Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

Seth L. Masters*, Vasiliki Lagou, Isabelle Jéru, Paul J. Baker, Lien Van Eyck, David A. Parry, Dylan Lawless, Dominic De Nardo, Josselyn E. Garcia-Perez, Laura F. Dagley, Caroline L. Holley, James Dooley, Fiona Moghaddas, Emanuela Pasciuto, Pierre Yves Jeandel, Raf Sciot, Dena Lyras, Andrew I. Webb, Sandra E. Nicholson, Lien De SomerErika Van Nieuwenhove, Julia Ruuth-Praz, Bruno Copin, Emmanuelle Cochet, Myrna Medlej-Hashim, Andre Megarbane, Kate Schroder, Sinisa Savic, An Goris, Serge Amselem, Carine Wouters, Adrian Liston

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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-1b 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.

Original languageEnglish
Article number332ra45
JournalScience Translational Medicine
Issue number332
Publication statusPublished - 30 Mar 2016


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