Cold-induced urticarial autoinflammatory syndrome related to factor XII activation.
Jörg ScheffelNiklas A MahnkeZonne L M HofmanSteven de MaatJim WuHanna BonnekohReuben J PengellySarah EnnisJohn W HollowayMarieluise KirchnerPhilipp MertinsMartin K ChurchMarcus MaurerCoen MaasKaroline KrausePublished in: Nature communications (2020)
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.
Keyphrases
- induced apoptosis
- disease activity
- cell cycle arrest
- innate immune
- rheumatoid arthritis
- systemic lupus erythematosus
- end stage renal disease
- diabetic rats
- oxidative stress
- high glucose
- genome wide
- wild type
- cell free
- ankylosing spondylitis
- chronic kidney disease
- drug induced
- newly diagnosed
- endoplasmic reticulum stress
- protein protein
- binding protein
- ejection fraction
- prognostic factors
- gene expression
- copy number
- cell death
- signaling pathway
- amino acid
- peripheral blood
- cell proliferation
- transcription factor
- nlrp inflammasome
- combination therapy
- case control