title: Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation.
abstract: 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.
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia. masters@wehi.edu.au carine.wouters@uzleuven.be adrian.liston@vib.be.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: Department of Neurosciences, KU Leuven, Leuven 3000, Belgium. Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Lagou
authors.affiliation: INSERM, UMR S933, Paris F-75012, France. Université Pierre et Marie Curie-Paris, UMR S933, Paris F-75012, France. Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris F-75012, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jéru
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Baker
authors.affiliation: Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Van Eyck
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh LS7 4SA, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Wellcome Trust Brenner Building, Saint James's University Hospital, Leeds LS7 4SA, UK.
authors.forename: Dylan
authors.initials: D
authors.lastname: Lawless
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Dominic
authors.initials: D
authors.lastname: De Nardo
authors.affiliation: Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.
authors.forename: Josselyn E
authors.initials: JE
authors.lastname: Garcia-Perez
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia. Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Laura F
authors.initials: LF
authors.lastname: Dagley
authors.affiliation: Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Holley
authors.affiliation: Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.
authors.forename: James
authors.initials: J
authors.lastname: Dooley
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Fiona
authors.initials: F
authors.lastname: Moghaddas
authors.affiliation: Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pasciuto
authors.affiliation: Département de Médecine Interne, Hôpital Archet 1, Université Nice Sophia-Antipolis, 06202 Nice, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Jeandel
authors.affiliation: Department of Pathology, KU Leuven, Leuven 3000, Belgium. University Hospitals Leuven, Leuven 3000, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.affiliation: Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia.
authors.forename: Dena
authors.initials: D
authors.lastname: Lyras
authors.affiliation: Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia. Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Webb
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Nicholson
authors.affiliation: University Hospitals Leuven, Leuven 3000, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: De Somer
authors.affiliation: Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. Translational Immunology Laboratory, VIB, Leuven 3000, Belgium. University Hospitals Leuven, Leuven 3000, Belgium.
authors.forename: Erika
authors.initials: E
authors.lastname: van Nieuwenhove
authors.affiliation: Université Pierre et Marie Curie-Paris, UMR S933, Paris F-75012, France. Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris F-75012, France.
authors.forename: Julia
authors.initials: J
authors.lastname: Ruuth-Praz
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris F-75012, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Copin
authors.affiliation: Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris F-75012, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Cochet
authors.affiliation: Department of Life and Earth Sciences, Faculty of Sciences II, Lebanese University, Beirut 1102 2801, Lebanon.
authors.forename: Myrna
authors.initials: M
authors.lastname: Medlej-Hashim
authors.affiliation: Al-Jawhara Center, Arabian Gulf University, Manama 26671, Bahrain.
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.affiliation: Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Schroder
authors.affiliation: Department of Allergy and Clinical Immunology, Saint James's University Hospital, Leeds LS9 7TF, UK. National Institute for Health Research-Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Rheumatic and Musculoskeletal Medicine, Wellcome Trust Brenner Building, Saint James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
authors.forename: Sinisa
authors.initials: S
authors.lastname: Savic
authors.affiliation: Department of Neurosciences, KU Leuven, Leuven 3000, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Goris
authors.affiliation: INSERM, UMR S933, Paris F-75012, France. Université Pierre et Marie Curie-Paris, UMR S933, Paris F-75012, France. Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris F-75012, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Amselem
authors.affiliation: Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. University Hospitals Leuven, Leuven 3000, Belgium. masters@wehi.edu.au carine.wouters@uzleuven.be adrian.liston@vib.be.
authors.forename: Carine
authors.initials: C
authors.lastname: Wouters
authors.affiliation: Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. Translational Immunology Laboratory, VIB, Leuven 3000, Belgium. masters@wehi.edu.au carine.wouters@uzleuven.be adrian.liston@vib.be.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
mesh_terms: D005260:Female; D057809:HEK293 Cells; D056660:Hereditary Autoinflammatory Diseases / Q000150:complications* / Q000276:immunology / Q000473:pathology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000473:pathology*; D010375:Pedigree; D000071198:Pyrin / Q000378:metabolism*; D012871:Skin Diseases / Q000150:complications* / Q000276:immunology / Q000473:pathology*
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071198:Pyrin