Top

Clinical Reviews in Allergy & Immunology

Published in:

01-10-2016

HAE Pathophysiology and Underlying Mechanisms

Authors: Bruce L. Zuraw, Sandra C. Christiansen

Published in: Clinical Reviews in Allergy & Immunology | Issue 2/2016

Abstract

Remarkable progress in understanding the pathophysiology and underlying mechanisms of hereditary angioedema has led to the development of effective treatment for this disorder. Progress in three separate areas has catalyzed our understanding of hereditary angioedema. The first is the recognition that HAE type I and type II result from a deficiency in the plasma level of functional C1 inhibitor. This observation has led to a detailed understanding of the SERPING1 mutations responsible for this deficiency as well as the molecular regulation of C1 inhibitor expression and function. The second is that the fundamental cause of swelling is enhanced contact system activation leading to increased generation of bradykinin. Substantial progress has been made in defining the parameters regulating bradykinin generation and catabolism as well as the receptors that transduce the biologic effects of kinins. The third is the understanding that tissue swelling in hereditary angioedema primarily involves the function of endothelial cell adherens junctions. This knowledge is driving increased attention to the role of endothelial biology in determining disease activity in hereditary angioedema. While there has been considerable progress made, large gaps still remain in our knowledge. Important areas that remain poorly understood include the factors that lead to very low plasma functional C1 inhibitor levels, the triggers of contact system activation in hereditary angioedema, and the role of the bradykinin B1 receptor. The phenotypic variability of hereditary angioedema has been extensively documented but never understood. The mechanisms discussed in this chapter likely contribute to this variability. Future progress in understanding these mechanisms should provide new means to improve the diagnosis and treatment of hereditary angioedema.

Osler W (1888) Hereditary angio-neurotic oedema. Am J Med Sci 95(4):362–367CrossRef

Landerman NS, Webster ME, Becker EL, Ratcliffe HE (1962) Hereditary angioneurotic edema. II. Deficiency of inhibitor for serum globulin permeability factor and/or plasma kallikrein. J Allergy 33:330–341PubMedCrossRef

Donaldson VH, Evans RR (1963) A biochemical abnormality in hereditary angioneurotic edema: absence of serum inhibitor of C’1-esterase. Am J Med 35:37–44PubMedCrossRef

Rosen FS, Pensky J, Donaldson V, Charache P (1965) Hereditary angioneurotic edema: two genetic variants. Science 148:957–958PubMedCrossRef

Bork K, Barnstedt SE, Koch P, Traupe H (2000) Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 356(9225):213–217PubMedCrossRef

Binkley KE, Davis A 3rd (2000) Clinical, biochemical, and genetic characterization of a novel estrogen- dependent inherited form of angioedema. J Allergy Clin Immunol 106(3):546–550PubMedCrossRef

Bock SC, Skriver K, Nielsen E, Thogersen HC, Wiman B, Donaldson VH, Eddy RL, Marrinan J, Radziejewska E, Huber R, Shows TB, Magnusson S (1986) Human C1 inhibitor: primary structure, cDNA cloning, and chromosomal localization. Biochemistry 25:4292–4301PubMedCrossRef

Davis AE III (1988) C1 inhibitor and hereditary angioneurotic edema. Annu Rev Immunol 6:595–628PubMedCrossRef

Bissler JJ, Aulak KS, Donaldson VH, Rosen FS, Cicardi M, Harrison RA, Davis AE 3rd (1997) Molecular defects in hereditary angioneurotic edema. Proc Assoc Am Physicians 109(2):164–173PubMed

10.

Verpy E, Biasotto M, Brai M, Misiano G, Meo T, Tosi M (1996) Exhaustive mutation scanning by fluorescence-assisted mismatch analysis discloses new genotype-phenotype correlations in angiodema [see comments]. Am J Hum Genet 59(2):308–319PubMedPubMedCentral

11.

Zuraw BL, Herschbach J (2000) Detection of C1 inhibitor mutations in patients with hereditary angioedema. J Allergy Clin Immunol 105(3):541–546PubMedCrossRef

12.

Huber R, Carrell RW (1989) Implications of the three-dimensional structure of alpha1-antitrypsin for structure and function of serpins. Biochemistry 28:8951–8966PubMedCrossRef

13.

Gettins PG (2002) Serpin structure, mechanism, and function. Chem Rev 102(12):4751–4804PubMedCrossRef

14.

Aulak KS, Pemberton PA, Rosen FS, Carrell RW, Lachmann PJ, Harrison RA (1988) Dysfunctional C1-inhibitor(At), isolated from a type II hereditary-angio-oedema plasma, contains a P1 `reactive centre’ (Arg444->His) mutation. Biochem J 253:615–618PubMedPubMedCentralCrossRef

15.

Donaldson VH, Harrison RA, Rosen FS, Bing DH, Kindness G, Canar J, Wagner CJ, Awad S (1985) Variability in purified dysfunctional C1-inhibitor proteins from patients with hereditary angioneurotic edema. Functional and analytical gel studies. J Clin Invest 75:124–132PubMedPubMedCentralCrossRef

16.

Donaldson VH, Bissler JJ (1992) C1 inhibitors and their genes: an update. J Lab Clin Med 119:330–333PubMed

17.

