A mathematical model of Familial Mediterranean Fever predicts mechanisms controlling inflammation
Copyright © 2023. Published by Elsevier Inc.
| Veröffentlicht in: | Clinical immunology (Orlando, Fla.). - 1999. - 257(2023) vom: 10. Dez., Seite 109839 |
|---|---|
| 1. Verfasser: | |
| Weitere Verfasser: | , , , , |
| Format: | Online-Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2023
|
| Zugriff auf das übergeordnete Werk: | Clinical immunology (Orlando, Fla.) |
| Schlagworte: | Journal Article Research Support, Non-U.S. Gov't Familial Mediterranean Fever In silico experiments Mathematical model Systems biology Inflammasomes MEFV protein, human Pyrin |
| Zusammenfassung: | Copyright © 2023. Published by Elsevier Inc. BACKGROUND: Familial Mediterranean Fever (FMF) is a monogenic disease caused by gain-of-function mutations in the MEditerranean FeVer (MEFV) gene. The molecular dysregulations induced by these mutations and the associated causal mechanisms are complex and intricate OBJECTIVE: We sought to provide a computational model capturing the mechanistic details of biological pathways involved in FMF physiopathology and enabling the study of the patient's immune cell dynamics METHODS: We carried out a literature survey to identify experimental studies published from January 2000 to December 2020, and integrated its results into a molecular map and a mathematical model. Then, we studied the network of molecular interactions and the dynamic of monocytes to identify key players for inflammation phenotype in FMF patients RESULTS: We built a molecular map of FMF integrating in a structured manner the current knowledge regarding pathophysiological processes participating in the triggering and perpetuation of the disease flares. The mathematical model derived from the map reproduced patient's monocyte behavior, in particular its proinflammatory role via the Pyrin inflammasome activation. Network analysis and in silico experiments identified NF-κB and JAK1/TYK2 as critical to modulate IL-1β- and IL-18-mediated inflammation CONCLUSION: The in silico model of FMF monocyte proved its ability to reproduce in vitro observations. Considering the difficulties related to experimental settings and financial investments to test combinations of stimuli/perturbation in vitro, this model could be used to test complex hypotheses in silico, thus narrowing down the number of in vitro and ex vivo experiments to perform |
|---|---|
| Beschreibung: | Date Completed 10.01.2024 Date Revised 10.04.2024 published: Print-Electronic Citation Status MEDLINE |
| ISSN: | 1521-7035 |
| DOI: | 10.1016/j.clim.2023.109839 |