title: Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions.
abstract: BACKGROUND
  Anaphylaxis is an acute, potentially lethal, multisystem syndrome resulting from the sudden release of mast cell-derived mediators into the circulation.
  
  
  OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Allergy Section, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Sala-Cunill
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jenny
authors.initials: J
authors.lastname: Björkqvist
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Department of Medicine, University of Padova, Padua, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Senter
authors.affiliation: Allergy Section, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Guilarte
authors.affiliation: Allergy Section, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cardona
authors.affiliation: Allergy Section, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Moises
authors.initials: M
authors.lastname: Labrador
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katrin F
authors.initials: KF
authors.lastname: Nickel
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Lynn
authors.initials: L
authors.lastname: Butler
authors.affiliation: Allergy Section, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain; Allergy Research Unit, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Luengo
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Parvin
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Labberton
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Andy
authors.initials: A
authors.lastname: Long
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Gennaro
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ellinor
authors.initials: E
authors.lastname: Kenne
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anne
authors.initials: A
authors.lastname: Jämsä
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Krieger
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Schlüter
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Fuchs
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Flohr
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Hassiepen
authors.affiliation: Novartis Institute for Biomedical Research, Novartis Campus, Basel, Switzerland.
authors.forename: Frederic
authors.initials: F
authors.lastname: Cumin
authors.affiliation: Departments of Hematology and Medical Oncology and Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Keith
authors.initials: K
authors.lastname: McCrae
authors.affiliation: Department of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Coen
authors.initials: C
authors.lastname: Maas
authors.affiliation: Department of Medicine, Hematology and Oncology Division, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio.
authors.forename: Evi
authors.initials: E
authors.lastname: Stavrou
authors.affiliation: Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: thomas@renne.net.
authors.forename: Thomas
authors.initials: T
authors.lastname: Renné
mesh_terms: D000328:Adult; D000368:Aged; D000707:Anaphylaxis / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers; D001920:Bradykinin / Q000378:metabolism; D004195:Disease Models, Animal; D005174:Factor XII / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007022:Hypotension / Q000209:etiology; D007704:Kininogens / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000276:immunology*; D018345:Mice, Knockout; D008875:Middle Aged; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007704:Kininogens; D043782:Receptor, Bradykinin B2; D005174:Factor XII; D001920:Bradykinin
keywords: Anaphylaxis; bradykinin; contact system; mast cell; mouse models; tryptase