Innate immune dysregulation in monocytes in sickle cell disease
Notice bibliographique
Résumé
Abstract Background : Sickle cell disease (SCD) is the most common genetic hematological disorder affecting ~100,000 people in the United States, resulting from a single base pair mutation resulting in a glutamic acid to valine substitution at position 6 in the beta-globin protein. Individuals with SCD have higher morbidity and mortality due to infectious diseases. A significant portion of patients with SCD, ~65% in some series, show impaired vaccine response and remain under-protected against vaccine-preventable infections. Chronic hemolysis associated with SCD results in splenic infarction and functional asplenia, but also overwhelms mechanisms to sequester heme and other damage-associated molecular patterns (DAMPs) released from erythrocytes that activate innate immune pattern recognition receptors such as Toll-like Receptors (TLRs). We aimed to investigate TLR function in monocytes and assess the effects of TLR 2/6, TLR4, and TLR7/8 agonists, lipoteichoic acid (LTA), lipopolysaccharide (LPS), and Resiquimod (R848) respectively, on cytokine production in monocytes from patients with and without SCD. Methods : Peripheral blood mononuclear cells (PBMC) were isolated from pediatric and young adult patients with SCD (n=17) and age and race-matched healthy participants (n=10), cryopreserved, and thawed before stimulation. We used flow cytometry to identify monocyte subsets and cytokine production by monocytes after stimulation with LTA, R848, or LPS. Monocyte subsets were classified as classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14dimCD16+). Cytokine production was evaluated in these populations using intracellular cytokine staining to detect TNF-a, IL-1b, IL-6, IL-8, and MCP-1. Statistical significance was compared using Mann-Whitney tests with a significance cutoff value of p=0.05. Results : SCD participants had total white blood cell counts and monocyte percentages within the normal range for their age. The median WBC count was 9.0x103 cell/µL, IQR 7.3x103 cell/µL-10.3x103 cells/µL, and the median monocyte percentage was 10%, IQR 8%-12.25%. SCD patients had a lower proportion of classical (CD14++CD16-) monocytes compared to healthy controls in the unstimulated group (p=0.0004), and in LTA (p=0.002), LPS (p=0.008), and R848 (p=0.03) groups after a 6-hour stimulation. There was a statistically significant increase in non-classical (CD14dimCD16+) monocytes in SCD patients in the unstimulated (p=0.02) group, and in the LTA (p=0.005) and R848 (p=0.04) groups following a 6-hour stimulation. After stimulation with LTA, there was a significant decrease in the percentage of classical monocytes producing IL-6 (p=0.02) in SCD patients compared to healthy controls and an increase in the percentage of classical monocytes producing IL-8 (p=0.006) in SCD patients compared to healthy controls. Following LPS stimulation, there was a significant increase in the percentage of classical monocytes producing IL-8 in SCD patients compared to healthy controls (p=0.002). After stimulation with R848, there was a significant increase in the percentage of classical monocytes producing IL-6 (p=0.04), IL-1b (p=0.0001), and IL-8 (p=<0.000001) compared to healthy controls. Conclusion: Monocytes from SCD patients show trends toward increased inflammatory responses, especially following TLR7/8 stimulation, compared to monocytes from age and race-matched healthy controls. This suggests alterations in TLR function in individuals with SCD, resulting in dysregulated innate immunity that may contribute to impaired responses to infection or vaccination.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».