Bradykinin and the Pathogenesis of Hereditary Angioedema

This article was originally published online on 15 April 2011 Hereditary angioedema (HAE) is a term coined for a familial form of potentially life-threatening angioedema first described by William Osler in 1888. It is inherited as an autosomal dominant and the older literature often employs the term angioneurotic edema because it was believed that swelling could be a consequence of an emotional disorder. This type of angioedema, in particular, often included family histories of death by asphyxiation so that family members appeared "neurotic," that is, overly fearful, anxious, depressed, and so on. It also turns out that episodes of angioedema may well be triggered by emotional events in addition to other known triggers such as trauma, infection, and estrogen-containing hormones, but the biochemical explanation for this is not yet known. However, the conception of the disorder changed in 1953 when Donaldson and Evans discovered that it is due to a mutation in a plasma enzyme inhibitor known as C1 inhibitor (C1 INH) 1.Donaldson V.H. Evans R.R. A biochemical abnormality in hereditary angioneurotic edema.Am J Med. 1963; 35: 37-44Abstract Full Text PDF PubMed Scopus (680) Google Scholar. It was then assumed that some vasoactive mediator from the complement system was the proximate cause of the angioedema. The next era dealt with attempts to identify this vasoactive factor. It then became clear that his inhibitor could inactivate enzymes that are not part of the complement cascade. The first discovery was that it inhibited plasma kallikrein 2.Gigli I. Mason J.W. Colman R.W. Austen K.F. Interaction of plasma kallikrein with the C1 inhibitor.J Immunol. 1970; 104: 574-581PubMed Google Scholar, an enzyme that cleaves a plasma kininogen to produce bradykinin. At that point, no one seriously considered bradykinin as a possible cause of the swelling. The focus was on a kinin thought to be derived from the complement cascade termed C2 kinin. The key experiment, published in a nonrefereed journal 3.Donaldson V.H. Rosen F.S. Bing D.H. Role of the second component of complement (C2) and plasmin in kinin release in hereditary angioneurotic edema (H.A.N.E.) plasma.Trans Assoc Am Physicians. 1977; 90: 174-183PubMed Google Scholar, was that activated C1 will cleave C2 (in the presence of C4 as a cofactor) to yield C2a + C2b, and that plasmin digestion of C2b would produce a kinin that could be distinguished from bradykinin by its inactivation by tryptic digestion. It could be assayed by contraction of an estrous rat uterus or with lesser sensitivity (but greater reliability), employing a guinea pig ileum. This observation was never confirmed by other workers but additional observations seemed to substantiate the idea. Studies of vascular permeability in human and rabbit skin indicated that injection of activated C1 led to increased vascular permeability that required C2; the swelling was augmented when skin testing of patients with hereditary angioedema was compared with normal controls 4.Strang C.J. Auerbach H.S. Rosen F.S. C1s-induced vascular permeability in C2-deficient guinea pigs.J Immunol. 1986; 137: 631-635PubMed Google Scholar. There was even one publication by Donaldson 5.Donaldson V.H. Mechanisms of activation of C'1 esterase in hereditary angioneurotic edema plasma in vitro.J Exp Med. 1968; 127: 411-429Crossref PubMed Scopus (78) Google Scholar suggesting a linkage between activated Factor XII (activated Hageman factor) and activation of the complement cascade so that simultaneous production of bradykinin (inhibited by Factor XII activation) and the C2-kinin seemed possible. During the years 1972-1990 I was studying the mechanism of activation of the plasma bradykinin cascade. Two forms of activated Factor XII were described, that is, Factor XIIa at about 80 kd and Factor XII fragment (XIIf) at 28.5-30 kd 6.Kaplan A.P. Austen K.F. A pre-albumin activator of prekallikrein.J Immunol. 