Phenotypic consequences of TLR7-driven interferon and proinflammatory cytokine production in lupus
Notice bibliographique
Résumé
Although type I interferons (IFN-I) are involved in the pathogenesis of SLE, clinical heterogeneity of the disease is not fully explained by IFN-I overproduction. We investigated the relative importance of IFN-I versus proinflammatory cytokine production downstream of TLR7 in a murine lupus model and in SLE patients. TLR7-mediated experimental lupus was induced in wild-type and knockout mice by pristane and the expression of IFN-I stimulated genes and numbers of plasmacytoid dendritic cells (pDCs) and inflammatory (Ly6C ) monocytes were assessed by PCR and flow cytometry, respectively. Production of TNFα and other proinflammatory cytokines was evaluated by intracellular staining. In parallel, we studied production of these cytokines in the bone marrow (BM) of SLE patients. SLE patients' BM exhibited striking death of niche and hematopoietic cells associated with local TNFα overproduction. BM from mice with pristane-induced lupus showed similar abnormalities. TNFα was produced mainly by BM neutrophils, many of which contained phagocytosed nuclear material (LE cells). TNFα production was abolished in TLR7 and μmt mice but was unaffected by C3 deficiency. Production was restored in μmt mice by infusing normal plasma, consistent with opsonization of endogenous TLR7 ligands by immunoglobulin. Although autoantibody production and glomerulonephritis are abolished in interferon receptor (IFNAR) mice, both wild-type and IFNAR mice developed anemia and BM hypocellularity following pristane treatment. These manifestations were absent in TLR7 and TNFα mice, indicating that the anemia is TNFα mediated. Unexpectedly, although TNF inhibitors can induce lupus manifestations, TNFα mice did not develop autoantibodies spontaneously. However, although IFN-I levels were comparable in untreated TNFα and B6 mice, TNFα mice had increased circulating pDCs and "pDC-like" cells, enhancing their potential to make IFN-I. When treated with pristane, TNFα mice developed more severe lupus than controls with increased levels of anti-Sm/RNP autoantibodies, IFN-I, pDCs, and peritoneal inflammatory (Ly6C ) monocytes. Although autoantibodies and glomerulonephritis are TLR7/IFN-I dependent, lupus-associated BM abnormalities were TLR7/TNFα driven, but IFN-I independent. TNFα had a downregulatory effect on pDC numbers and TNFα-deficient mice exhibited an enhanced potential to produce IFN-I in response to TLR7 ligands. Our data suggest that the clinical manifestations of lupus reflect the complex interplay of cells producing IFN-I (causing autoantibodies and nephritis) and TNFα (causing hematologic involvement and arthritis). Engagement of TLR7 by RNA ligands released by dead cells may be a central defect in lupus, whereas the balance of IFN-I versus TNFα production may help determine the disease phenotype.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 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 | 0,001 |
| 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) | 0,000 | 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 tête enseignante, 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 ».