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

• Published in: Science translational medicine Vol. 8; no. 332; p. 332ra45
• Main Authors: Masters, Seth L, Lagou, Vasiliki, Jéru, Isabelle, Baker, Paul J, Van Eyck, Lien, Parry, David A, Lawless, Dylan, De Nardo, Dominic, Garcia-Perez, Josselyn E, Dagley, Laura F, Holley, Caroline L, Dooley, James, Moghaddas, Fiona, Pasciuto, Emanuela, Jeandel, Pierre-Yves, Sciot, Raf, Lyras, Dena, Webb, Andrew I, Nicholson, Sandra E, De Somer, Lien, van Nieuwenhove, Erika, Ruuth-Praz, Julia, Copin, Bruno, Cochet, Emmanuelle, Medlej-Hashim, Myrna, Megarbane, Andre, Schroder, Kate, Savic, Sinisa, Goris, An, Amselem, Serge, Wouters, Carine, Liston, Adrian
• Format: Journal Article
• Language: English
• Published: United States 30.03.2016
• Subjects: Female; HEK293 Cells; Hereditary Autoinflammatory Diseases - complications; Hereditary Autoinflammatory Diseases - immunology; Hereditary Autoinflammatory Diseases - pathology; Humans; Inflammasomes - metabolism; Interleukin-1beta - metabolism; Male; Mutation - genetics; Neutrophils - pathology; Pedigree; Pyrin - metabolism; Skin Diseases - complications; Skin Diseases - immunology; Skin Diseases - pathology
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.aaf1471

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.