Short Analytical ReviewThe pathophysiology of hereditary angioedema
Introduction
Hereditary angioedema (HAE) results from deficiency of the plasma protease inhibitor, C1 inhibitor (C1INH). Individuals with HAE are heterozygous for deficiency, which results in autosomal dominant inheritance. Complete deficiency has never been reported. Absence of expression from one allele, which results simply in decreased expression of C1INH in the plasma, is called type 1 HAE, while expression of a dysfunctional C1INH protein, together with decreased levels of normal protein, is termed type 2 HAE.
C1INH is a serpin. Most, but not all members of this group of proteins, are protease inhibitors; they share amino acid sequence homology and a similar distinctive three-dimensional structure. Inactivation of proteases by serpins is initiated following protease recognition of a pseudosubstrate reactive center loop displayed over the surface of the molecule. This results in cleavage of the inhibitor at the reactive center peptide bond, covalent bond formation between the reactive center amino acid residue of the serpin and the active site serine of the protease, and distortion of the protease catalytic triad [1]. Complex formation results in inactivation of both the protease and the inhibitor. Serpins, therefore, are called suicide substrates [2]. Based both on amino acid sequence homology and on functional criteria, the mechanism of protease inactivation by C1INH clearly is the same as with other serpins [2], [3]. Most serpins, in addition to a protease inhibitory domain, have an amino terminal domain that does not share homology with those of other serpins. The amino terminal domain of C1INH is the longest among the serpins (approximately 120 amino acids). In addition, this domain in C1INH is extremely heavily glycosylated, with three N-linked and seven O-linked carbohydrates [4]. The amino terminal domain is not involved in protease inhibitory function [5], [6], [7].
Section snippets
Regulation of complement system activation
The primary biological activities of C1INH are to regulate activation of the complement [8], [9] and contact systems [10], [11], [12], [13], [14] (Table 1). In addition, C1INH is able to inactivate several other proteases. Inhibition of fibrinolysis, via complex formation with both tissue plasminogen activator and plasmin may occasionally be biologically important (Table 1) [15], [16], [17]. C1INH controls activation of the classical complement pathway via inactivation of the proteases C1r and
Complement and contact system activation in HAE
The first indication that C1INH is required for normal regulation of vascular permeability was the discovery that hereditary angioedema (HAE) was associated with very low levels of C1INH [52]. During asymptomatic periods, plasma C1INH levels average approximately 30% of normal. The explanation for this decrease below 50%, which would be expected in a heterozygous disorder, is that the decreased inhibitor level results in increased activation of some or all of the proteases regulated by C1INH.
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