1970; 105: 802-811PubMed Google Scholar, 7.Kaplan A.P. Austen K.F. A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin.J Exp Med. 1971; 133: 696-712Crossref PubMed Scopus (215) Google Scholar; soon thereafter, the Factor XII native protein was purified 8.Cochrane C.G. Wuepper K.D. The first component of the kinin-forming system in human and rabbit plasma. Its relationship to clotting factor XII (Hageman Factor).J Exp Med. 1971; 134: 986-1004Crossref PubMed Scopus (84) Google Scholar. Factor XIIa or Factor XIIf was shown to be required for kallikrein activity to be produced in plasma; prekallikrein was purified 9.Mandle Jr, R. Kaplan A.P. Hageman factor substrates. Human plasma prekallikrein: mechanism of activation by Hageman factor and participation in Hageman factor-dependent fibrinolysis.J Biol Chem. 1977; 252: 6097-6104PubMed Google Scholar, and its mechanism of conversion to kallikrein described. A controversy regarding the number of kininogens in plasma was resolved to indicate that there is a high molecular weight kininogen (HK) that is rather selectively cleaved by plasma kallikrein 10.Wuepper K.D. Miller D.R. Lacombe M.J. Flaujeac trait. Deficiency of human plasma kininogen.J Clin Invest. 1975; 56: 1663-1672Crossref Scopus (136) Google Scholar, 11.Colman R.W. Bagdasarian A. Talamo R.C. et al.Williams trait. Human kininogen deficiency with diminished levels of plasminogen proactivator and prekallikrein associated with abnormalities of the Hageman factor-dependent pathways.J Clin Invest. 1975; 56: 1650-1662Crossref Scopus (222) Google Scholar to yield bradykinin, whereas low molecular weight kininogen is preferentially cleaved by tissue kallikrein to produce lysylbradykinin (kallidin). About 80% of plasma kallikrein was found to circulate as a complex with HK 12.Mandle R.J. Colman R.W. Kaplan A.P. Identification of prekallikrein and high-molecular-weight kininogen as a complex in human pl.Proc Natl Acad Sci. 1976; 73: 4179-4183Crossref PubMed Scopus (284) Google Scholar and the distal light chain segment of HK was shown to be the feature that distinguishes it from low molecular weight kininogen (LK). This HK domain has the site of prekallikrein binding 13.Thompson R.E. Mandle Jr, R. Kaplan A.P. Characterization of human high molecular weight kininogen. Procoagulant activity associated with the light chain of kinin-free high molecular weight kininogen.J Exp Med. 1978; 147: 488-499Crossref PubMed Scopus (86) Google Scholar, 14.Thompson R.E. Mandle Jr, R. Kaplan A.P. Studies of binding of prekallikrein and Factor XI to high molecular weight kininogen and its light chain.Proc Natl Acad Sci USA. 1979; 76: 4862-4866Crossref PubMed Scopus (74) Google Scholar and the site responsible for the cofactor activity of HK, which accelerates the conversion of prekallikrein to kallikrein and also conversion of coagulation factor XI to factor XIa 14.Thompson R.E. Mandle Jr, R. Kaplan A.P. Studies of binding of prekallikrein and Factor XI to high molecular weight kininogen and its light chain.Proc Natl Acad Sci USA. 1979; 76: 4862-4866Crossref PubMed Scopus (74) Google Scholar. Activation of the bradykinin-forming cascade was known to occur upon binding to negatively charged surfaces (eg, a glass test tube to clot blood) and this acceleration by surface binding was studied in some detail 15.Griffin J.H. Role of surface in surface-dependent activation of Hageman factor (blood coagulation factor XII).Proc Natl Acad Sci USA. 1978; 75: 1998-2002Crossref PubMed Scopus (198) Google Scholar, 16.Tankersley D.L. Finlayson J.S. Kinetics of activation and autoactivation of human factor XII.Biochemistry. 