TY - JOUR
T1 - Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation
AU - Masters, Seth L.
AU - Lagou, Vasiliki
AU - Jeru, Isabelle
AU - Baker, Paul J.
AU - Van Eyck, Lien
AU - Parry, David A.
AU - Lawless, Dylan
AU - De Nardo, Dominic
AU - Garcia-Perez, Josselyn E.
AU - Dagley, Laura F.
AU - Holley, Caroline L.
AU - Dooley, James
AU - Moghaddas, Fiona
AU - Pasciuto, Emanuela
AU - Jeandel, Pierre-Yves
AU - Sciot, Raf
AU - Lyras, Dena
AU - Webb, Andrew I.
AU - Nicholson, Sandra E.
AU - De Somer, Lien
AU - van Nieuwenhove, Erika
AU - Ruuth-Praz, Julia
AU - Copin, Bruno
AU - Cochet, Emmanuelle
AU - Medlej-Hashim, Myrna
AU - Megarbane, Andre
AU - Schroder, Kate
AU - Savic, Sinisa
AU - Goris, An
AU - Amselem, Serge
AU - Wouters, Carine
AU - Liston, Adrian
PY - 2016/3/30
Y1 - 2016/3/30
N2 - 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.
AB - 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.
UR - http://www.ncbi.nlm.nih.gov/pubmed/27030597
U2 - 10.1126/scitranslmed.aaf1471
DO - 10.1126/scitranslmed.aaf1471
M3 - Article
VL - 8
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 332
M1 - 332ra45
ER -