Pathophysiology and underlying mechanisms in hereditary angioedema

This review aims to summarize the main pathophysiological events involved in the development of hereditary angioedema (OMIM#106100).Hereditary angioedema is a rare genetic disease inherited in an autosomal dominant manner and caused by a loss of control over theplasma contact system or kallikrein-kinin system, which results in unrestrained bradykinin generation or signaling. In patients with hereditary angioedema, BK binding to endothelial cells leads to recurrentepisodes of swelling at subcutaneous or submucosal tissues that can belife threatening when affecting the upper respiratory tract. The diseasecan either present with hypocomplementemia owing to the presenceof pathogenic variants in the gene encoding complement C1 inhibitor(hereditary angioedema with C1-inhibitor deficiency) or present withnormocomplementemia and associate with elevated estrogen levelsowing to gain-of-function variants in the genes encoding coagulationproteins involved in the kallikrein-kinin system (namely, coagulationFXII [FXII-associated hereditary angioedema], plasminogen [PLG-associated hereditary angioedema], and high-molecular-weight kininogen[KNG1-associated hereditary angioedema]). Moreover, in recent years,novel pathogenic variants have been described in the genes encodingangiopoietin 1 (ANGPT1-associated hereditary angioedema) and myoferlin (MYOF-associated hereditary angioedema), which further expand the pathophysiological picture of hereditary angioedema.

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1. Caballero T, Baeza ML, Cabañas R, et al. Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis. J Investig Allergol Clin Immunol. 2011;21(5):333-347; quiz follow 347.
2. Donaldson VH, Evans RR. A biochemical abnormality in herediatry angioneurotic edema: absence of serum inhibitor of C’ 1-ESTERASE. Am J Med. 1963;35:37-44. [Crossref]
3. Marcelino-Rodriguez I, Callero A, Mendoza-Alvarez A, et al. Bradykinin-mediated angioedema: an update of the genetic causes and the impact of genomics. Front Genet. 2019;10:900. [Crossref]
4. Schmaier AH. The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities. J Thromb Haemost. 2016 J;14(1):28-39. [Crossref]
5. Renné T. The procoagulant and proinflammatory plasma contact system. Semin Immunopathol. 2012;34(1):31-41. [Crossref]
6. Weidmann H, Heikaus L, Long AT, Naudin C, Schlüter H, Renné T. The plasma contact system, a protease cascade at the nexus of inflammation, coagulation and immunity. Biophys Acta Mol Cell Res. 2017;1864(11 Pt B):2118-2127. [Crossref]
7. Pathak M, Wilmann P, Awford J, et al. Coagulation factor XII protease domain crystal structure. J Thromb Haemost. 2015;13(4):580-591. [Crossref]
8. Kaplan AP, Joseph K. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammatory pathway. Adv Immunol. 2014;121:41-89. [Crossref]
9. Ghebrehiwet B, Silverberg M, Kaplan AP. Activation of the classical pathway of complement by Hageman factor fragment. J Exp Med. 1981;153(3):665-676. [Crossref]
10. Mandle RJ, Colman RW, Kaplan AP. Identification of prekallikrein and high-molecular-weight kininogen as a complex in human plasma. Proc Natl Acad Sci U S A. 1976;73(11):4179-4183. [Crossref]
11. Scott CF, Colman RW. Function and immunochemistry of prekallikrein-high molecular weight kininogen complex in plasma. J Clin Invest. 1980;65(2):413-421.
12. Tankersley DL, Finlayson JS. Kinetics of activation and autoactivation of human factor XII. Biochemistry. 1984;23(2):273-279. [Crossref]
13. Irmscher S, Döring N, Halder LD, et al. Kallikrein Cleaves C3 and Activates Complement. J Innate Immun. 2018;10(2):94-105. [Crossref]
14. Colman RW, Schmaier AH. Contact system: A vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood. 1997;90(10):3819-3843. [Crossref]
15. Lalmanach G, Naudin C, Lecaille F, Fritz H. Kininogens: More than cysteine protease inhibitors and kinin precursors. Biochimie. 2010 ;92(11):1568-1579. [Crossref]
16. Herwald H, Dedio J, Kellner R, Loos M, Muller-Esterl W. Isolation and characterization of the kininogen-binding protein p33 from endothelial cells. Identity with the gC1q receptor. J Biol Chem. 1996;271(22):13040-13047. [Crossref]
17. Mahdi F, Madar ZS, Figueroa CD, Schmaier AH. Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes. Blood. 2002;99(10):3585-3596. [Crossref]
18. Colman RW, Pixley RA, Najamunnisa S, et al. Binding of high molecular weight kininogen to human endothelial cells is mediated via a site within domains 2 and 3 of the urokinase receptor. J Clin Invest. 1997;100(6):1481-1487. [Crossref]
