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.
Clinical Chemistry, Department of Molecular Medicine and Surgery, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
J Allergy Clin Immunol. 2015 Apr;135(4):1031-1043.e6. doi: 10.1016/j.jaci.2014.07.057. Epub 2014 Sep 18.
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.
过敏反应是一种急性、潜在致命的多系统综合征，是由于肥大细胞来源的介质突然释放到循环中引起的。
我们在此报告，血浆蛋白水解酶级联反应，即 XII 因子驱动的接触系统，在小鼠模型和人类受试者中对过敏反应的发病机制具有重要作用。
XII 因子、血浆激肽释放酶、高分子量激肽原或缓激肽 B2 受体的缺乏或药物抑制，而不是 B1 受体，在很大程度上减轻了过敏原/IgE 介导的小鼠肥大细胞高反应性。用人 XII 因子重建 XII 因子缺陷小鼠恢复了对过敏原/IgE 介导的低血压的敏感性。激活的肥大细胞系统性释放肝素，为 XII 因子自动激活提供带负电荷的表面。激活的 XII 因子生成血浆激肽释放酶，其蛋白水解激肽原，导致缓激肽的释放。我们评估了过敏反应患者的接触系统。在所有 10 个血浆样本中，免疫印迹显示在过敏反应的急性期，而不是在基础条件或健康对照中，XII 因子、血浆激肽释放酶和激肽原被激活。过敏反应的严重程度与肥大细胞脱颗粒、血浆肝素水平升高、接触系统激活的强度以及缓激肽的形成有关。
总之，这些数据共同表明接触系统在过敏反应患者中的作用，并支持靶向缓激肽生成和信号转导为过敏反应发作提供新的替代治疗策略的假说。
