Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation
Masters, SL; Lagou, V; Jeru, I; Baker, PJ; Van Eyck, L; Parry, DA; Lawless, D; De Nardo, D; Garcia-Perez, JE; Dagley, LF; Holley, CL; Dooley, J; Moghaddas, F; Pasciuto, E; Jeandel, PY; Sciot, R; Lyras, D; Webb, AI; Nicholson, SE; De Somer, L; van Nieuwenhove, E; Ruuth-Praz, J; Copin, B; Cochet, E; Medlej-Hashim, M; Megarbane, A; Schroder, K; Savic, S; Goris, A; Amselem, S; Wouters, C; Liston, A
Sci Transl Med
Pyrin responds to pathogen signals and loss of cellular homeostasis by forming an inflammasome complex that drives the cleavage and secretion of interleukin-1beta (IL-1beta). 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 inMEFV, 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 asClostridiumdifficiletoxin B (TcdB). The S242R mutation thus recapitulated the effect of pathogen sensing, triggering inflammasome activation and IL-1beta production. Successful therapy targeting IL-1beta 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.
Inflammation; Systems Biology and Personalised Medicine