19. Kaplan AP, Austen KF. A pre-albumin activator of prekallikrein. J Immunol. 1970;105(4):802-811.
20. Shariat-Madar Z, Mahdi F. Schmaier A. Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Biol Chem. 2002;277(20):17962-17969. [Crossref]
21. Adams GN, LaRusch GA, Stavrou E, et al. Murine prolylcarboxypeptidase depletion induces vascular dysfunction with hypertension and faster arterial thrombosis. Blood. 2011;117:3929-3937. [Crossref]
22. Joseph K, Tholanikunnel BG, Kaplan AP. Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci U S A. 2002;99(2):896-900. [Crossref]
23. Joseph K, Tholanikunnel BG, Kaplan AP. Activation of the bradykinin-forming cascade on endothelial cells: a role for heat shock protein 90. Int Immunopharmacol. 2002;2(13-14):1851-1859. [Crossref]
24. Maas C, Schiks B, Strangi RD, et al. Identification of fibronectin type I domains as amyloid-binding modules on tissue-type plasminogen activator and three homologs. Amyloid. 2008;15(3):166-180. [Crossref]
25. Cameron CL, Fisslthaler B, Sherman A, Reddigari S, Silverberg M. Studies on contact activation: effects of surface and inhibitors. Med Prog Technol. 1989;15(1-2):53- 62.
26. Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G. Nonallergic angioedema: role of bradykinin. Allergy. 2007;62(8):842-856. [Crossref]
27. Howl J, Payne S. Bradykinin receptors as a therapeutic target. Expert Opin Ther Targets. 2003;7(2):277-285. [Crossref]
28. Marceau F, Hess JF, Bachvarov DR. The B1 receptors for kinins. Pharmacol Rev. 1998;50(3):357-386.
29. Marceau F, Regoli D. Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov. 2004;3(10):845-852. [Crossref]
30. Marceau F, Rivard GE, Gauthier JM, et al. Measurement of bradykinin formation and degradation in blood plasma: relevance for acquired angioedema associated with angiotensin converting enzyme inhibition and for hereditary angioedema due to factor XII or plasminogen gene variants. Front Med (Lausanne). 2020;7:358. [Crossref]
31. de Maat S, Björkqvist J, Suffritti C, Wiesenekker CP, Nagtegaal W, Koekman A, van Dooremalen S, Pasterkamp G, de Groot PG, Cicardi M, Renné T, Maas C. Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations. J Allergy Clin Immunol. 2016;138(5):1414-1423.e9. [Crossref]
32. Sheikh I, Kaplan A. Studies of the digestion of bradykinin, Lys-bradykinin, and des-Arg9-bradykinin by angiotensin converting enzyme. Biochem Pharmacol. 1986;35(12):1951-1956. [Crossref]
33. Sheikh I, Kaplan A. Studies of the digestion of bradykinin, lysyl bradykinin, and kinin-degradation products by carboxypeptidases A, B, and N. Biochem Pharmacol. 1986;35(12):1957-1963. [Crossref]
34. Nussberger J, Cugno M, Amstutz C, Cicardi M, Pellacani A, Agostoni A. Plasma bradykinin in angioedema. Lancet. 1998;351(9117):1693-1697. [Crossref]
35. Griesbacher T, Sametz W, Legat FJ, Diethart S, Hammer S, Juan H. Effects of the non-peptide B2 antagonist FR173657 on kinin-induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release. Br J Pharmacol. 1997;121(3):469-476. [Crossref]
36. Griesbacher T, Legat FJ. Effects of FR173657, a non-peptide B2 antagonist, on kinin-induced hypotension, visceral and peripheral oedema formation and bronchoconstriction. Br J Pharmacol. 1997;120(5):933-939. [Crossref]
37. Su JB. Kinins and cardiovascular diseases. Curr Pharm Des. 2006;12(26):3423-3435. [Crossref]
38. Loffredo S, Bova M, Suffritti C, et al. Elevated plasma levels of vascular permeability factors in C1 inhibitor-deficient hereditary angioedema. Allergy. 2016;71(7):989-996. [Crossref]
39. Loffredo S, Ferrara AL, Bova M, et al. Secreted Phospholipases A(2) in Hereditary Angioedema With C1-Inhibitor Deficiency. Front Immunol. 2018;9:1721. [Crossref]
40. Koumbadinga GA, Désormeaux A, Adam A, Marceau F. Effect of interferon-γ on inflammatory cytokine-induced bradykinin B1 receptor expression in human vascular cells. Eur J Pharmacol. 2010;647(1-3):117-125. [Crossref]
41. Enquist J, Sandén C, Skröder C, Mathis SA, Leeb-Lundberg LM. Kinin-stimulated B1 receptor signaling depends on receptor endocytosis whereas B2 receptor signaling does not. Neurochem Res. 2014;39(6):1037-1047. [Crossref]
42. Wolsing DH, Rosenbaum JS. Bradykinin-stimulated inositol phosphate production in NG108-15 cells is mediated by a small population of binding sites which rapidly desensitize. J Pharmacol Exp Ther. 1991;257(2):621-633.
