Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis

Abstract

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.

Penicillin causes non-allergic anaphylaxis by activating the contact system

“…The severity of anaphylaxis is correlated with the intensity of CSA and BK formation 20 . The abnormal production of BK leads to anaphylaxis and angioedema via its ability to increase inflammation and vessel permeability 21 , 45 . There are common triggers for anaphylactic reactions such as food, medications or insect venom, of which 44–57% of the fatal anaphylaxis was triggered by medications, far more than other inducements 3 , 46 – 48 .…”

“…The name “contact system” comes from the mode of FXII being activated, as “contact” with negatively charged surfaces triggers FXII activation via conformational rearrangement. Activators that initiate FXIIa formation in vivo include polyphosphate, heparin, misfolded proteins, collagen, nucleic acids (DNA and RNA), oversulfated chondroitin sulfate and artificial surfaces 21 , 22 .…”

Polyphosphate as a Target for Interference With Inflammation and Thrombosis

“…Impaired FXIIa inhibition augments BK formation by the kallikrein-kinin system and is associated with a BK-mediated life-threatening inherited swelling disorder, hereditary angioedema (HAE) [reviewed in (109)]. C1INH deficiency has no impact on thrombosis and HAE patients have a normal thromboembolic risk [reviewed in (110)]. HAE is a rare disease that is mainly autosomal dominant inherited and characterized by reduced C1INH levels (HAE type I) or function (HAE type II).…”

Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics

“…A number of studies have established that the inhibition of FXII activity reduces the formation of pathological thrombi without compromising physiological haemostasis in both murine and primate models of cardiovascular disease (Renné et al, 2012;Kleinschnitz et al, 2006;Matafonov et al, 2014). FXII has also been implicated in inflammatory pathways (Hess et al, 2017;Bender et al, 2017) and in hereditary angioedema via the identification of a gainof-function mutation in the F12 gene (which encodes FXII) that results in excessive formation of BK (Cichon et al, 2006).…”