Cold-induced urticarial autoinflammatory syndrome related to factor XII activation.
Nat Commun
; 11(1): 179, 2020 01 10.
Article
em En
| MEDLINE
| ID: mdl-31924766
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-1ß (IL-1ß) 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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator XII
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Temperatura Baixa
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Doenças Hereditárias Autoinflamatórias
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article