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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Fast diagnostic test for familial Mediterranean fever based on a kinase inhibitor
Flora Magnotti1, Tiphaine Malsot1, Sophie Georgin-Lavialle2,3
1Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard-Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, Lyon, France.
Background And Objective:
Familial Mediterranean fever (FMF) is the most frequent hereditary autoinflammatory disease. Its diagnosis relies on a set of clinical criteria and a genetic confirmation on identification of biallelic pathogenic MEFV variants. MEFV encodes pyrin, an inflammasome sensor. Using a kinase inhibitor, UCN-01, we recently identified that dephosphorylation of FMF-associated pyrin mutants leads to inflammasome activation. The aim of this study was to assess whether quantifying UCN-01-mediated inflammasome activation could discriminate FMF patients from healthy donors (HD) and from patients with other inflammatory disorders (OID).
Methods:
Real-time pyroptosis and IL-1β secretion were monitored in response to UCN-01 in monocytes from FMF patients (n=67), HD (n=71) and OID patients (n=40). Sensitivity and specificity of the resulting diagnostic tests were determined by receiver operating characteristic curve analyses.
Results:
Inflammasome monitoring in response to UCN-01 discriminates FMF patients from other individuals. Pyroptosis assessment leads to a fast FMF diagnosis while combining pyroptosis and IL-1β dosage renders UCN-01-based assays highly sensitive and specific. UCN-01-triggered monocytes responses were influenced by MEFV gene dosage and MEFV mutations in a similar way as clinical phenotypes are.
Conclusions:
UCN-01-based inflammasome assays could be used to rapidly diagnose FMF, with high sensitivity and specificity.
Insights
A new test using UCN-01 reliably distinguishes Familial Mediterranean Fever (FMF) patients from healthy individuals and those with other inflammatory conditions. This inflammasome activation assay offers a rapid and accurate diagnostic method for FMF.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory disease.
- Diagnosis typically requires clinical criteria and genetic confirmation of pathogenic *MEFV* variants.
- Pyrin, encoded by *MEFV*, is an inflammasome sensor; its dephosphorylation activates the inflammasome.
Purpose of the Study:
- To evaluate if quantifying UCN-01-mediated inflammasome activation can differentiate FMF patients from healthy donors (HD) and patients with other inflammatory disorders (OID).
Main Methods:
- Monocytes from FMF patients (n=67), HD (n=71), and OID patients (n=40) were analyzed for real-time pyroptosis and IL-1β secretion upon UCN-01 stimulation.
- Diagnostic test sensitivity and specificity were assessed using receiver operating characteristic curve analyses.
Main Results:
- UCN-01-induced inflammasome activation effectively discriminated FMF patients from other groups.
- Pyroptosis assessment enabled rapid FMF diagnosis.
- Combining pyroptosis and IL-1β measurements yielded highly sensitive and specific UCN-01-based assays.
- Monocyte responses correlated with *MEFV* gene dosage and mutation status, mirroring clinical phenotypes.
Conclusions:
- UCN-01-based inflammasome activation assays provide a sensitive and specific method for the rapid diagnosis of FMF.
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