1984; 23: 273-279Crossref PubMed Scopus (140) Google Scholar. Factor XII was shown to autoactivate upon binding 17.Silverberg M. Dunn J.T. Garen L. Kaplan A.P. Autoactivation of human Hageman factor. Demonstration utilizing a synthetic substrate.J Biol Chem. 1980; 255: 7281-7286Abstract Full Text PDF PubMed Google Scholar so a molecular mechanism for initiation of the cascade seemed to be in place. From the onset of these studies, in the late 1970s, I was of the opinion that bradykinin is the mediator of the swelling seen in hereditary angioedema and that C2 kinin might be an artifact. My bias was based on a conversation with Frank Austen that occurred when the C2 kinin data were presented at a plenary session of The Association of American Physicians and I was seated in the audience. A rat uterus-based bioassay was used to demonstrate the new kinin and I had been trying to use such an assay to measure bradykinin for months. Its baseline was poor, it contracted when agonist (any agonist, at times including the buffer control) was added to the bath solution, and I could not be sure what was real and what was not. I switched to using a guinea pig ileum. I looked at the data being presented, I turned to Frank Austen, who was sitting next to me, and exclaimed, "That's an artifact!" I could not, however, explain the C2-dependent increase in vascular permeability reported by skin testing and am not sure I could do so even now. One issue is that anything injected into hereditary angioedema skin will produce bradykinin because of the trauma. It was by then clear that all enzymes required for the production of bradykinin are inhibited by C1 inhibitor 18.Schreiber A.D. Kaplan A.P. Austen K.F. Inhibition by C1INH of Hagemann factor fragment activation of coagulation, fibrinolysis, and kinin generation.J Clin Invest. 1973; 52: 1402-1409Crossref PubMed Scopus (124) Google Scholar and that active kallikrein was demonstrable within induced blisters of HAE patients 19.Curd J.G. Prograis Jr, L.J. Cochrane C.G. Detection of active kallikrein in induced blister fluids of hereditary angioedema patients.J Exp Med. 1980; 152: 742-747Crossref PubMed Scopus (113) Google Scholar. Nevertheless, in 1983 I decided to try to reproduce these experiments demonstrating plasmin cleavage of C2a or C2b to generate a kinin-like molecule. We activated C1 by immune complexes in the presence of C4 and C2, added plasmin, and could not demonstrate any kinin 20.Fields T. Ghebrehiwet B. Kaplan A.P. Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of "spontaneous" formation of bradykinin.J Allergy Clin Immunol. 1983; 72: 54-60Abstract Full Text PDF PubMed Scopus (172) Google Scholar. By contrast, incubation of HAE plasma, collected in EDTA to inhibit kininases, generated increasing amounts of bradykinin even in the absence of an initiating surface 20.Fields T. Ghebrehiwet B. Kaplan A.P. Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of "spontaneous" formation of bradykinin.J Allergy Clin Immunol. 1983; 72: 54-60Abstract Full Text PDF PubMed Scopus (172) Google Scholar, whereas normal plasma generated nothing. Thus, plasma deficient in C1 INH was unstable and activated seemingly spontaneously to generate bradykinin upon in vitro incubation. We concluded that C2-kinin is not present, implied that it does not exist, and stated that bradykinin is the likely mediator of swelling in HAE. A subsequent publication found a 25 amino acid peptide with permeability increasing properties within the C2 amino acid sequence, but it is not released by any known peptide 21.Strang C.J. Cholin S. Spragg J. Davis A.E. Schneeberger E.E. Donaldson V.H. Rosen F.S. Angioedema induced by a peptide derived from complement component C2.J Exp Med. 1988; 168: 1685-1698Crossref PubMed Scopus (61) Google Scholar. Because C2-kinin and bradykinin were the only 2 possibilities considered as possible mediators of the swelling of HAE and the data upon which C2-kinin was based could not be reproduced, bradykinin would be the "answer." But not being mathematicians (who accept disproving 1 of 2 possible choices as answering the question), this conclusion was not accepted until an additional 15 years passed, even after the nonexistence of C2-kinin was confirmed by a second study 22.Smith M. Kerr M. Cleavage of the second component of complement by plasma proteases: implications in hereditary C1-inhibitor deficiency.Immunology. 