Frangi D, Aulak KS, Cicardi M, Harrison RA, Davis AE III (1992) A dysfunctional C1 inhibitor protein with a new reactive center mutation (Arg-444–>Leu). FEBS Lett 301:34–36PubMedCrossRef

18.

Skriver K, Radziejewska E, Silbermann JA, Donaldson VH, Bock SC (1989) CpG mutations in the reactive site of human C1 inhibitor. J Biol Chem 264:3066–3071PubMed

19.

Parad RB, Kramer J, Strunk RC, Rosen FS, Davis AE III (1990) Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site. Proc Natl Acad Sci U S A 87:6786–6790PubMedPubMedCentralCrossRef

20.

Lachmann PJ, Rosen FS (1984) The catabolism of C1-inhibitor and the pathogenesis of hereditary angio-edema. Acta Pathol Microbiol Scand 92:35–39

21.

Rosen FS, Alper CA, Pensky J, Klemperer MR, Donaldson VH (1971) Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema. J Clin Invest 50:2143–2149PubMedPubMedCentralCrossRef

22.

Davis AE 3rd (2006) Mechanism of angioedema in first complement component inhibitor deficiency. Immunol Allergy Clin N Am 26(4):633–651CrossRef

23.

Spath PJ, Wuthrich B, Butler R (1984) Quantification of C1-inhibitor functional activities by immunodiffusion assay in plasma of patients with hereditary angioedema - evidence of a functionally critical level of C1-inhibitor concentration. Complement 1:147–159PubMed

24.

Zuraw BL, Cicardi M, Longhurst HJ, Bernstein JA, Li HH, Magerl M, Martinez-Saguer I, Rehman SM, Staubach P, Feuersenger H, Parasrampuria R, Sidhu J, Edelman J, Craig T (2015) Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate. Allergy 70(10):1319–1328. doi:10.1111/all.12658 PubMedPubMedCentralCrossRef

25.

Quastel M, Harrison R, Cicardi M, Alper CA, Rosen FS (1983) Behavior in vivo of normal and dysfunctional C1 inhibitor in normal subjects and patients with hereditary angioneurotic edema. J Clin Invest 71(4):1041–1046PubMedPubMedCentralCrossRef

26.

Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L, Bucher C, Castaldo AJ, Cicardi M, Davis AE, De Carolis C, Drouet C, Duponchel C, Farkas H, Fay K, Fekete B, Fischer B, Fontana L, Fust G, Giacomelli R, Groner A, Hack CE, Harmat G, Jakenfelds J, Juers M, Kalmar L, Kaposi PN, Karadi I, Kitzinger A, Kollar T, Kreuz W, Lakatos P, Longhurst HJ, Lopez-Trascasa M, Martinez-Saguer I, Monnier N, Nagy I, Nemeth E, Nielsen EW, Nuijens JH, O’Grady C, Pappalardo E, Penna V, Perricone C, Perricone R, Rauch U, Roche O, Rusicke E, Spath PJ, Szendei G, Takacs E, Tordai A, Truedsson L, Varga L, Visy B, Williams K, Zanichelli A, Zingale L (2004) Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 114(3 Suppl):S51–131PubMedCrossRef

27.

Kunschak M, Engl W, Maritsch F, Rosen FS, Eder G, Zerlauth G, Schwarz HP (1998) A randomized, controlled trial to study the efficacy and safety of C1 inhibitor concentrate in treating hereditary angioedema. Transfusion 38(6):540–549PubMedCrossRef

28.

Zuraw BL, Curd JG (1986) Demonstration of modified inactive first component of complement (C1) inhibitor in the plasmas of C1 inhibitor-deficient patients. J Clin Invest 78:567–575PubMedPubMedCentralCrossRef

29.

Ernst SC, Circolo A, Davis AE 3rd, Gheesling-Mullis K, Fliesler M, Strunk RC (1996) Impaired production of both normal and mutant C1 inhibitor proteins in type I hereditary angioedema with a duplication in exon 8. J Immunol 157(1):405–410PubMed

30.

Kramer J, Rosen FS, Colten HR, Rajczy K, Strunk RC (1993) Transinhibition of C1 inhibitor synthesis in type I hereditary angioneurotic edema. J Clin Invest 91:1258–1262PubMedPubMedCentralCrossRef

31.

Zuraw BL, Lotz M (1990) Regulation of the hepatic synthesis of C1 inhibitor by the hepatocyte stimulating factors interleukin 6 and interferon gamma. J Biol Chem 265:12664–12670PubMed

32.

Lotz M, Zuraw BL (1987) Interferon gamma is a major regulator of C1-inhibitor synthesis by human blood monocytes. J Immunol 139:3382–3387PubMed

33.

Bensa JC, Reboul A, Colomb MG (1983) Biosynthesis in vitro of complement subcomponents C1q, C1s, and C1 inhibitor by resting and stimulated human monocytes. Biochem J 216:385–392PubMedPubMedCentralCrossRef

34.

Yeung-Laiwah AC, Jones L, Hamilton AO, Whaley K (1985) Complement-subcomponent-C1-inhibitor synthesis by human monocytes. Biochem J 226:199–205PubMedPubMedCentralCrossRef

35.

