Regulation and function of Toll-like receptor 4 in allergic diseases
Bibliographic record
Abstract
The hygiene hypothesis states that exposure to microbes limits the development of allergic diseases, whereas the lack of microbial stimulation of the immune system early in life would promote their development. The beneficial effects of microbes against allergies would be mediated by pathogen-derived molecules interacting with Toll-like receptors (TLR), and interfering with allergic T âhelper' lymphocyte type-2 (Th2) inflammation seen in asthma and rhinitis. Few studies investigated whether allergies interfere with the expression and function of Toll-like receptor-4 (TLR4), the receptor for bacterial lipopolysaccharide (LPS). We hypothesized that a history of allergies and Th2-type mediators affect the expression and the function of TLR4 on peripheral leukocytes and the airway epithelium. Secondly, we hypothesized that GATA-3, a transcription factor driving the Th2 phenotype, regulates TLR4 expression of airway epithelial cells in allergic conditions. Peripheral leukocytes from a paediatric cohort of atopic and non-atopic subjects were discriminated based on LPS-induced TLR4 surface expression, activation of its signalling pathways, and expression of anti-inflammatory interleukin (IL)-10. Monocytes from atopics were significantly less responsive to LPS than cells from non-atopic children, while CD4 T lymphocytes failed to respond. The TLR4 expression on monocytes diminished as a function of age in atopic, but not in non-atopic subjects. In the nasal mucosa of adults, a reduced epithelial TLR4 expression was seen in tissues from subjects with allergic rhinitis compared with controls. Concomitantly, tissues from rhinitis patients displayed an increased Th2-type inflammatory profile. We also detected a reduced TLR4 and an increased GATA-3 expression in bronchial epithelial cells from asthmatic adults compared with non-asthmatics, as well as in epithelial cells cultured under pro-allergic conditions. Finally, epithelial cells over-expressing GATA-3 gene slightly reduced TLR4 expression, whereas those in which endogenous GATA-3 was silenced significantly augmented it. These data suggest a direct regulation of epithelial TLR4 by GATA-3. In summary, this work demonstrates that a history of atopy or allergy, as well as the Th2 inflammatory milieu, reduce the ability of atopic individuals to respond to LPS in circulating monocytes of children and airway epithelial cells of adults. This thesis project provides a new perspective to TLR agonists-based therapies that aim at preventing allergic disorders. Our data stress that the preventive effect of LPS would occur early during childhood or the absence of atopy since in atopic adolescents and adults with on-going allergic diseases displayed blunted TLR4 expression and/or function.
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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".