Interstitial lung disease in STING-associated vasculopathy with onset in infancy (SAVI): preliminary genotype-phenotype correlation
Notice bibliographique
Résumé
Some monogenic interferonopathies are caused by innate immune dysregulation and form a subclass of autoinflammatory disorders characterized by systemic inflammation due to chronic Type I interferon stimulation. STING-Associated Vasculopathy with Onset in Infancy (SAVI) is an IFN-mediated disease caused by gain-of-function mutations in TMEM173 , the gene encoding the stimulator of interferon genes (STING). This study was undertaken to understand the variable disease severity of the interstitial lung disease (ILD) in SAVI patients. We hypothesized that the severity of the interstitial lung disease may be modulated by a common SNP (R232H, rs1131769) that is functionally associated with decreased IFNB1 transcription. We studied nine SAVI patients with N154S, V155M, or V147L mutations. Lung involvement was assessed by chest computed tomography (CT) and pulmonary function tests (PFTs) for all patients, a lung biopsy was available for five patients. Peripheral blood genomic DNA samples were obtained and TMEM173 (NM_198282.3) was sequenced by Sanger technique. STING function was evaluated in the different TMEM173 haplotypes by IFNB1 Luciferase Reporter assays performed with cells transfected with wildtype or mutant TMEM173 on the R232 and the H232 backgrounds. We described the clinical features of ILD in nine SAVI patients. Six patients had evidence of severe ILD characterized by moderate to severe abnormalities on chest CT, PFTs and/or lung biopsy. Two patients presented with mild ILD and one did not have any evidence of ILD. Four out of the six patients with severe ILD succumbed to pulmonary complications. Five patients with severe ILD were homozygous for R232 (R232/R232) and one was heterozygous for the SNP. Conversely, the two patients with mild ILD were heterozygous (R232/H232) and the patient without ILD was homozygous for the H232 allele (H232/H232). Thus, the severity of interstitial lung disease seems to correlate with the STING haplotype. Transfection of HEK293T cells with the H232 TMEM173 haplotype with or without SAVI causing mutations results in decreased IFNB1 expression in the presence of both low affinity and high affinity STING stimulator cGAMP in comparison with cells transfected with the R232 haplotype. These findings suggest that the H232 haplotype background may be protective from the development of ILD. The variable presentation and severity of ILD in SAVI patients seems to correlate with the TMEM173 haplotype at position 232 and possibly with the local induction of an IFN response. Our data suggest that common variants can modify disease expression specific to one organ and provide a model to assess the variable disease phenotype in other interferonopathies.
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 | 0,000 | 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) | 0,000 | 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 ».