Randazzo BP, Dattwyler RJ, Kaplan AP, Ghebrehiwet B (1985) Synthesis of C1 inhibitor (C1-INA) by a human monocyte-like cell line, U937. J Immunol 135:1313–1319PubMed

36.

Schmaier AH, Murray SC, Heda GD, Farber A, Kuo A, McCrae K, Cines DB (1989) Synthesis and expression of C1 inhibitor by human umbilical vein endothelial cells. J Biol Chem 264:18173–18179PubMed

37.

Katz Y, Strunk RC (1988) Synovial fibroblast-like cells synthesize seven proteins of the complement system. Arthritis Rheum 31:1365–1370PubMedCrossRef

38.

Schmaier AH, Amenta S, Xiong T, Heda GD, Gewirtz AM (1993) Expression of platelet C1 inhibitor. Blood 82(2):465–474PubMed

39.

Walker DG, Yasuhara O, Patston PA, McGeer EG, McGeer PL (1995) Complement C1 inhibitor is produced by brain tissue and is cleaved in Alzheimer disease. Brain Res 675(1–2):75–82PubMedCrossRef

40.

Klausegger A, Wiednig M, Urban C, Lackner H, Reiter H, Bauer JW, Aberer W (2012) Successful allogeneic cord blood transplantation in a patient with Evans syndrome leads to correction of hereditary angioedema type I as secondary effect. Bone Marrow Transplant 47(9):1259–1261. doi:10.1038/bmt.2012.7 PubMedCrossRef

41.

Heda GD, Mardente S, Weiner L, Schmaier AH (1990) Interferon gamma increases in vitro and in vivo expression of C1 inhibitor. Blood 75:2401–2407PubMed

42.

Falus A, Fehér KG, Walcz E, Brozik M, Füst G, Hidvégi T, Fehér T, Merétey K (1990) Hormonal regulation of complement biosynthesis in human cell lines–I. Androgens and gamma-interferon stimulate the biosynthesis and gene expression of C1 inhibitor in human cell lines U937 and HepG2. Mol Immunol 27:191–195PubMedCrossRef

43.

Al Abdullah IH, Sim RB, Sheil J, Greally JF (1984) The effect of danazol on the production of C1 inhibitor in the Guinea pig. Complement 1:27–35PubMed

44.

Lappin DF, McPhaden AR, Yap PL, Carter PE, Birnie GD, Fothergill JE, Whaley K (1989) Monocyte C1-inhibitor synthesis in patients with C1-inhibitor deficiency. Eur J Clin Investig 19:45–52CrossRef

45.

Pappalardo E, Zingale LC, Cicardi M (2003) Increased expression of C1-inhibitor mRNA in patients with hereditary angioedema treated with Danazol. Immunol Lett 86(3):271–276PubMedCrossRef

46.

Cicardi M, Igarashi T, Rosen FS, Davis AE III (1987) Molecular basis for the deficiency of complement 1 inhibitor in type 1 hereditary angioneurotic edema. J Clin Invest 79:698–702PubMedPubMedCentralCrossRef

47.

Kramer J, Katz Y, Rosen FS, Davis AE III, Strunk RC (1991) Synthesis of C1 inhibitor in fibroblasts from patients with type I and type II hereditary angioneurotic edema. J Clin Invest 87:1614–1620PubMedPubMedCentralCrossRef

48.

Csuka D, Fust G, Farkas H, Varga L (2011) Parameters of the classical complement pathway predict disease severity in hereditary angioedema. Clin Immunol 139(1):85–93. doi:10.1016/j.clim.2011.01.003 PubMedCrossRef

49.

Christiansen SC, Zuraw BL, Proud D, Cochrane CG (1989) Inhibition of human bronchial kallikrein in asthma. Am Rev Respir Dis 139(5):1125–1131. doi:10.1164/ajrccm/139.5.1125 PubMedCrossRef

50.

Christiansen SC, Proud D, Cochrane CG (1987) Detection of tissue kallikrein in the bronchoalveolar lavage fluid of asthmatic subjects. J Clin Invest 79:188–197PubMedPubMedCentralCrossRef

51.

Donaldson VH, Rosen FS, Bing DH (1977) 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 Phys 90:174–183PubMed

52.

Curd JG, Prograis LJ Jr, Cochrane CG (1980) Detection of active kallikein in induced blister fluids of hereditary angioedema patients. J Exp Med 152:742–747PubMedCrossRef

53.

Curd JG, Yelvington M, Burridge N, Stimler NP, Gerard C, Prograis LJ Jr, Cochrane CG (1982) Generation of bradykinin during incubation of hereditary angioedema plasma. Mol Immunol 19:1365–1365CrossRef

54.

Fields T, Ghebrehiwet B, Kaplan AP (1983) Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of "spontaneous" formation of bradykinin. J Allergy Clin Immunol 72:54–60PubMedCrossRef

55.

Schapira M, Silver LD, Scott CF, Schmaier AH, Prograis LJ, Curd JG, Colman RW (1983) Prekallikrein activation and high- molecular-weight kininogen consumption in hereditary angioedema. N Engl J Med 308:1050–1054PubMedCrossRef

56.

