Bradykinin and the Pathogenesis of Hereditary Angioedema

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 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 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 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 There was even one publication by Donaldson5 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 kd6,7; soon thereafter, the Factor XII native protein was purified.8 Factor XIIa or Factor XIIf was shown to be required for kallikrein activity to be produced in plasma; prekallikrein was purified,9 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 kallikrein10,11 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 HK12 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 binding13,14 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 Activation of the bradykininforming 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.15,16 Factor XII was shown to autoactivate upon binding17 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 Medical University of South Carolina, Charleston, South Carolina. Correspondence to Allen P. Kaplan, MD, FAAAAI, 17 Logan Street, Charleston, SC 29401. Telephone: (843) 573-9373. E-mail: kaplana@musc.edu. Copyright © 2011 by World Allergy Organization