1985; 56: 561-570Google Scholar. Finally, years later bradykinin was accepted to be the cause of the swelling of HAE after the following studies were reported 1.Donaldson V.H. Evans R.R. A biochemical abnormality in hereditary angioneurotic edema.Am J Med. 1963; 35: 37-44Abstract Full Text PDF PubMed Scopus (680) Google Scholar. A confirmation of our 1983 paper demonstrated that bradykinin is the only vasoactive kinin generated in HAE plasma assayed by vascular permeability or radioimmunoassay and anti-C2 could not prevent the phenomenon 23.Shoemaker L.R. Schurman S.J. Donaldson V.H. Davis A.E. Hereditary angioneurotic oedema: characterization of plasma kinin and vascular permeability-enhancing activities.Clin Exp Immunol. 1994; 95: 22-28Crossref PubMed Scopus (104) Google Scholar, 2.Gigli I. Mason J.W. Colman R.W. Austen K.F. Interaction of plasma kallikrein with the C1 inhibitor.J Immunol. 1970; 104: 574-581PubMed Google Scholar. A rodent model in which C1 INH was knocked could be "cured" not only by repleting the C1 INH but also by knocking out the bradykinin B-2 receptor 24.Han E.D. MacFarlane R.C. Mulligan A.N. Scafidi J. Davis A.E. Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor.J Clin Invest. 2002; 109: 1057-1063Crossref PubMed Scopus (308) Google Scholar, 3.Donaldson V.H. Rosen F.S. Bing D.H. Role of the second component of complement (C2) and plasmin in kinin release in hereditary angioneurotic edema (H.A.N.E.) plasma.Trans Assoc Am Physicians. 1977; 90: 174-183PubMed Google Scholar. Bradykinin levels are elevated locally at the site of swelling in HAE 25.Nussberger J. Cugno M. Cicardi M. Agostoni A. Local bradykinin generation in hereditary angioedema.J Allergy Clin Immunol. 1999; 104: 1321-1322Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 4.Strang C.J. Auerbach H.S. Rosen F.S. C1s-induced vascular permeability in C2-deficient guinea pigs.J Immunol. 1986; 137: 631-635PubMed Google Scholar. A unique family in which a mutation of C1 INH renders it inactive on activated C1 but normally active as an inhibitor of the enzymes of the bradykinin-forming cascade (ie, Factor XIIa, Factor XIIf, and kallikrein) has no episodes of angioedema in any family members 26.Zahedi R. Bissler J.J. Davis A.E. Andreadis C. Wisnieski J.J. Unique C1 inhibitor dysfunction in a kindred without angioedema. II. Identification of an Ala443- > Val substitution and functional analysis of the recombinant mutant protein.J Clin Invest. 1995; 95: 1299-1305Crossref PubMed Scopus (62) Google Scholar. Curiously, review articles during this period often mentioned C2-kinin as a viable alternative to bradykinin as the key mediator, and I wrote an editorial entitled "Does C2-kinin exist," indicating, in detail, why it does not 27.Kaplan A. Ghebrehiwet B. Does C-2 kinin exist?.J Allergy Clin Immunol. 2004; 115: 876Abstract Full Text Full Text PDF Scopus (13) Google Scholar. Until someone else shows it existence, and that it has some role in HAE based on experimental evidence, it should not be mentioned in anything but an historical context and it should certainly not be included in diagrams dealing with the pathogenesis of HAE. The notion that bradykinin is the mediator of HAE has lead to therapeutic advances that specifically target the Factor XII-prekallikrein HK-bradykinin cascade. Of course, repleting C1 INH by infusion can be employed to control acute episodes of swelling and for prophylaxis 28.Zuraw B.L. Busse P.J. White M. Jacobs J. Lumry W. et al.Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema.N Engl J Med. 2010; 363: 513-522Crossref PubMed Scopus (362) Google Scholar. When prophylaxis is considered, C1 INH infusion may replace attenuated androgens primarily because it eliminates the possibility of cumulative androgen side effects, although it is far more costly. C1 INH does require intravenous infusion but having home access to treatment is an important step forward. Perhaps a subcutaneous preparation will be seen in the future as has occurred with intravenous immunoglobulin. Therapy for acute episodes of swelling now include ecallantide, a plasma kallikrein inhibitor 29.Cicardi M. Levy R.J. McNeil D.L. Li H.H. Sheffer A.L. et al.Ecallantide for the treatment of acute attacks in