Lammle B, Zuraw BL, Heeb MJ, Schwarz HP, Berrettini M, Curd JG, Griffin JH (1988) Detection and quantitation of cleaved and uncleaved high molecular weight kininogen in plasma by ligand blotting with radiolabeled plasma prekallikrein or factor XI. Thromb Haemost 59:151–161PubMed

57.

Berrettini M, Lammle B, White T, Heeb MJ, Schwarz HP, Zuraw B, Curd J, Griffin JH (1986) Detection of in vitro and in vivo cleavage of high molecular weight kininogen in human plasma by immunoblotting with monoclonal antibodies. Blood 68(2):455–462PubMed

58.

Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A (1998) Plasma bradykinin in angio-oedema. Lancet 351(9117):1693–1697PubMedCrossRef

59.

Nussberger J, Cugno M, Cicardi M, Agostoni A (1999) Local bradykinin generation in hereditary angioedema. J Allergy Clin Immunol 104(6):1321–1322PubMedCrossRef

60.

Dewald G, Bork K (2006) Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 343(4):1286–1289PubMedCrossRef

61.

Cichon S, Martin L, Hennies HC, Muller F, Van Driessche K, Karpushova A, Stevens W, Colombo R, Renne T, Drouet C, Bork K, Nothen MM (2006) Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet 79(6):1098–1104PubMedPubMedCentralCrossRef

62.

Bjorkqvist J, de Maat S, Lewandrowski U, Di Gennaro A, Oschatz C, Schonig K, Nothen MM, Drouet C, Braley H, Nolte MW, Sickmann A, Panousis C, Maas C, Renne T (2015) Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III. J Clin Invest 125(8):3132–3146. doi:10.1172/JCI77139 PubMedPubMedCentralCrossRef

63.

Bouillet L, Ponard D, Rousset H, Cichon S, Drouet C (2007) A case of hereditary angio-oedema type III presenting with C1-inhibitor cleavage and a missense mutation in the F12 gene. Br J Dermatol 156(5):1063–1065. doi:10.1111/j.1365-2133.2007.07778.x PubMedCrossRef

64.

Zuraw BL, Sugimoto S, Curd J (1986) Modified inactive C1 inhibitor (C1inh) is generated during attacks of angioedema in hereditary angioedema (HAE). J Allergy Clin Immunol 77:188–188

65.

Defendi F, Charignon D, Ghannam A, Baroso R, Csopaki F, Allegret-Cadet M, Ponard D, Favier B, Cichon S, Nicolie B, Fain O, Martin L, Drouet C, National Reference Centre for Angioedema C (2013) Enzymatic assays for the diagnosis of bradykinin-dependent angioedema. PLoS One 8(8):e70140. doi:10.1371/journal.pone.0070140 PubMedPubMedCentralCrossRef

66.

Joseph K, Tholanikunnel BG, Wolf B, Bork K, Kaplan AP (2015) Deficiency of plasminogen activator inhibitor 2 in plasma of patients with hereditary angioedema with normal C1 inhibitor levels. J Allergy Clin Immunol. doi:10.1016/j.jaci.2015.07.041 PubMedCentral

67.

Kaplan AP, Austen KF (1971) A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin. J Exp Med 133(4):696–712PubMedPubMedCentralCrossRef

68.

Zotter Z, Csuka D, Szabo E, Czaller I, Nebenfuhrer Z, Temesszentandrasi G, Fust G, Varga L, Farkas H (2014) The influence of trigger factors on hereditary angioedema due to C1-inhibitor deficiency. Orphanet J Rare Dis 9(1):44. doi:10.1186/1750-1172-9-44 PubMedPubMedCentralCrossRef

69.

Cochrane CG, Griffin JH (1982) The biochemistry and pathophysiology of the contact system of plasma. Adv Immunol 33:241–306PubMedCrossRef

70.

White-Adams TC, Berny MA, Patel IA, Tucker EI, Gailani D, Gruber A, McCarty OJ (2010) Laminin promotes coagulation and thrombus formation in a factor XII-dependent manner. J Thromb Haemost 8(6):1295–1301. doi:10.1111/j.1538-7836.2010.03850.x PubMedPubMedCentralCrossRef

71.

van der Meijden PE, Munnix IC, Auger JM, Govers-Riemslag JW, Cosemans JM, Kuijpers MJ, Spronk HM, Watson SP, Renne T, Heemskerk JW (2009) Dual role of collagen in factor XII-dependent thrombus formation. Blood 114(4):881–890. doi:10.1182/blood-2008-07-171066 PubMedCrossRef

72.

Bork K, Meng G, Staubach P, Hardt J (2006) Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 119(3):267–274PubMedCrossRef

73.

Longhurst H, Cicardi M (2012) Hereditary angio-oedema. Lancet 379(9814):474–481. doi:10.1016/S0140-6736(11)60935-5 PubMedCrossRef

74.

Agostoni A, Cicardi M (1992) Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine (Baltimore) 71(4):206–215CrossRef

75.

Bouillet L, Gompel A (2013) Hereditary angioedema in women: specific challenges. Immunol Allergy Clin N Am 33(4):505–511. doi:10.1016/j.iac.2013.07.006 CrossRef

76.

