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Cold-induced urticarial autoinflammatory syndrome related to factor XII activation

Cold-induced urticarial autoinflammatory syndrome related to factor XII activation
Cold-induced urticarial autoinflammatory syndrome related to factor XII activation
Hereditary autoinflammatory diseases are caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). Here, we report a four-generation family with cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identify a substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Functional analysis reveals enhanced autocatalytic cleavage of the mutated protein and spontaneous FXII activation in patient plasma and in supernatant of transfected HEK293 cells expressing recombinant W268R-mutated proteins. Furthermore, we observe reduced plasma prekallikrein, cleaved high molecular weight kininogen and elevated plasma bradykinin. Neutrophils are identified as a local source of FXII. Interleukin-1β (IL-1β) is upregulated in lesional skin and mononuclear donor cells exposed to recombinant mutant proteins. Treatment with icatibant (bradykinin-B2-antagonist) or anakinra (interleukin-1-antagonist) reduces disease activity in patients. In conclusion, our findings provide a link between contact system activation and cytokine-mediated inflammation.
2041-1723
Scheffel, Jörg
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Mahnke, Niklas A.
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Hofman, Zonne
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de Maat, Steven
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Wu, Jim
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Bonnekoh, Hanna
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Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Ennis, Sarah
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Holloway, John
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Kirchner, Marieluise
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Mertins, Philipp
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Church, Martin
dad189d5-866e-4ae1-b005-0d87f74282b8
Maurer, Marcus
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Maas, Coen
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Krause, Karoline
f0c77186-3c93-4718-9fbe-66cf3d32f095
Scheffel, Jörg
557a8830-af6a-4fcf-a7ba-f262f91e2d46
Mahnke, Niklas A.
80b24a63-5302-4a94-b44d-779d9ec64e37
Hofman, Zonne
0144b1aa-444e-4788-b41d-a43c0ab03720
de Maat, Steven
3bd619f0-c229-47ae-8020-4d01ac040ccb
Wu, Jim
ecaef88b-e548-4648-a554-4acc295756ae
Bonnekoh, Hanna
da12c3f9-00f3-4873-b547-2b56e36ff670
Pengelly, Reuben
af97c0c1-b568-415c-9f59-1823b65be76d
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Holloway, John
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Kirchner, Marieluise
fccbe603-1518-4823-aa1e-09c1c6adfec2
Mertins, Philipp
eee756b9-979b-4ec7-a131-d62cfb58070a
Church, Martin
dad189d5-866e-4ae1-b005-0d87f74282b8
Maurer, Marcus
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Maas, Coen
54f19ec2-8875-47a4-af69-6206b4653d11
Krause, Karoline
f0c77186-3c93-4718-9fbe-66cf3d32f095

Scheffel, Jörg, Mahnke, Niklas A., Hofman, Zonne, de Maat, Steven, Wu, Jim, Bonnekoh, Hanna, Pengelly, Reuben, Ennis, Sarah, Holloway, John, Kirchner, Marieluise, Mertins, Philipp, Church, Martin, Maurer, Marcus, Maas, Coen and Krause, Karoline (2020) Cold-induced urticarial autoinflammatory syndrome related to factor XII activation. Nature Communications, 11 (1), [179]. (doi:10.1038/s41467-019-13984-8).

Record type: Article

Abstract

Hereditary autoinflammatory diseases are caused by gene mutations of the innate immune pathway, e.g. nucleotide receptor protein 3 (NLRP3). Here, we report a four-generation family with cold-induced urticarial rash, arthralgia, chills, headache and malaise associated with an autosomal-dominant inheritance. Genetic studies identify a substitution mutation in gene F12 (T859A, resulting in p.W268R) which encodes coagulation factor XII (FXII). Functional analysis reveals enhanced autocatalytic cleavage of the mutated protein and spontaneous FXII activation in patient plasma and in supernatant of transfected HEK293 cells expressing recombinant W268R-mutated proteins. Furthermore, we observe reduced plasma prekallikrein, cleaved high molecular weight kininogen and elevated plasma bradykinin. Neutrophils are identified as a local source of FXII. Interleukin-1β (IL-1β) is upregulated in lesional skin and mononuclear donor cells exposed to recombinant mutant proteins. Treatment with icatibant (bradykinin-B2-antagonist) or anakinra (interleukin-1-antagonist) reduces disease activity in patients. In conclusion, our findings provide a link between contact system activation and cytokine-mediated inflammation.

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More information

Accepted/In Press date: 5 December 2019
e-pub ahead of print date: 10 January 2020
Published date: 10 January 2020

Identifiers

Local EPrints ID: 436864
URI: http://eprints.soton.ac.uk/id/eprint/436864
ISSN: 2041-1723
PURE UUID: d86298fd-41b1-4cfb-a72c-34f5366186f5
ORCID for Reuben Pengelly: ORCID iD orcid.org/0000-0001-7022-645X
ORCID for Sarah Ennis: ORCID iD orcid.org/0000-0003-2648-0869
ORCID for John Holloway: ORCID iD orcid.org/0000-0001-9998-0464

Catalogue record

Date deposited: 13 Jan 2020 17:30
Last modified: 26 Nov 2021 03:01

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Contributors

Author: Jörg Scheffel
Author: Niklas A. Mahnke
Author: Zonne Hofman
Author: Steven de Maat
Author: Jim Wu
Author: Hanna Bonnekoh
Author: Reuben Pengelly ORCID iD
Author: Sarah Ennis ORCID iD
Author: John Holloway ORCID iD
Author: Marieluise Kirchner
Author: Philipp Mertins
Author: Martin Church
Author: Marcus Maurer
Author: Coen Maas
Author: Karoline Krause

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