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Sci Transl Med. 2016 Mar 30;8(332):332ra45. doi: 10.1126/scitranslmed.aaf1471.

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

Author information

1
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.
2
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.
3
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.
4
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.
5
Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. Translational Immunology Laboratory, VIB, Leuven 3000, Belgium.
6
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.
7
Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Wellcome Trust Brenner Building, Saint James's University Hospital, Leeds LS7 4SA, UK.
8
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.
9
Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland 4072, Australia.
10
Département de Médecine Interne, Hôpital Archet 1, Université Nice Sophia-Antipolis, 06202 Nice, France.
11
Department of Pathology, KU Leuven, Leuven 3000, Belgium. University Hospitals Leuven, Leuven 3000, Belgium.
12
Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia.
13
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.
14
University Hospitals Leuven, Leuven 3000, Belgium.
15
Department of Microbiology and Immunology, KU Leuven, Leuven 3000, Belgium. Translational Immunology Laboratory, VIB, Leuven 3000, Belgium. University Hospitals Leuven, Leuven 3000, Belgium.
16
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.
17
Assistance Publique Hôpitaux de Paris, Hôpital Trousseau, Service de Génétique et d'Embryologie médicales, Paris F-75012, France.
18
Department of Life and Earth Sciences, Faculty of Sciences II, Lebanese University, Beirut 1102 2801, Lebanon.
19
Al-Jawhara Center, Arabian Gulf University, Manama 26671, Bahrain.
20
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.
21
Department of Neurosciences, KU Leuven, Leuven 3000, Belgium.
22
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.
23
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.

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.

PMID:
27030597
DOI:
10.1126/scitranslmed.aaf1471
[Indexed for MEDLINE]
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