Articles
Hereditary angioedema: a current state-of-the-art review, III: mechanisms of hereditary angioedema

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Objective

To review the available evidence on the pathophysiologic mechanism of episodes of edema in hereditary angioedema (HAE).

Data Sources

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

Study Selection

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.

Section snippets

INTRODUCTION

Although hereditary angioedema (HAE) was described earlier, its hereditary nature was first clearly recognized in 1888 by Sir William Osler,1 who also provided the first complete, detailed, clinical description of this autosomal-dominant inherited disease. The explanation for this inheritance pattern is that people with HAE are heterozygous for deficiency of C1 inhibitor (C1-INH). Donaldson and Evans2 were the first to recognize that C1-INH was deficient in the plasma of patients with HAE.

THE BIOLOGICAL FUNCTION OF C1-INH

C1-INH is the only serine protease inhibitor that plays a significant role in regulation of complement activation. It is the primary regulator of classic pathway activation via inactivation of C1r and C1s (Table 1).5 It also regulates lectin pathway activation via inactivation of a C1s-like protease known as mannan-binding lectin-associated protease 2 (MASP2), which is activated after binding of mannan-binding lectin to a microorganism surface.6 α2-Macroglobulin also is able to inactivate MASP2.

PATHOPHYSIOLOGIC CHARACTERISTICS OF ANGIOEDEMA ATTACKS

Attacks of angioedema in HAE are not associated with signs of inflammation, although attacks may be triggered by inflammatory conditions. There also is no indication that allergy plays a role. Although some reports initially suggested that histamine levels in the urine were elevated during HAE attacks, a later study10 demonstrated that urinary histamine levels are not elevated. Furthermore, antihistamines are ineffective. Epinephrine also is ineffective in HAE.

C1-INH is a member of the serpin

The Complement and Contact Systems in HAE Attacks

Both the complement and contact systems are activated during HAE attacks. Low plasma levels of C1-INH in HAE result in apparent spontaneous activation of the complement and contact systems. This clearly occurs during attacks of angioedema but may also take place at a low level during asymptomatic intervals. The most readily identifiable indication of contact system activation is the presence of circulating, cleaved, high-molecular-weight kininogen during episodes of angioedema.21 C2 and C4

CONCLUSIONS

The major biological roles of C1-INH relate to the regulation of vascular permeability and the modulation of inflammation. The C1-INH regulates activation of the complement and contact systems. Suppression of contact system activation by inactivation of plasma kallikrein and factor XIIa, which prevents bradykinin release, helps to maintain the endothelial barrier. The loss of this function is illustrated by the recurrent episodes of angioedema that develop in patients with HAE. As outlined in

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    Disclosure: The author has served as a consultant to each of the companies that are developing therapies for HAE: Jerini, Dyax, Lev Pharmaceuticals, Pharming, and CSL Behring.

    Funding Sources: This study was supported by grants HD22082 and AI057366 from the National Institutes of Health.

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