Hereditary angioedema: a current state-of-the-art review, III: mechanisms of hereditary angioedema.
OBJECTIVE
To review the available evidence on the pathophysiologic mechanism of episodes of edema in hereditary angioedema (HAE).


METHODS
MEDLINE and PubMed were searched using the following keywords: hereditary angioedema, C1 inhibitor, complement system, contact system, and bradykinin.


METHODS
Studies were selected based on their relevance to the pathophysiologic features of HAE.


RESULTS
Early studies from the 1970s and 1980s disagreed as to whether the symptoms in HAE were mediated via complement or contact system activation. Studies have demonstrated that, in vitro, in C1 inhibitor (C1-INH)-deficient plasma, only contact system activation results in generation of a vascular permeability enhancing factor. Furthermore, individuals who express a variant C1-INH that is a normal inhibitor of contact system proteases but is deficient in the ability to inactivate complement system proteases do not develop angioedema. The blood of patients with HAE, during attacks, contains elevated levels of cleaved high-molecular-weight kininogen and bradykinin. Last, C1-INH-deficient mice develop increased vascular permeability that is mediated via contact system activation.


CONCLUSIONS
Hereditary angioedema attacks are mediated by bradykinin generated via contact system activation. The specific factors that trigger attacks remain unclear.
Davis
Alvin E
AE
CBR Institute for Biomedical Research, Harvard Medical School, Boston, Massachusetts 02115, USA. aldavis@cbr.med.harvard.edu
D054179:Angioedemas, Hereditary / Q000503:physiopathology*; D000818:Animals; D001920:Bradykinin / Q000096:biosynthesis / Q000097:blood; D050718:Complement C1 Inhibitor Protein / Q000235:genetics / Q000378:metabolism; D015923:Complement C1r / Q000378:metabolism; D003173:Complement C1s / Q000378:metabolism; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D007704:Kininogens / Q000097:blood; D051379:Mice; D018345:Mice, Knockout
D050718:Complement C1 Inhibitor Protein; D007704:Kininogens; D007610:Kallikreins; D015923:Complement C1r; D003173:Complement C1s; D001920:Bradykinin