Complement Activation and Its Implication in the Pathophysiology of Hemolytic Anemia and Aging in Mouse Models of Sickle Cell Disease and Beta-Thalassemia
Notice bibliographique
Résumé
Introduction: complement activation plays a crucial role in the immune response and has been increasingly recognized for its involvement in various hemolytic anemias. In sickle cell disease (SCD), chronic hemolysis and inflammation are thought to activate the complement system, contributing to the disease's pathophysiology. Elevated levels of complement components, such as C3 and C5, have been reported in SCD patients, indicating a link between complement activation and disease severity. Similarly, beta-thalassemia intermedia, characterized by ineffective erythropoiesis and increased red blood cells (RBCs) destruction, also suggests potential complement involvement. This study aims to elucidate the role of complement in these hemolytic conditions by examining the levels of complement components and RBC opsonization overtime in aging mouse models of SCD (Townes model) and beta-thalassemia intermedia (Hbbth1/th1). Methods: we employed ELISA to measure the evolution of plasma levels of complement components overtime, including C3, factor B, C5, C5a, and the membrane attack complex (C5b9), in naturally aging Townes mice model of SCD (from 8-weeks up to 24-weeks old) and Hbbth1/th1 mice model of beta-thalassemia intermedia (from 8-weeks up to 12-months old). Additionally, we assessed the opsonization of RBCs by C3b and C5b9 fragments by flow cytometry. Tissues were collected for evaluation of end-organ damage and injury score. Results: our findings reveal a significant increase in plasma levels of C3, factor B, C5, C5a, and sC5b9 in both SCD and beta-thalassemia intermedia models and a significant correlation with age. In Hbbth1/th1 mice, C3 levels increased to 655 µg/ml from 6 months of age and were maintained at high levels up to 12 months, while C5 and C5a levels were elevated to 11.8 µg/ml and 24.7 ng/ml, respectively, starting from 5 months and sustained up to 12 months. Factor B levels rose to 367.2 µg/ml at 9 months, and sC5b9 levels reached 46.6 ng/ml at 12 months, all significantly higher compared to wild-type mice (p<0.05). In Townes HbSS mice, a time-dependent increase in complement activation was observed, with C3 levels rising from 744 µg/ml at 3 months to 1042 µg/ml at 6 months. Similarly, factor B levels increased from 561 µg/ml at 3 months to 1328 µg/ml at 6 months, C5 levels from 12 µg/ml at 3 months to 18.3 µg/ml at 6 months, C5a levels from 11.7 ng/ml at 3 months to 32.1 ng/ml at 6 months, and sC5b9 levels from 51.1 ng/ml at 3 months to 182.9 ng/ml at 6 months, all significantly higher compared to HbAA control mice (p<0.05). RBC opsonization by C3b was evident in Hbbth1/th1 mice starting at 6 months, with levels reaching 4.8% (p<0.05). In Townes HbSS mice, C3b opsonization was observed from 3 months, increasing from 3.8% to 8.1% at 6 months, with levels peaking at 5 months and remaining elevated with age (p<0.05). C5b9 opsonization followed a similar pattern, indicating sustained complement activation and RBC opsonization in these models. Tissue histology analysis revealed important organ injury in both Hbbth1/th1 and HbSS mice. Hbbth1/th1 showed predominantly iron overload in liver, kidneys, spleen and heart. In HbSS mice we observed significant damage in liver (hepatomegaly, inflammation, necrosis), kidneys (glomerulosclerosis, medullary ischemia), lungs (inflammation, fibrosis) and cardiac hypertrophy. We are currently performing experiments to quantify C3/C3b and C5b9 deposition and correlate it to end-organ damage within injured tissues. Conclusion: we demonstrate that complement activation, marked by increased levels of C3, factor B, C5, C5a, and C5b9, is a significant feature in both SCD and beta-thalassemia intermedia models, worsening with age. Our results suggest that complement activation might be correlated to end-organ damage and disease severity in aging SCD and beta-thalassemia mice. The opsonization of RBCs by complement fragments further underscores the role of complement in the pathophysiology of hemolytic anemia. These findings suggest that targeting the complement alternative pathway may offer a promising therapeutic approach for treating hemolytic anemias.
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Prédiction machine sur la base complète
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Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 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 | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».