Martinez-Saguer I, Rusicke E, Aygoren-Pursun E, Heller C, Klingebiel T, Kreuz W (2010) Characterization of acute hereditary angioedema attacks during pregnancy and breast-feeding and their treatment with C1 inhibitor concentrate. Am J Obstet Gynecol 203(2):131 e131–131 e137. doi:10.1016/j.ajog.2010.03.003 CrossRef

77.

Czaller I, Visy B, Csuka D, Fust G, Toth F, Farkas H (2010) The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey. Eur J Obstet Gynecol Reprod Biol 152(1):44–49. doi:10.1016/j.ejogrb.2010.05.008 PubMedCrossRef

78.

Farsetti A, Misiti S, Citarella F, Felici A, Andreoli M, Fantoni A, Sacchi A, Pontecorvi A (1995) Molecular basis of estrogen regulation of Hageman factor XII gene expression. Endocrinology 136(11):5076–5083PubMed

79.

Brunnee T, Reddigari SR, Shibayama Y, Kaplan AP, Silverberg M (1997) Mast cell derived heparin activates the contact system: a link to kinin generation in allergic reactions. Clin Exp Allergy 27(6):653–663PubMedCrossRef

80.

Oschatz C, Maas C, Lecher B, Jansen T, Bjorkqvist J, Tradler T, Sedlmeier R, Burfeind P, Cichon S, Hammerschmidt S, Muller-Esterl W, Wuillemin WA, Nilsson G, Renne T (2011) Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity 34(2):258–268. doi:10.1016/j.immuni.2011.02.008 PubMedCrossRef

81.

Sala-Cunill A, Bjorkqvist J, Senter R, Guilarte M, Cardona V, Labrador M, Nickel KF, Butler L, Luengo O, Kumar P, Labberton L, Long A, Di Gennaro A, Kenne E, Jamsa A, Krieger T, Schluter H, Fuchs T, Flohr S, Hassiepen U, Cumin F, McCrae K, Maas C, Stavrou E, Renne T (2015) Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions. J Allergy Clin Immunol 135(4):1031–1043 e1036. doi:10.1016/j.jaci.2014.07.057 PubMedCrossRef

82.

Ishizaka T, Iwata M, Ishizaka K (1985) Release of histamine and arachidonate from mouse mast cells induced by glycosylation-enhancing factor and bradykinin. J Immunol 134:1880–1887PubMed

83.

Lawrence ID, Warner JA, Cohan VL, Lichtenstein LM, Kagey-Sobotka A, Vavrek RJ, Stewart JM, Proud D (1989) Induction of histamine release from human skin mast cells by bradykinin analogs. Biochem Pharmacol 38:227–233PubMedCrossRef

84.

Maurer M, Church MK (2012) Inflammatory skin responses induced by icatibant injection are mast cell mediated and attenuated by H(1)-antihistamines. Exp Dermatol 21(2):154–155. doi:10.1111/j.1600-0625.2011.01410.x PubMedCrossRef

85.

Morrison DC, Cochrane CG (1974) Direct evidence for Hageman factor (factor XII) activation by bacterial lipopolysaccharides (endotoxins). J Exp Med 140(3):797–811PubMedPubMedCentralCrossRef

86.

Maas C, Govers-Riemslag JW, Bouma B, Schiks B, Hazenberg BP, Lokhorst HM, Hammarstrom P, ten Cate H, de Groot PG, Bouma BN, Gebbink MF (2008) Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation. J Clin Invest 118(9):3208–3218. doi:10.1172/JCI35424 PubMedPubMedCentral

87.

Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P, Song Y, Tzima E, Kennerknecht E, Niepmann M, von Bruehl ML, Sedding D, Massberg S, Gunther A, Engelmann B, Preissner KT (2007) Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A 104(15):6388–6393. doi:10.1073/pnas.0608647104 PubMedPubMedCentralCrossRef

88.

Muller F, Mutch NJ, Schenk WA, Smith SA, Esterl L, Spronk HM, Schmidbauer S, Gahl WA, Morrissey JH, Renne T (2009) Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 139(6):1143–1156. doi:10.1016/j.cell.2009.11.001 PubMedPubMedCentralCrossRef

89.

Van Der Meijden PE, Van Schilfgaarde M, Van Oerle R, Renne T, ten Cate H, Spronk HM (2012) Platelet- and erythrocyte-derived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 10(7):1355–1362. doi:10.1111/j.1538-7836.2012.04758.x CrossRef

90.

Long YM, Zhao XC, Clermont AC, Zhou QF, Liu Q, Feener EP, Yan B, Jiang GB (2015) Negatively charged silver nanoparticles cause retinal vascular permeability by activating plasma contact system and disrupting adherens junction. Nanotoxicology:1–11. doi:10.3109/17435390.2015.1088589

91.

Leeb-Lundberg LM, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL (2005) International union of pharmacology. XLV classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 57(1):27–77. doi:10.1124/pr.57.1.2 PubMedCrossRef

92.

Israili ZH, Hall WD (1992) Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 117:234–242PubMedCrossRef

93.

Brown NJ, Snowden M, Griffin MR (1997) Recurrent angiotensin-converting enzyme inhibitor–associated angioedema. JAMA 278(3):232–233PubMedCrossRef

94.

