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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.

Rheumatology (Oxford, England)
|October 18, 2017
PubMed

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Summary
This summary is machine-generated.

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.
Keywords:
IL-18IL-1βMEFVNLRC4NLRP3Pyrinautoinflammationfamilial mediterranean feverinflammasome

Related Experiment Videos

  • 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.