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

Seth L. Masters, Vasiliki Lagou, Isabelle Jeru, Paul J. Baker, Lien Van Eyck, David A. 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 & 12 others Erika van Nieuwenhove, Julia Ruuth-Praz, Bruno Copin, Emmanuelle Cochet, Myrna Medlej-Hashim, Andre Megarbane, Kate Schroder, Sinisa Savic, An Goris, Serge Amselem, Carine Wouters, Adrian Liston

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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.
Original languageEnglish
Article number332ra45
Number of pages10
JournalScience Translational Medicine
Volume8
Issue number332
DOIs
Publication statusPublished - 30 Mar 2016

Cite this

Masters, S. L., Lagou, V., Jeru, I., Baker, P. J., Van Eyck, L., Parry, D. A., ... Liston, A. (2016). Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Science Translational Medicine, 8(332), [332ra45]. https://doi.org/10.1126/scitranslmed.aaf1471
Masters, Seth L. ; Lagou, Vasiliki ; Jeru, Isabelle ; Baker, Paul J. ; Van Eyck, Lien ; Parry, David A. ; Lawless, Dylan ; De Nardo, Dominic ; Garcia-Perez, Josselyn E. ; Dagley, Laura F. ; Holley, Caroline L. ; Dooley, James ; Moghaddas, Fiona ; Pasciuto, Emanuela ; Jeandel, Pierre-Yves ; Sciot, Raf ; Lyras, Dena ; Webb, Andrew I. ; Nicholson, Sandra E. ; De Somer, Lien ; van Nieuwenhove, Erika ; Ruuth-Praz, Julia ; Copin, Bruno ; Cochet, Emmanuelle ; Medlej-Hashim, Myrna ; Megarbane, Andre ; Schroder, Kate ; Savic, Sinisa ; Goris, An ; Amselem, Serge ; Wouters, Carine ; Liston, Adrian. / Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. In: Science Translational Medicine. 2016 ; Vol. 8, No. 332.
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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.",
author = "Masters, {Seth L.} and Vasiliki Lagou and Isabelle Jeru and Baker, {Paul J.} and {Van Eyck}, Lien and Parry, {David A.} and Dylan Lawless and {De Nardo}, Dominic and Garcia-Perez, {Josselyn E.} and Dagley, {Laura F.} and Holley, {Caroline L.} and James Dooley and Fiona Moghaddas and Emanuela Pasciuto and Pierre-Yves Jeandel and Raf Sciot and Dena Lyras and Webb, {Andrew I.} and Nicholson, {Sandra E.} and {De Somer}, Lien and {van Nieuwenhove}, Erika and Julia Ruuth-Praz and Bruno Copin and Emmanuelle Cochet and Myrna Medlej-Hashim and Andre Megarbane and Kate Schroder and Sinisa Savic and An Goris and Serge Amselem and Carine Wouters and Adrian Liston",
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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, P-Y, 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 2016, 'Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation', Science Translational Medicine, vol. 8, no. 332, 332ra45. https://doi.org/10.1126/scitranslmed.aaf1471

Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. / Masters, Seth L.; Lagou, Vasiliki; Jeru, Isabelle; Baker, Paul J.; Van Eyck, Lien; Parry, David A.; Lawless, Dylan; De Nardo, Dominic; Garcia-Perez, Josselyn E.; Dagley, Laura F.; Holley, Caroline L.; Dooley, James; Moghaddas, Fiona; Pasciuto, Emanuela; Jeandel, Pierre-Yves; Sciot, Raf; Lyras, Dena; Webb, Andrew I.; Nicholson, Sandra E.; De Somer, Lien; van Nieuwenhove, Erika; Ruuth-Praz, Julia; Copin, Bruno; Cochet, Emmanuelle; Medlej-Hashim, Myrna; Megarbane, Andre; Schroder, Kate; Savic, Sinisa; Goris, An; Amselem, Serge; Wouters, Carine; Liston, Adrian.

In: Science Translational Medicine, Vol. 8, No. 332, 332ra45, 30.03.2016.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation

AU - Masters, Seth L.

AU - Lagou, Vasiliki

AU - Jeru, Isabelle

AU - Baker, Paul J.

AU - Van Eyck, Lien

AU - Parry, David A.

AU - Lawless, Dylan

AU - De Nardo, Dominic

AU - Garcia-Perez, Josselyn E.

AU - Dagley, Laura F.

AU - Holley, Caroline L.

AU - Dooley, James

AU - Moghaddas, Fiona

AU - Pasciuto, Emanuela

AU - Jeandel, Pierre-Yves

AU - Sciot, Raf

AU - Lyras, Dena

AU - Webb, Andrew I.

AU - Nicholson, Sandra E.

AU - De Somer, Lien

AU - van Nieuwenhove, Erika

AU - Ruuth-Praz, Julia

AU - Copin, Bruno

AU - Cochet, Emmanuelle

AU - Medlej-Hashim, Myrna

AU - Megarbane, Andre

AU - Schroder, Kate

AU - Savic, Sinisa

AU - Goris, An

AU - Amselem, Serge

AU - Wouters, Carine

AU - Liston, Adrian

PY - 2016/3/30

Y1 - 2016/3/30

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/27030597

U2 - 10.1126/scitranslmed.aaf1471

DO - 10.1126/scitranslmed.aaf1471

M3 - Article

VL - 8

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 332

M1 - 332ra45

ER -

Masters SL, Lagou V, Jeru I, Baker PJ, Van Eyck L, Parry DA et al. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Science Translational Medicine. 2016 Mar 30;8(332). 332ra45. https://doi.org/10.1126/scitranslmed.aaf1471

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