43. Nussberger J, Cugno M, Cicardi M. Bradykinin-mediated angioedema. N Engl J Med. 2002;347(8):621-622. [Crossref]
44. Cugno M, Cicardi M, Coppola R, Agostoni A. Activation of factor XII and cleavage of high molecular weight kininogen during acute attacks in hereditary and acquired C1-inhibitor deficiencies. Immunopharmacology 1996;33(1-3):361-364. [Crossref]
45. Suffritti C, Zanichelli A, Maggioni L, Bonanni E, Cugno M, Cicardi M. High-molecular-weight kininogen cleavage correlates with disease states in the bradykinin-mediated angioedema due to hereditary C1-inhibitor deficiency. Clin Exp Allergy. 2014;44(12):1503-1514. [Crossref]
46. Defendi F, Charignon D, Ghannam A, et al. Enzymatic assays for the diagnosis of bradykinin-dependent angioedema. PLoS One. 2013;8(8):e70140. [Crossref]
47. Curd J, Prograis LJ, Cochrane C. Detection of active kallikrein in induced blister fluids of hereditary angioedema patients. J Exp Med. 1980;152(3):742-747. [Crossref]
48. Nussberger J, Cugno M, Cicardi M, Agostoni A. Local bradykinin generation in hereditary angioedema. J Allergy Clin Immunol 1999;104(6):1321-1322. [Crossref]
49. Hofman ZL, Relan A, Zeerleder S, Drouet C, Zuraw B, Hack CE. Angioedema attacks in patients with hereditary angioedema: Local manifestations of a systemic activation process. J Allergy Clin Immunol. 2016;138(2):359-366. [Crossref]
50. Bork K, Barnstedt SE, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet. 2000;356(9225):213-217. [Crossref]
51. Binkley KE, Davis A 3rd. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol. 2000;106(3):546-550. [Crossref]
52. Cugno M, Zanichelli A, Bellatorre AG, Griffini S, Cicardi M. Plasma biomarkers of acute attacks in patients with angioedema due to C1-inhibitor deficiency. Allergy. 2009;64(2):254-257. [Crossref]
53. Kaplan A. Enzymatic pathways in the pathogenesis of hereditary angioedema: the role of C1 inhibitor therapy. J Allergy Clin Immunol. 2010;126(5):918-925. [Crossref]
54. de Maat S, Björkqvist J, Suffritti C, et al. Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations. J Allergy Clin Immunol. 2016;138(5):1414-1423.e9. [Crossref]
55. Ivanov I, Matafonov A, Sun MF, et al. A mechanism for hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the factor XII heavy chain. Blood. 2019;133(10):1152-1163. [Crossref]
56. Farsetti A, Misiti S, Citarella F, et al. Molecular basis of estrogen regulation of Hageman factor XII gene expression. Endocrinology. 1995;136(11):5076-5083. [Crossref]
57. Bork K, Wulff K, Steinmüller-Magin L, et al. Hereditary angioedema with a mutation in the plasminogen gene. Allergy. 2018;73(2):442-450. [Crossref]
58. Dewald G. A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun. 2018;498(1):193-198. [Crossref]
59. Sheffer A, Austen K, Rosen F. Tranexamic acid therapy in hereditary angioneurotic edema. N Engl J Med. 1972; 1972287(9):452-454.
60. Bork K, Wulff K, Witzke G, Hardt J. Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII). Allergy. 2017;72(2):320-324. [Crossref]
61. Bork K. Acquired and hereditary forms of recurrent angioedema: Update of treatment. Allergol Select. 2018;2(1):121-131. [Crossref]
62. Joseph K, Tholanikunnel BG, Wolf B, Bork K, Kaplan AP. Deficiency of plasminogen activator inhibitor 2 in plasma of patients with hereditary angioedema with normal C1 inhibitor levels. J Allergy Clin Immunol. 2016;137(6):1822-1829.e1. [Crossref]
63. Bafunno V, Firinu D, D’Apolito M, et al. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. J Allergy Clin Immunol. 2018;141(3):1009-1017. [Crossref]
64. Baffert F, Le T, Thurston G, McDonald DM. Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules. Am J Physiol Heart Circ Physiol. 2006;290(1):H107-118. [Crossref]
65. D’Apolito M, Santacroce R, Colia AL, Cordisco G, Maffione AB, Margaglione M. Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema. Clin Exp Allergy. 2019;49(5):626-635. [Crossref]
66. Bork K, Wulff K, Rossmann H, et al. Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin. Allergy. 2019;74(12):2479-2481. [Crossref]
67. Ariano A, D’Apolito M, Bova M, et al. A myoferlin gain-of-function variant associates with a new type of hereditary angioedema. Allergy. 2020;75(11):2989-2992. [Crossref]