Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis

Lysann Bender, Henri Weidmann, Stefan Rose-John, Thomas Renné, Andy T. Long

Anaphylaxis is a life-threatening allergic reaction. It is triggered by the release of pro-inflammatory cytokines and mediators from mast cells and basophils in response to immunologic or non-immunologic mechanisms. Mediators that are released upon mast cell activation include the highly sulfated polysaccharide and inorganic polymer heparin and polyphosphate (polyP), respectively. Heparin and polyP supply a negative surface for factor XII (FXII) activation, a serine protease that drives contact system-mediated coagulation and inflammation. Activation of the FXII substrate plasma kallikrein leads to further activation of zymogen FXII and triggers the pro-inflammatory kallikrein-kinin system that results in the release of the mediator bradykinin (BK). The severity of anaphylaxis is correlated with the intensity of contact system activation, the magnitude of mast cell activation, and BK formation. The main inhibitor of the complement system, C1 esterase inhibitor, potently interferes with FXII activity, indicating a meaningful cross-link between complement and kallikrein-kinin systems. Deficiency in a functional C1 esterase inhibitor leads to a severe swelling disorder called hereditary angioedema (HAE). The significance of FXII in these disorders highlights the importance of studying how these processes are integrated and can be therapeutically targeted. In this review, we focus on how FXII integrates with inflammation and the complement system to cause anaphylaxis and HAE as well as highlight current diagnosis and treatments of BK-related diseases.