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

作者：Seth L. Masters, Vasiliki Lagou, Isabelle Jéru, Paul J. Baker, Lien Van Eyck, David 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 Somer, Erika Van Nieuwenhove, Julia Ruuth-Praz, Bruno Copin, Emmanuelle Cochet, Myrna Medlej‐Hashim, André Mégarbané, Kate Schroder, Sinisa Savic, An Goris, Serge Amselem, Carine Wouters, Adrian Liston · 发表于：Science Translational Medicine · 年份：2016 · DOI：10.1126/scitranslmed.aaf1471 · 被引用次数：318 · 研究领域：Inflammasome and immune disorders、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Autoimmune and Inflammatory Disorders

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.