Agostoni A, Cicardi M, Cugno M, Zingale LC, Gioffre D, Nussberger J (1999) Angioedema due to angiotensin-converting enzyme inhibitors. Immunopharmacology 44(1–2):21–25PubMedCrossRef

95.

Agostoni A, Cicardi M (1991) Contraindications to the use of ACE inhibitors in patients with C1 esterase inhibitor deficiency. Am J Med 90:278–278PubMedCrossRef

96.

Cilia La Corte AL, Carter AM, Rice GI, Duan QL, Rouleau GA, Adam A, Grant PJ, Hooper NM (2011) A functional XPNPEP2 promoter haplotype leads to reduced plasma aminopeptidase P and increased risk of ACE inhibitor-induced angioedema. Hum Mutat 32(11):1326–1331. doi:10.1002/humu.21579 PubMedCrossRef

97.

Drouet C, Desormeaux A, Robillard J, Ponard D, Bouillet L, Martin L, Kanny G, Moneret-Vautrin DA, Bosson JL, Quesada JL, Lopez-Trascasa M, Adam A (2008) Metallopeptidase activities in hereditary angioedema: effect of androgen prophylaxis on plasma aminopeptidase P. J Allergy Clin Immunol 121(2):429–433. doi:10.1016/j.jaci.2007.10.048 PubMedCrossRef

98.

Duan QL, Binkley K, Rouleau GA (2009) Genetic analysis of factor XII and bradykinin catabolic enzymes in a family with estrogen-dependent inherited angioedema. J Allergy Clin Immunol 123(4):906–910. doi:10.1016/j.jaci.2008.12.010 PubMedCrossRef

99.

Pan ZK, Christiansen SC, Ptasznik A, Zuraw BL (1999) Requirement of phosphatidylinositol 3-kinase activity for bradykinin stimulation of NF-kappa B activation in cultured human epithelial cells. J Biol Chem 274:9918–9922PubMedCrossRef

100.

Pan ZK, Ye RD, Christiansen SC, Jagels MA, Bokoch GM, Zuraw BL (1998) Role of the rho GTPase in bradykinin stimulated NF-kB activation and interleukin-1b Gene expression in cultured human epithelial cells. J Immunol 160:3038–3045PubMed

101.

Pan ZK, Zuraw BL, Lung CC, Prossnitz ER, Browning DD, Ye RD (1996) Bradykinin stimulates NF-kB activation and interleukin-1b gene expression in cultured human fibroblasts. J Clin Invest 98(9):2042–2049PubMedPubMedCentralCrossRef

102.

Han ED, MacFarlane RC, Mulligan AN, Scafidi J, Davis AE 3rd (2002) Increased vascular permeability in C1 inhibitor-deficient mice mediated by the bradykinin type 2 receptor. J Clin Invest 109(8):1057–1063PubMedPubMedCentralCrossRef

103.

Cicardi M, Banerji A, Bracho F, Malbran A, Rosenkranz B, Riedl M, Bork K, Lumry W, Aberer W, Bier H, Bas M, Greve J, Hoffmann TK, Farkas H, Reshef A, Ritchie B, Yang W, Grabbe J, Kivity S, Kreuz W, Levy RJ, Luger T, Obtulowicz K, Schmid-Grendelmeier P, Bull C, Sitkauskiene B, Smith WB, Toubi E, Werner S, Anne S, Bjorkander J, Bouillet L, Cillari E, Hurewitz D, Jacobson KW, Katelaris CH, Maurer M, Merk H, Bernstein JA, Feighery C, Floccard B, Gleich G, Hebert J, Kaatz M, Keith P, Kirkpatrick CH, Langton D, Martin L, Pichler C, Resnick D, Wombolt D, Fernandez Romero DS, Zanichelli A, Arcoleo F, Knolle J, Kravec I, Dong L, Zimmermann J, Rosen K, Fan WT (2010) Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 363(6):532–541. doi:10.1056/NEJMoa0906393 PubMedPubMedCentralCrossRef

104.

Bossi F, Fischetti F, Regoli D, Durigutto P, Frossi B, Gobeil F Jr, Ghebrehiwet B, Peerschke EI, Cicardi M, Tedesco F (2009) Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency. J Allergy Clin Immunol 124(6):1303–1310 e1304. doi:10.1016/j.jaci.2009.08.007 PubMedPubMedCentralCrossRef

105.

Hofman ZLM, Relan A, Zeerleeder S, Drouet C, Zuraw BL, Hack E (2016) Angioedema attacks of hereditary angioedema: local manifestations of a systemic activation process. J Allergy Clin Immunol in revision

106.

Aptecar E, Lecorvoisier P, Teiger E, Garot P, Dupouy P, Sediame S, Vermes E, Loisance D, Hittinger L, Dubois-Rande JL, Montagne O (2006) Coronary vasomotor response to the selective B1-kinin-receptor agonist Des-Arg9-bradykinin in humans. J Heart Lung Transplant: Off Publ Int Soc Heart Transplant 25(2):187–194. doi:10.1016/j.healun.2005.08.020 CrossRef

107.

