title: C1-inhibitor polymers activate the FXII-dependent kallikrein-kinin system: Implication for a role in hereditary angioedema.
abstract: BACKGROUND
  The FXII-dependent kallikrein-kinin system (KKS) is tightly regulated by the serine protease inhibitor (serpin) C1-inhibitor (C1-inh). When regulation of the FXII-dependent KKS fails, which is the case in hereditary angioedema (HAE), patients consequently experience invalidating edema attacks. HAE is caused by mutations in the C1-inh encoding gene, and we recently demonstrated that some mutations give rise to the presence of polymerized C1-inh in the plasma of HAE patients.
  
  
  METHODS
  C1-inh polymers corresponding to the size of polymers observed in vivo were produced using heat denaturation and gel filtration. The ability of these polymers to facilitate FXII activation was assessed in vitro in an FXII activation bandshift assay. After spiking of plasma with C1-inh polymers, kallikrein generation was analyzed in a global kallikrein generation method. Prekallikrein consumption in the entire Danish HAE cohort was analyzed using an ELISA method.
  
  
  RESULTS
  C1-inh polymers mediated FXII activation, and a dose dependent kallikrein generation in plasma spiked with C1-inh polymers. An increased (pre)kallikrein consumption was observed in plasma samples from HAE patients presenting with C1-inh polymers in vivo.
  
  
  CONCLUSIONS
  Polymerization of the C1-inh transforms the major inhibitor of the FXII-dependent KKS, into a potent activator of the very same system.
  
  
  CONCLUSIONS
  The C1-inh polymers might play a role in the pathophysiology of HAE, but several diseases are characterized by the presence of serpin polymers. The role of serpin polymers has so far remained elusive, but our results indicate that such polymers can play a role as inflammatory mediators through the FXII-dependent KKS.
authors: University of Southern Denmark, Institute of Public Health, Unit for Thrombosis Research, Niels Bohrs Vej 9-10, 6700 Esbjerg, Denmark. Electronic address: daniel@elenius.eu.
authors: Daniel Elenius
authors: DE
authors: Madsen
authors: University of Southern Denmark, Institute of Public Health, Unit for Thrombosis Research, Niels Bohrs Vej 9-10, 6700 Esbjerg, Denmark.
authors: Johannes Jakobsen
authors: JJ
authors: Sidelmann
authors: University of Southern Denmark, Institute of Public Health, Unit for Thrombosis Research, Niels Bohrs Vej 9-10, 6700 Esbjerg, Denmark.
authors: Daniel
authors: D
authors: Biltoft
authors: University of Southern Denmark, Institute of Public Health, Unit for Thrombosis Research, Niels Bohrs Vej 9-10, 6700 Esbjerg, Denmark.
authors: Jørgen
authors: J
authors: Gram
authors: University of Southern Denmark, Institute of Molecular Medicine, Department of Cancer and Inflammation Research, J.B. Winsløws Vej 21, 5000 Odense C, Denmark.
authors: Soren
authors: S
authors: Hansen
mesh_terms: D054179:Angioedemas, Hereditary / Q000097:blood* / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D015153:Blotting, Western; D016022:Case-Control Studies; D003174:Complement C1 Inactivator Proteins / Q000235:genetics / Q000378:metabolism*; D050718:Complement C1 Inhibitor Protein; D003718:Denmark; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D015956:Factor XIIa / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D007610:Kallikreins / Q000097:blood*; D007700:Kinetics; D007705:Kinins / Q000097:blood*; D009154:Mutation; D063347:Native Polyacrylamide Gel Electrophoresis; D010641:Phenotype; D058105:Polymerization
chemical_list: D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D007705:Kinins; C469952:SERPING1 protein, human; D007610:Kallikreins; D015956:Factor XIIa
keywords: Coagulation factor XII; Complement C1 esterase inhibitor; Hereditary angioedema; Kallikrein-kinin system; Polymerization; Serpinopathy