Publication date: Available online 6 April 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Steven de Maat, Jenny Björkqvist, Chiara Suffritti, Chantal P. Wiesenekker, Willem Nagtegaal, Arnold Koekman, Sanne van Dooremalen, Gerard Pasterkamp, Philip G. de Groot, Marco Cicardi, Thomas Renné, Coen Maas
BackgroundPatients with angioedema develop unpredictable attacks of tissue swelling in which bradykinin is implicated. Several distinct mutations in factor XII (FXII) are associated with hereditary angioedema in the presence of normal C1 esterase inhibitor activity (FXII-HAE). The underlying disease mechanisms are unclear, which complicates diagnosis and treatment.ObjectiveTo identify the natural trigger for FXII activation that causes uncontrolled bradykinin production in FXII-HAE.MethodsWe generated recombinant variants of FXII, representing health and disease, and studied their behavior in functional studies. We investigated bradykinin-forming pathways in blood plasma with newly developed nanobody-based analytical methods.ResultsWe here report that FXII-HAE mutations collectively introduce new sites that are sensitive to enzymatic cleavage by plasmin. These FXII mutants rapidly activate after cleavage by plasmin, escape from inhibition by C1 esterase inhibitor and elicit excessive bradykinin formation. Furthermore, our findings indicate that plasmin modulates disease activity in FXII-HAE patients. Finally, we show that soluble lysine analogs attenuate this mechanism, explaining their therapeutic value in HAE.ConclusionOur findings indicate a new pathway for bradykinin formation in HAE, in which FXII is cleaved and activated by plasmin. This should lead to the identification of new markers for diagnosis and targets for treatment.
Teaser
Excessive bradykinin production in FXII-HAE occurs when the enzyme plasmin activates factor XII. This interaction can be specifically targeted with therapeutic lysine analogs, like tranexamic acid or epsilon aminocaproic acid.from #ENT via xlomafota13 on Inoreader http://ift.tt/23kne3t
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