Wu H, Roks AJ, Leijten FP, Garrelds IM, Musterd-Bhaggoe UM, van den Bogaerdt AJ, de Maat MP, Simoons ML, Danser AH, Oeseburg H (2014) Genetic variation and gender determine bradykinin type 1 receptor responses in human tissue: implications for the ACE-inhibitor-induced effects in patients with coronary artery disease. Clin Sci (Lond) 126(6):441–449. doi:10.1042/CS20130204 CrossRef

108.

Leeb-Lundberg LM, Kang DS, Lamb ME, Fathy DB (2001) The human B1 bradykinin receptor exhibits high ligand-independent, constitutive activity. Roles of residues in the fourth intracellular and third transmembrane domains. J Biol Chem 276(12):8785–8792PubMedCrossRef

109.

Ni A, Chao L, Chao J (1998) Transcription factor nuclear factor kappaB regulates the inducible expression of the human B1 receptor gene in inflammation. J Biol Chem 273(5):2784–2791PubMedCrossRef

110.

Christiansen SC, Eddleston J, Woessner KM, Chambers SS, Ye R, Pan ZK, Zuraw BL (2002) Up-regulation of functional kinin B1 receptors in allergic airway inflammation. J Immunol 169(4):2054–2060PubMedCrossRef

111.

Zhang X, Tan F, Zhang Y, Skidgel RA (2008) Carboxypeptidase M and kinin B1 receptors interact to facilitate efficient b1 signaling from B2 agonists. J Biol Chem 283(12):7994–8004. doi:10.1074/jbc.M709837200 PubMedCrossRef

112.

Zhang X, Tan F, Brovkovych V, Zhang Y, Skidgel RA (2011) Cross-talk between carboxypeptidase M and the kinin B1 receptor mediates a new mode of G protein-coupled receptor signaling. J Biol Chem 286(21):18547–18561. doi:10.1074/jbc.M110.214940 PubMedPubMedCentralCrossRef

113.

Zhang X, Tan F, Skidgel RA (2013) Carboxypeptidase M is a positive allosteric modulator of the kinin B1 receptor. J Biol Chem 288(46):33226–33240. doi:10.1074/jbc.M113.520791 PubMedPubMedCentralCrossRef

114.

Komarova Y, Malik AB (2010) Regulation of endothelial permeability via paracellular and transcellular transport pathways. Annu Rev Physiol 72:463–493. doi:10.1146/annurev-physiol-021909-135833 PubMedCrossRef

115.

Dejana E, Giampietro C (2012) Vascular endothelial-cadherin and vascular stability. Curr Opin Hematol 19(3):218–223. doi:10.1097/MOH.0b013e3283523e1c PubMedCrossRef

116.

Dejana E, Tournier-Lasserve E, Weinstein BM (2009) The control of vascular integrity by endothelial cell junctions: molecular basis and pathological implications. Dev Cell 16(2):209–221. doi:10.1016/j.devcel.2009.01.004 PubMedCrossRef

117.

Baumgartner W, Schutz GJ, Wiegand J, Golenhofen N, Drenckhahn D (2003) Cadherin function probed by laser tweezer and single molecule fluorescence in vascular endothelial cells. J Cell Sci 116(Pt 6):1001–1011PubMedCrossRef

118.

Huber AH, Stewart DB, Laurents DV, Nelson WJ, Weis WI (2001) The cadherin cytoplasmic domain is unstructured in the absence of beta-catenin. A possible mechanism for regulating cadherin turnover. J Biol Chem 276(15):12301–12309. doi:10.1074/jbc.M010377200 PubMedCrossRef

119.

Davis MA, Ireton RC, Reynolds AB (2003) A core function for p120-catenin in cadherin turnover. J Cell Biol 163(3):525–534. doi:10.1083/jcb.200307111 PubMedPubMedCentralCrossRef

120.

Pokutta S, Weis WI (2007) Structure and mechanism of cadherins and catenins in cell–cell contacts. Annu Rev Cell Dev Biol 23:237–261. doi:10.1146/annurev.cellbio.22.010305.104241 PubMedCrossRef

121.

Dyer LA, Patterson C (2010) Development of the endothelium: an emphasis on heterogeneity. Semin Thromb Hemost 36(3):227–235. doi:10.1055/s-0030-1253446 PubMedPubMedCentralCrossRef

122.

Schmaier AH, Kuo A, Lundberg D, Murray S, Cines DB (1988) The expression of high molecular weight kininogen on human umbilical vein endothelial cells. J Biol Chem 263:16327–16333PubMed

123.

Joseph K, Ghebrehiwet B, Peerschke EI, Reid KB, Kaplan AP (1996) Identification of the zinc-dependent endothelial cell binding protein for high molecular weight kininogen and factor XII: identity with the receptor that binds to the globular "heads" of C1q (gC1q-R). Proc Natl Acad Sci U S A 93(16):8552–8557PubMedPubMedCentralCrossRef

124.

Herwald H, Dedio J, Kellner R, Loos M, Muller-Esterl W (1996) Isolation and characterization of the kininogen-binding protein p33 from endothelial cells. Identity with the gC1q receptor. J Biol Chem 271(22):13040–13047PubMedCrossRef

125.

