Cold-induced urticarial autoinflammatory syndrome related to factor XII activation
Scheffel, Jörg; Mahnke, Niklas A; Hofman, Zonne L M; Maat, Steven de; Wu, Jim; Bonnekoh, Hanna; Pengelly, Reuben J; Ennis, Sarah; Holloway, John W; Kirchner, Marieluise; Mertins, Philipp; Church, Martin K; Maurer, Marcus; Maas, Coen; Krause, Karoline
(2020) Nature Communications, volume 11, issue 1
(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
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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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Keywords: Autoinflammatory syndrome, Coagulation system, Immunogenetics, Medical genetics, General Physics and Astronomy, General Chemistry, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 2041-1723
Publisher: Nature Publishing Group
Note: Funding Information: M.Mau. received consultation fees and research support from Shire/Takeda outside the submitted work. K.K. received research support from Shire/Takeda outside the submitted work. The remaining authors declare no competing interests. Funding Information: This work was supported by the Fritz Thyssen Foundation (to K.K.). M.M. acknowledges support by the DFG (MA1919/14-1). C.M. acknowledges support from the Landsteiner Foundation for Blood Transfusion Research and the Netherlands Thrombosis Foundation. Z.L.H. is supported by the Alexandre Suerman Programme of the Utrecht University Medical Center. We thank Evelin Hagen for excellent technical assistance. Most of all, we would like to thank the family members for their great support and cooperation. Publisher Copyright: © 2020, The Author(s).
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