Short Analytical Review
The pathophysiology of hereditary angioedema

https://doi.org/10.1016/j.clim.2004.05.007Get rights and content

Abstract

Hereditary angioedema (HAE), characterized by recurrent episodes of angioedema involving the skin, or the mucosa of the upper respiratory or the gastrointestinal tracts, results from heterozygosity for deficiency of the serine proteinase inhibitor (serpin), C1 inhibitor (C1INH). The primary biological role of C1INH is to regulate activation of the complement system, the contact system, and the intrinsic coagulation system. During attacks of angioedema, together with decreasing levels of C1INH, the complement and contact systems are activated: C2 and C4 levels fall and high molecular weight kininogen is cleaved. Although previous data suggested that symptoms in HAE might be mediated via complement system activation, a combination of recent clinical data, in vitro studies, and analysis of C1INH-deficient mice all indicate that the major mediator of angioedema is bradykinin: (1) a vascular permeability enhancing factor can be generated in vitro in C1INH-depleted, C2-deficient plasma, but not from C1INH-depleted, contact system-deficient plasma; this factor was identified by sequence analysis as bradykinin; (2) bradykinin can be detected in the plasma of HAE patients during attacks of angioedema; (3) in several members of one family, expression of a C1INH variant that inhibits contact system proteases but has defective inhibition of C1r and C1s does not result in HAE; (4) C1INH-deficient (C1INH−/−) mice have a defect in vascular permeability that is suppressed by treatment with specific plasma kallikrein inhibitors and by bradykinin type 2 receptor (Bk2R) antagonists, and is eliminated in C1INH−/−, Bk2R−/− double-deficient mice.

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.

References (77)

  • F.J. Meloni et al.

    High molecular weight kininogen binds to platelets by its heavy and light chains and when bound has altered susceptibility to kallikrein cleavage

    Blood

    (1992)
  • A.H. Schmaier et al.

    The expression of high molecular weight kininogen on human umbilical vein endothelial cells

    J. Biol. Chem

    (1988)
  • F. Van Iwaarden et al.

    The binding of high molecular weight kininogen to cultured human endothelial cells

    J. Biol. Chem

    (1988)
  • R.W. Colman et al.

    Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes

    Blood

    (1997)
  • H. Herwald et al.

    Isolation and characterization of the kininogen-binding protein p33 from endothelial cells

    J. Biol. Chem

    (1996)
  • Z. Shariat-Madar et al.

    Mapping binding domains of kininogens on endothelial cell cytokeratin 1

    J. Biol. Chem

    (1999)
  • F. Mahdi et al.

    Expression and co-localization of cytokeratin 1 and urokinase plasminogen activator receptor on endothelial cells

    Blood

    (2001)
  • S.R. Reddigari et al.

    Human hageman factor (factor xii) and high molecular weight kininogen compete for the same binding site on human umbilical vein endothelial cells

    J. Biol. Chem

    (1993)
  • K. Joseph et al.

    Activation of the bradykinin-forming cascade on endothelial cells: a role for heat shock protein 90

    Int. Immunopharmacol

    (2002)
  • A.P. Kaplan et al.

    Pathways for bradykinin formation and inflammatory disease

    J. Allergy Clin. Immunol

    (2002)
  • F. Mahdi et al.

    Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qr, and cytokeratin 1 on endothelial cell membranes

    Blood

    (2002)
  • Z. Shariat-Madar et al.

    Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator

    J. Biol. Chem

    (2002)
  • Z. Shariat-Madar et al.

    Assembly and activation of the plasma kallikrein/kinin system: a new interpretation

    Int. Immunopharmacol

    (2002)
  • V.H. Donaldson et al.

    A biochemical abnormality in hereditary angioneurotic edema

    Am. J. Med

    (1963)
  • M. Berrettini et al.

    Detection of in vitro and in vivo cleavage of high molecular weight kininogen in human plasma by immunoblotting with monoclonal antibodies

    Blood

    (1986)
  • M. Cugno et al.

    Activation of factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired C1-inhibitor deficiencies

    Immunopharmacology

    (1996)
  • J.G. Curd et al.

    Generation of bradykinin during incubation of hereditary angioedema plasma

    Mol. Immunol

    (1982)
  • T. Fields et al.

    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)
  • J. Nussberger et al.

    Plasma bradykinin in angio-oedema

    Lancet

    (1998)
  • E. Han Lee et al.

    Approaches toward reversal of increased vascular permeability in C1 inhibitor deficient mice

    Immunol. Lett

    (2003)
  • J.A. Huntington et al.

    Structure of a serpin–protease complex shows inhibition by deformation

    Nature

    (2000)
  • P.A. Patston et al.

    Mechanism of serpin action: evidence that C1 inhibitor functions as a suicide substrate

    Biochemistry

    (1991)
  • S.C. Bock et al.

    Human C1 inhibitor: primary structure, cdna cloning, and chromosomal localization

    Biochemistry

    (1986)
  • M. Coutinho et al.

    Functional analysis of the serpin domain of C1 inhibitor

    J. Immunol

    (1994)
  • A. Reboul et al.

    Proteolysis and deglycosylation of human C1 inhibitor: effect on functional properties

    Biochem. J

    (1987)
  • R.J. Ziccardi

    Activation of the early components of the classical complement pathway under physiological conditions

    J. Immunol

    (1981)
  • M. Schapira et al.

    Contribution of plasma protease inhibitors to the inactivation of kallikrein in plasma

    J. Clin. Invest

    (1982)
  • F. van der Graaf et al.

    Inactivation of kallikrein in human plasma

    J. Clin. Invest

    (1983)
  • Cited by (0)

    View full text