses and biochemical assays, ER stress was identified as a potential mechanism dysregulating p38 MAP kinase activity and leading to potentiated immune responses. Together, this thesis provides data underscoring the importance of TLR5-mediated excessive pro-inflammatory immune response by CF airway cells to P. aeruginosa. The association of the TLR5392STOP SNP with higher BMI in adult CF patients indicates an important role for TLR5 in CF disease severity. Finally, ER stress may potentiate the immune response to flagellin by signalling through p38 MAP kinase, supporting an emerging paradigm in which the imbalance of protein homeostasis can lead to altered signalling events. Strategies to inhibit either TLR5 signalling, ER stress signalling or to improve the cellular protein homeostasis may prove useful in treating life limiting inflammation in CF.
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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".