Plasma contact system activation drives anaphylaxis in severe mast cell–mediated allergic reactions

• Published in: Journal of allergy and clinical immunology Vol. 135; no. 4; pp. 1031 - 1043.e6
• Main Authors: Sala-Cunill, Anna, Björkqvist, Jenny, Senter, Riccardo, Guilarte, Mar, Cardona, Victoria, Labrador, Moises, Nickel, Katrin F., Butler, Lynn, Luengo, Olga, 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, McCrae, Keith, Maas, Coen, Stavrou, Evi, Renné, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2015; Elsevier Limited
• Subjects: Adult; Aged; Allergies; Allergy and Immunology; Anaphylaxis; Anaphylaxis - complications; Anaphylaxis - genetics; Anaphylaxis - immunology; Anaphylaxis - metabolism; Animals; Biomarkers; bradykinin; Bradykinin - metabolism; contact system; Disease Models, Animal; Factor XII - antagonists & inhibitors; Factor XII - genetics; Factor XII - metabolism; Female; Food allergies; Humans; Hypersensitivity - complications; Hypersensitivity - genetics; Hypersensitivity - immunology; Hypersensitivity - metabolism; Hypotension - etiology; Kininogens - metabolism; Male; mast cell; Mast Cells - immunology; Mice, Knockout; Middle Aged; mouse models; Plasma; Receptor, Bradykinin B2 - genetics; Receptor, Bradykinin B2 - metabolism; Rodents; Signal Transduction; Stem cells; Time Factors; tryptase; Young Adult; mouse models; MABP; NO; B1R; HK; Anti-Xa; Bdkrb2; Klkb1; PRCP; Bdkrb1; Kng1; Anaphylaxis; FXII; WT; aPTT; B2R; ACE; mast cell; bradykinin; IQR; FXIIa; HAE; contact system; DNP-HSA; C1INH; FXI; PCK; PK; tryptase; Factor XI; Activated partial thromboplastin time; Plasma kallikrein; Dinitrophenyl–human serum albumin; B2R coding gene; High-molecular-weight kininogen coding murine gene; Wild-type; H-D-Pro-Phe-Arg-chloromethyl ketone; Mean arterial blood pressure; Nitric oxide; Interquartile range; Angiotensin-converting enzyme; Bradykinin B1 receptor; High-molecular-weight kininogen; Plasma kallikrein coding gene; C1 esterase inhibitor; Bradykinin B2 receptor; Activated factor XII; B1R coding gene; Prolylcarboxypeptidase; Factor XII; Hereditary angioedema; Anti–factor Xa activity
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.07.057

Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell–derived mediators into the circulation. We report here that a plasma protease cascade, the factor XII–driven contact system, critically contributes to the pathogenesis of anaphylaxis in both murine models and human subjects. Deficiency in or pharmacologic inhibition of factor XII, plasma kallikrein, high-molecular-weight kininogen, or the bradykinin B2 receptor, but not the B1 receptor, largely attenuated allergen/IgE-mediated mast cell hyperresponsiveness in mice. Reconstitutions of factor XII null mice with human factor XII restored susceptibility for allergen/IgE-mediated hypotension. Activated mast cells systemically released heparin, which provided a negatively charged surface for factor XII autoactivation. Activated factor XII generates plasma kallikrein, which proteolyzes kininogen, leading to the liberation of bradykinin. We evaluated the contact system in patients with anaphylaxis. In all 10 plasma samples immunoblotting revealed activation of factor XII, plasma kallikrein, and kininogen during the acute phase of anaphylaxis but not at basal conditions or in healthy control subjects. The severity of anaphylaxis was associated with mast cell degranulation, increased plasma heparin levels, the intensity of contact system activation, and bradykinin formation. In summary, the data collectively show a role of the contact system in patients with anaphylaxis and support the hypothesis that targeting bradykinin generation and signaling provides a novel and alternative treatment strategy for anaphylactic attacks.