Schmaier AH (2016) The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost 14(1):28–39. doi:10.1111/jth.13194 PubMedCrossRef

126.

Mahdi F, Madar ZS, Figueroa CD, Schmaier AH (2002) Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes. Blood 99(10):3585–3596PubMedCrossRef

127.

Joseph K, Tholanikunnel BG, Ghebrehiwet B, Kaplan AP (2004) Interaction of high molecular weight kininogen binding proteins on endothelial cells. Thromb Haemost 91(1):61–70. doi:10.1160/TH03-07-0471 PubMed

128.

Renne T, Schuh K, Muller-Esterl W (2005) Local bradykinin formation is controlled by glycosaminoglycans. J Immunol 175(5):3377–3385PubMedCrossRef

129.

Ravindran S, Grys TE, Welch RA, Schapira M, Patston PA (2004) Inhibition of plasma kallikrein by C1-inhibitor: role of endothelial cells and the amino-terminal domain of C1-inhibitor. Thromb Haemost 92(6):1277–1283. doi:10.1160/TH04-01-0008 PubMed

130.

Joseph K, Tholanikunnel BG, Kaplan AP (2002) Activation of the bradykinin-forming cascade on endothelial cells: a role for heat shock protein 90. Int Immunopharmacol 2(13–14):1851–1859PubMedCrossRef

131.

Joseph K, Tholanikunnel BG, Kaplan AP (2002) Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci U S A 99(2):896–900. doi:10.1073/pnas.022626899 PubMedPubMedCentralCrossRef

132.

Shariat-Madar Z, Mahdi F, Schmaier AH (2002) Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Biol Chem 277(20):17962–17969. doi:10.1074/jbc.M106101200 PubMedCrossRef

133.

Mayhan WG (1994) Nitric oxide accounts for histamine-induced increases in macromolecular extravasation. Am J Phys 266(6 Pt 2):H2369–H2373

134.

Duran WN, Beuve AV, Sanchez FA (2013) Nitric oxide, S-nitrosation, and endothelial permeability. IUBMB Life 65(10):819–826. doi:10.1002/iub.1204 PubMedPubMedCentralCrossRef

135.

Nielsen EW, Johansen HT, Hogasen K, Wuillemin W, Hack CE, Mollnes TE (1996) Activation of the complement, coagulation, fibrinolytic and kallikrein-kinin systems during attacks of hereditary angioedema. Immunopharmacology 33(1–3):359–360PubMedCrossRef

136.

Bossi F, Fischetti F, Pellis V, Bulla R, Ferrero E, Mollnes TE, Regoli D, Tedesco F (2004) Platelet-activating factor and kinin-dependent vascular leakage as a novel functional activity of the soluble terminal complement complex. J Immunol 173(11):6921–6927PubMedCrossRef

137.

Bouillet L, Mannic T, Arboleas M, Subileau M, Massot C, Drouet C, Huber P, Vilgrain I (2011) Hereditary angioedema: key role for kallikrein and bradykinin in vascular endothelial-cadherin cleavage and edema formation. J Allergy Clin Immunol 128(1):232–234. doi:10.1016/j.jaci.2011.02.017 PubMedCrossRef

138.

Czucz J, Schaffer G, Csuka D, Walentin S, Kunde J, Prohaszka Z, Farkas H, Cervenak L (2012) Endothelial cell function in patients with hereditary angioedema: elevated soluble E-selectin level during inter-attack periods. J Clin Immunol 32(1):61–69. doi:10.1007/s10875-011-9606-7 PubMedCrossRef

139.

Kajdacsi E, Jani PK, Csuka D, Varga LA, Prohaszka Z, Farkas H, Cervenak L (2014) Endothelial cell activation during edematous attacks of hereditary angioedema types I and II. J Allergy Clin Immunol 133(6):1686–1691. doi:10.1016/j.jaci.2013.12.1072 PubMedCrossRef

140.

Demirturk M, Gelincik A, Cinar S, Kilercik M, Onay-Ucar E, Colakoglu B, Arda N, Buyukozturk S, Deniz G (2014) Increased eNOS levels in hereditary angioedema. Int Immunopharmacol 20(1):264–268. doi:10.1016/j.intimp.2014.03.007 PubMedCrossRef

Title: HAE Pathophysiology and Underlying Mechanisms
Authors: Bruce L. Zuraw
Sandra C. Christiansen
Publication date: 01-10-2016
Publisher: Springer US
Published in: Clinical Reviews in Allergy & Immunology / Issue 2/2016
Print ISSN: 1080-0549
Electronic ISSN: 1559-0267
DOI: https://doi.org/10.1007/s12016-016-8561-8

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

HAE Pathophysiology and Underlying Mechanisms

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2016

Review of Select Practice Parameters, Evidence-Based Treatment Algorithms, and International Guidelines for Hereditary Angioedema

The Humanistic, Societal, and Pharmaco-economic Burden of Angioedema

A Decade of Change: Recent Developments in Pharmacotherapy of Hereditary Angioedema (HAE)

Bradykinin: Inflammatory Product of the Coagulation System

The Story of Angioedema: from Quincke to Bradykinin

“Nuts and Bolts” of Laboratory Evaluation of Angioedema

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page