title: Angioedema attacks in patients with hereditary angioedema: Local manifestations of a systemic activation process.
abstract: Hereditary angioedema (HAE) caused by a deficiency of functional C1-inhibitor (C1INH) becomes clinically manifest as attacks of angioedema. C1INH is the main inhibitor of the contact system. Poor control of a local activation process of this system at the site of the attack is believed to lead to the formation of bradykinin (BK), which increases local vasopermeability and mediates angioedema on interaction with BK receptor 2 on the endothelium. However, several observations in patients with HAE are difficult to explain from a pathogenic model claiming a local activation process at the site of the angioedema attack. Therefore we postulate an alternative model for angioedema attacks in patients with HAE, which assumes a systemic, fluid-phase activation of the contact system to generate BK and its breakdown products. Interaction of these peptides with endothelial receptors that are locally expressed in the affected tissues rather than with receptors constitutively expressed by the endothelium throughout the whole body explains that such a systemic activation process results in local manifestations of an attack. In particular, BK receptor 1, which is induced on the endothelium by inflammatory stimuli, such as kinins and cytokines, meets the specifications of the involved receptor. The pathogenic model discussed here also provides an explanation for why angioedema can occur at multiple sites during an attack and why HAE attacks respond well to modest increases of circulating C1INH activity levels because inhibition of fluid-phase Factor XIIa and kallikrein requires lower C1INH levels than inhibition of activator-bound factors.
authors.affiliation: Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Zonne L M
authors.initials: ZL
authors.lastname: Hofman
authors.affiliation: Pharming Technologies BV, Leiden, The Netherlands.
authors.forename: Anurag
authors.initials: A
authors.lastname: Relan
authors.affiliation: Department Immunopathology, Sanquin Research, and the Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: Zeerleder
authors.affiliation: University Joseph Fourier, Grenoble, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Drouet
authors.affiliation: Department of Medicine, University of California San Diego, and San Diego VA Healthcare, La Jolla, Calif.
authors.forename: Bruce
authors.initials: B
authors.lastname: Zuraw
authors.affiliation: Laboratory for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: C.E.Hack@UMCUtrecht.nl.
authors.forename: C Erik
authors.initials: CE
authors.lastname: Hack
mesh_terms: D054179:Angioedemas, Hereditary / Q000175:diagnosis* / Q000209:etiology*; D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D050718:Complement C1 Inhibitor Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D040542:Mechanotransduction, Cellular; D010641:Phenotype; D011485:Protein Binding; D018002:Receptors, Bradykinin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D050718:Complement C1 Inhibitor Protein; D018002:Receptors, Bradykinin; D001920:Bradykinin
keywords: Hereditary angioedema; angioedema attack; complement system; contact system; efficacy; human C1-inhibitor