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Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold
Yvan Jamilloux1,2, Lucie Lefeuvre1,3, Flora Magnotti1,4,5
1Centre International de Recherche en Infectiologie (CIRI), Inserm U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, University of Lyon, F-69007.
Objectives:
FMF is the most frequent autoinflammatory disease and is associated in most patients with bi-allelic MEFV mutations. MEFV encodes Pyrin, an inflammasome sensor activated following RhoGTPase inhibition. The functional consequences of MEFV mutations on the ability of Pyrin variants to act as inflammasome sensors are largely unknown. The aim of this study was to assess whether MEFV mutations affect the ability of Pyrin to detect RhoGTPase inhibition and other inflammasome stimuli.
Methods:
IL-1β and IL-18 released by monocytes from healthy donors (HDs) and FMF patients were measured upon specific engagement of the Pyrin, NLRP3 and NLRC4 inflammasomes. Cell death kinetics following Pyrin activation was monitored in real time.
Results:
Monocytes from FMF patients secreted significantly more IL-1β and IL-18 and died significantly faster than HD monocytes in response to low concentrations of Clostridium difficile toxin B (TcdB), a Pyrin-activating stimulus. Monocytes from patients bearing two MEFV exon 10 pathogenic variants displayed an increased Pyrin inflammasome response compared with monocytes from patients with a single exon 10 pathogenic variant indicating a gene-dosage effect. Using a short priming step, the response of monocytes from FMF patients to NLRP3- and NLRC4-activating stimuli was normal indicating that MEFV mutations trigger a specific hypersensitivity of monocytes to low doses of a Pyrin-engaging stimulus.
Conclusion:
Contrary to the NLRP3 mutations described in cryopyrin-associated periodic syndrome, FMF-associated MEFV mutations do not lead to a constitutive activation of Pyrin. Rather, FMF-associated mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome without affecting other canonical inflammasomes.
Insights
Familial Mediterranean fever (FMF) mutations in MEFV lower the activation threshold of the Pyrin inflammasome, leading to increased IL-1β and IL-18 release and faster cell death in FMF patients. This hypersensitivity is specific to Pyrin inflammasome activation.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Familial Mediterranean fever (FMF) is the most common autoinflammatory disorder, primarily caused by mutations in the MEFV gene.
- MEFV encodes Pyrin, a key sensor protein in the inflammasome pathway, crucial for detecting cellular stress and microbial invasion.
- The precise functional impact of MEFV mutations on Pyrin's sensing capabilities remains largely uncharacterized.
Purpose of the Study:
- To investigate how MEFV mutations affect Pyrin's ability to sense RhoGTPase inhibition and other inflammasome stimuli.
- To determine if FMF-associated MEFV mutations alter the activation threshold or specificity of the Pyrin inflammasome.
Main Methods:
- Monocyte-derived cytokine release (IL-1β, IL-18) and cell death kinetics were measured in healthy donors and FMF patients.
- Specific inflammasomes (Pyrin, NLRP3, NLRC4) were engaged using various stimuli, including Clostridium difficile toxin B (TcdB).
- Real-time monitoring of cell death kinetics post-Pyrin activation was performed.
Main Results:
- FMF patient monocytes exhibited heightened secretion of IL-1β and IL-18 and faster cell death upon Pyrin inflammasome activation by TcdB.
- A gene-dosage effect was observed, with patients carrying two MEFV exon 10 mutations showing a stronger Pyrin response than those with one.
- Monocytes from FMF patients responded normally to NLRP3 and NLRC4 inflammasome activation, indicating a specific Pyrin hypersensitivity.
Conclusions:
- MEFV mutations in FMF are hypermorphic, specifically lowering the activation threshold of the Pyrin inflammasome.
- Unlike constitutive activation seen in other inflammasome-associated diseases, FMF mutations confer a heightened sensitivity to Pyrin-activating signals.
- This Pyrin inflammasome hypersensitivity, rather than constitutive activation, underlies the autoinflammatory phenotype in FMF.