hereditary angioedema.N Engl J Med. 2010; 363: 523-531Crossref PubMed Scopus (262) Google Scholar, and Icatibant 30.Cicardi M. Banerji A. Bracho F. Malbran A. Rosenkranz B. et al.Icatibant, a new bradykinin receptor antogonist in hereditary angioedema.N Engl J Med. 2010; 363: 532-541Crossref PubMed Scopus (456) Google Scholar, a B-2 bradykinin receptor antagonist. These have a short half-life and therefore cannot be used for prophylaxis. They are administered subcutaneously and can be repeated within an hour should control of symptoms be suboptimal. Both are quite effective, particularly if given early at the onset of an episode, and can abort symptoms of peripheral angioedema, gastrointestinal attacks, and laryngeal edema. At present, ecallantide is approved in the United States and Icatibant is approved in Europe. The efficacy of these drugs add to the cumulative data demonstrating this bradykinin-forming cascade as the one responsible for symptoms despite the fact that the complement is activated. In fact, C1 is unstable in the absence of C1 INH so that C4 is continually being cleaved, and if synthesis does not keep up, a low C4 level will result. Thus, quantitation of C4 is a good screening determination, along with measurement of C1 INH by protein and function C4 is low 95% of the time in HAE patients who are asymptomatic; C2 remains normal. However, during an attack of swelling formation of Factor XIIf 31.Ghebrehiwet B. Randazzo B.P. Dunn J.T. Silverberg M. Kaplan A.P. Mechanisms of activation of the classical pathway of complement by Hageman factor fragment.J Clin Invest. 1983; 71: 1450-1456Crossref PubMed Scopus (166) Google Scholar directly activates the C1r subcomponent of complement so that further lowering of C4 occurs during episodes of swelling which approaches zero, and C2 levels decrease. This is the main connection between the bradykinin-forming cascade and complement activation. New observations requiring more work in terms of their relationship to HAE include the following 1.Donaldson V.H. Evans R.R. A biochemical abnormality in hereditary angioneurotic edema.Am J Med. 1963; 35: 37-44Abstract Full Text PDF PubMed Scopus (680) Google Scholar: Prekallikrein is an enzyme (ie, it stoichiometrically digests the HK to which it is bound without being converted to kallikrein) and this reaction is inhibited by C1 INH 32.Joseph K. Tholanikunnel B.G. Kaplan A.P. Factor XII-independent cleavage of high molecular weight kininogen by prekallikrein and inhibition by C1 inhibitor.J Allergy Clin Immunol. 2009; 124: 143-149Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 2.Gigli I. Mason J.W. Colman R.W. Austen K.F. Interaction of plasma kallikrein with the C1 inhibitor.J Immunol. 1970; 104: 574-581PubMed Google Scholar. Heat shock protein 90 derived from endothelial cells will interact with the prekallikrein-HK complex 33.Joseph K. Tholanikunnel B.G. Kaplan A.P. Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII.Proc Natl Acad Sci. 2002; PubMed Scopus (140) Google Scholar and stoichiometrically prekallikrein to Thus, initiation of bradykinin formation and attacks of swelling might from endothelial activation and conversion of prekallikrein to kallikrein and not with Factor XII activation. However, the kallikrein that forms will then Factor XII so that the normal cascade for bradykinin generation can Because complexes of 1 and at the surface Factor XII and HK which prekallikrein is at the surface K. Tholanikunnel B.G. Ghebrehiwet B. Kaplan A.P. Interaction of high molecular weight kininogen binding on endothelial 2004; PubMed Google Scholar, activation of Factor XII upon binding to as a can bradykinin formation in the K. Ghebrehiwet B. Kaplan A.P. Factor activation on endothelial cells and binding and Scopus Google Scholar, K. Ghebrehiwet B. Kaplan A.P. Activation of the kinin-forming cascade on the surface of endothelial Chem. PubMed Scopus Google Scholar so that initiation might in the XII work along these may of the of are to Does activation with Factor XII or does some kallikrein form emotional an