Sala-Cunill, Anna, Björkqvist, Jenny, Senter, Riccardo, Guilarte, Mar, Cardona, Victoria, Labrador, Moises, Nickel, Katrin F., Lynn, Butler, Olga, Luengo, Kumar, Parvin, Labberton, Linda, Long, Andy, Di Gennaro, Antonio, Kenne, Ellinor, Jämsä, Anne, Krieger, Thorsten, Schlüter, Hartmut, Fuchs, Tobias, Flohr, Stefanie, Hassiepen, Ulrich, Cumin, Frederic, McCrea, Keith, Maas, Coen, Stavrou, Evi and Renné, Thomas (2014) ACTIVATION OF THE PLASMA CONTACT SYSTEM IN ANAPHYLAXIS – INSIGHT TO SEVERE MAST CELL-MEDIATED ALLERGIC REACTIONS. Journal of Allergy and Clinical Immunology, 135 (4). pp. 1031-1043. ISSN 00916749

Abstract

Background: Anaphylaxis is an acute, potentially lethal, multi-system syndrome resulting from the sudden release of mast cell-derived mediators into the circulation.
Objectives & Methods: We report here that a plasma protease cascade, the factor XII (FXII)-driven contact system critically contributes to the pathogenesis of anaphylaxis in murine models and in human subjects.
Results: Deficiency in or pharmacologic inhibition of FXII, plasma kallikrein, high molecular mass kininogen (HK) or the bradykinin B2 receptor, but not B1 receptor, largely attenuated allergen/Immunoglobulin E-mediated mast cell hyper-responsiveness in mice.Reconstitutions of FXII null mice with human FXII restored susceptibility for allergen/Immunoglobulin E triggered drop in blood pressure. Activated mast cells systemically released heparin that provided a negatively-charged surface for FXII autoactivation. Activated FXII generates plasma kallikrein, which proteolyzes HK leading to the liberation of bradykinin. We evaluated the contact system in patients with anaphylaxis. In all 10 plasma samples immunoblotting revealed activation of FXII, plasma kallikrein and HK during the acute phase of anaphylaxis, but not at basal conditions nor in healthy controls. The severity of anaphylaxis was associated with mast cell degranulation, elevated plasma heparin levels, the intensity of contact system activation and bradykinin formation, respectively.
Conclusions: In summary, the data collectively show a role of the contact system in anaphylaxis and support the hypothesis that targeting bradykinin generation and signaling provides a novel and alternative treatment strategy for anaphylactic attacks.

Item Type:	Article
Keywords:	Anaphylaxis, Mast cell, Bradykinin, Mouse models, Tryptase, Contact system
Date Deposited:	26 Apr 2016 23:45
Last Modified:	06 Jul 2016 23:45
URI:	https://oak.novartis.com/id/eprint/22854