Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation
Seth Masters
(1)
,
James Dooley
(2)
,
Vasiliki Lagou
(3)
,
Isabelle Jéru
(4)
,
Paul Baker
(1)
,
Lien van Eyck
(3)
,
Laura Dagley
(1)
,
David Parry
(5)
,
Dylan Lawless
(6)
,
Dominic de Nardo
(1)
,
Caroline Holley
(7)
,
Josselyn Garcia-Perez
(3)
,
Fiona Moghaddas
(1, 8)
,
Emanuela Pasciuto
(3)
,
Pierre-Yves Jeandel
(9)
,
Raf Sciot
(2)
,
Dena Lyras
(10)
,
Andrew Webb
(1)
,
Sandra Nicholson
(1)
,
Lien de Somer
(2)
,
Erika van Nieuwenhove
(2)
,
Julia Ruuth-Praz
(4, 11)
,
Bruno Copin
(11)
,
Emmanuelle Cochet
(11)
,
Myrna Medlej-Hashim
(12)
,
Andre Megarbane
(13)
,
Kate Schroder
(7)
,
Sinisa Savic
(6)
,
An Goris
(3)
,
Serge Amselem
(4, 11)
,
Carine Wouters
(3, 2)
,
Adrian Liston
(3)
1
WEHI -
The Walter and Eliza Hall Institute of Medical Research
2 University Hospitals Leuven [Leuven]
3 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
4 Physiopathologie des maladies génétiques d'expression pédiatrique
5 Edin. - University of Edinburgh
6 St James's University Hospital
7 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
8 University of Melbourne
9 UNS - Université Nice Sophia Antipolis (1965 - 2019)
10 Monash university
11 CHU Trousseau [APHP]
12 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]
13 AUB - American University of Beirut Faculty of Medicine and Medical Center
2 University Hospitals Leuven [Leuven]
3 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
4 Physiopathologie des maladies génétiques d'expression pédiatrique
5 Edin. - University of Edinburgh
6 St James's University Hospital
7 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
8 University of Melbourne
9 UNS - Université Nice Sophia Antipolis (1965 - 2019)
10 Monash university
11 CHU Trousseau [APHP]
12 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]
13 AUB - American University of Beirut Faculty of Medicine and Medical Center
Seth Masters
- Fonction : co premier-auteur
- PersonId : 1198235
Serge Amselem
- Fonction : Auteur
- PersonId : 936326
- IdHAL : serge-amselem
- ORCID : 0000-0001-9506-3968
- IdRef : 066957761
Carine Wouters
- Fonction : co dernier-auteur
- PersonId : 944383
Adrian Liston
- Fonction : co dernier-auteur
- PersonId : 944648
Résumé
Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1β (IL-1β). Mutations in the B30.2/SPRY domain cause pathogen-independent activation of pyrin and are responsible for the autoinflammatory disease familial Mediterranean fever (FMF). We studied a family with a dominantly inherited autoinflammatory disease, distinct from FMF, characterized by childhood-onset recurrent episodes of neutrophilic dermatosis, fever, elevated acute-phase reactants, arthralgia, and myalgia/myositis. The disease was caused by a mutation in MEFV, the gene encoding pyrin (S242R). The mutation results in the loss of a 14-3-3 binding motif at phosphorylated S242, which was not perturbed by FMF mutations in the B30.2/SPRY domain. However, loss of both S242 phosphorylation and 14-3-3 binding was observed for bacterial effectors that activate the pyrin inflammasome, such as Clostridium difficile toxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1β production. Successful therapy targeting IL-1β has been initiated in one patient, resolving pyrin-associated autoinflammation with neutrophilic dermatosis. This disease provides evidence that a guard-like mechanism of pyrin regulation, originally identified for Nod-like receptors in plant innate immunity, also exists in humans.