Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.
Sci Transl Med
; 8(332): 332ra45, 2016 Mar 30.
Article
em En
| MEDLINE
| ID: mdl-27030597
ABSTRACT
Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1ß (IL-1ß). 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-1ß production. Successful therapy targeting IL-1ß 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dermatopatias
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Doenças Hereditárias Autoinflamatórias
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Pirina
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Neutrófilos
Limite:
Female
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Humans
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Male
Idioma:
En
Revista:
Sci Transl Med
Ano de publicação:
2016
Tipo de documento:
Article