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Cold-induced urticarial autoinflammatory syndrome related to factor XII activation

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Item Type:Article
Title:Cold-induced urticarial autoinflammatory syndrome related to factor XII activation
Creators Name:Scheffel, J. and Mahnke, N.A. and Hofman, Z.L.M. and Maat, S.d. and Wu, J. and Bonnekoh, H. and Pengelly, R.J. and Ennis, S. and Holloway, J.W. and Kirchner, M. and Mertins, P. and Church, M.K. and Maurer, M. and Maas, C. and Krause, K.
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.
Keywords:Blood Coagulation, Bradykinin, Cold Temperature, Factor XII, HEK293 Cells, Hereditary Autoinflammatory Diseases, High-Molecular-Weight Kininogen, Inflammation Mediators, Interleukin 1 Receptor Antagonist Protein, Interleukin-1beta, Mutation, Neutrophils, Pedigree, Phenotype, Plasma Kallikrein, Pyrin Domain-Containing 3 Protein NLR Family, Recombinant Proteins, Skin
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:179
Date:10 January 2020
Official Publication:https://doi.org/10.1038/s41467-019-13984-8
PubMed:View item in PubMed

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