Cold-induced urticarial autoinflammatory syndrome related to factor XII activation

Jörg Scheffel, Niklas A. Mahnke, Zonne L. M. Hofman, Steven de Maat, Jim Wu, Hanna Bonnekoh, Reuben J. Pengelly, Sarah Ennis, John W. Holloway, Marieluise Kirchner, Philipp Mertins, Martin K. Church, Marcus Maurer (), Coen Maas and Karoline Krause
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Jörg Scheffel: Charité — Universitätsmedizin Berlin
Niklas A. Mahnke: Charité — Universitätsmedizin Berlin
Zonne L. M. Hofman: University Medical Center Utrecht, Department of Clinical Chemistry and Haematology
Steven de Maat: University Medical Center Utrecht, Department of Clinical Chemistry and Haematology
Jim Wu: Charité — Universitätsmedizin Berlin
Hanna Bonnekoh: Charité — Universitätsmedizin Berlin
Reuben J. Pengelly: Human Genetics & Genomic Medicine, Faculty of Medicine, University of Southampton, University Hospitals Southampton, Southampton
Sarah Ennis: Human Genetics & Genomic Medicine, Faculty of Medicine, University of Southampton, University Hospitals Southampton, Southampton
John W. Holloway: Human Genetics & Genomic Medicine, Faculty of Medicine, University of Southampton, University Hospitals Southampton, Southampton
Marieluise Kirchner: Proteomics Platform, Berlin Institute of Health (BIH) and Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Philipp Mertins: Proteomics Platform, Berlin Institute of Health (BIH) and Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Martin K. Church: Charité — Universitätsmedizin Berlin
Marcus Maurer: Charité — Universitätsmedizin Berlin
Coen Maas: University Medical Center Utrecht, Department of Clinical Chemistry and Haematology
Karoline Krause: Charité — Universitätsmedizin Berlin

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13984-8

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