Advances in the Pathogenesis of Hereditary Angioedema

Xiangyi CUI, Yuxiang ZHI

Acta Academiae Medicinae Sinicae ›› 2024, Vol. 46 ›› Issue (6) : 924-931.

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Acta Academiae Medicinae Sinicae

Abbreviation (ISO4): Acta Academiae Medicinae Sinicae      Editor in chief: Xuetao CAO

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Acta Academiae Medicinae Sinicae ›› 2024, Vol. 46 ›› Issue (6) : 924-931. DOI: 10.3881/j.issn.1000-503X.15915
Review Articles

Advances in the Pathogenesis of Hereditary Angioedema

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Abstract

Hereditary angioedema (HAE) is a rare,unpredictable,autosomal dominant disorder characterized by recurrent swelling in subcutaneous and submucosal tissue.In recent years,the pathophysiology and pathogenesis of HAE have been continuously studied and elucidated.In addition to the genes encoding complement 1 esterase inhibitors,new pathogenic variants have been identified in the genes encoding coagulation factor Ⅻ,plasminogen,angiopoietin-1,kininogen,heparan sulfate 3-O-sulfotransferase 6,and myoferlin in HAE.Moreover,different pathogenic variants have different mechanisms in causing HAE.In addition,the pathogenic genes of some patients remain unknown.This review summarizes the recent progress in the classification,epidemiology,pathophysiology,and pathogenesis of HAE,aiming to provide ideas for further fundamental research,clinical diagnosis,and drug development of HAE.

Key words

hereditary angioedema / pathogenesis / C1 esterase inhibitor / SERPING1 gene / bradykinin

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Xiangyi CUI , Yuxiang ZHI. Advances in the Pathogenesis of Hereditary Angioedema[J]. Acta Academiae Medicinae Sinicae. 2024, 46(6): 924-931 https://doi.org/10.3881/j.issn.1000-503X.15915

References

[1]
Aberer W. Hereditary angioedema:an orphan but an original disease[J]. J Allergy Clin Immunol, 2021, 148(4):994-995.DOI:10.1016/j.jaci.2021.07.026.
[2]
Launay D, Bouillet L, Boccon-Gibod I, et al. Hereditary angioedema and its new treatments:an update[J]. Rev Med Interne, 2023, 44(7):344-353.DOI:10.1016/j.revmed.2023.01.020.
[3]
Santacroce R, D’andrea G, Maffione AB, et al. The genetics of hereditary angioedema:a review[J]. J Clin Med, 2021, 10(9):2023.DOI:10.3390/jcm10092023.
[4]
Quincke HI. Über akutes umschriebenes Hautödem[J]. Monatsh Prakt Dermatol, 1882, 1:129-131.
[5]
Osler W. Hereditary angio-neurotic oedema[J]. Am J Med Sci, 1888, 95:362-367.
[6]
Donaldson VH, Evans RR. A biochemical abnormality in hereditary angioneurotic edema:absence of serum inhibitor of C’1-esterase[J]. Am J Med, 1963, 35(1):37-44.DOI:10.1016/0002-9343(63)90162-1.
[7]
Rosen FS, Pensky J, Donaldson V, et al. Hereditary angioneurotic edema:two genetic variants[J]. Science, 1965, 148(3672):957-958.DOI:10.1126/science.148.3672.957.
[8]
Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema:the clinical syndrome and its management[J]. Ann Intern Med, 1976, 84(5):580-593.DOI:10.7326/0003-4819-84-5-580.
[9]
Rosen FS, Alper CA, Pensky J, et al. Genetically determined heterogeneity of the C1 esterase inhibitor in patients with hereditary angioneurotic edema[J]. J Clin Invest, 1971, 50(10):2143-2149.DOI:10.1172/jci106708.
[10]
Nussberger J, Cugno M, Amstutz C, et al. Plasma bradykinin in angio-oedema[J]. Lancet, 1998, 351(9117):1693-1697.DOI:10.1016/s0140-6736(97)09137-x.
[11]
Binkley KE, Davis A 3rd. Clinical,biochemical,and genetic characterization of a novel estrogen-dependent inherited form of angioedema[J]. J Allergy Clin Immunol, 2000, 106(3):546-550.DOI:10.1067/mai.2000.108106.
[12]
Bork K, Barnstedt SE, Koch P, et al. Hereditary angioedema with normal C1-inhibitor activity in women[J]. Lancet, 2000, 356(9225):213-217.DOI:10.1016/s0140-6736(00)02483-1.
[13]
支玉香, 安利新, 赖荷, 等. 遗传性血管性水肿的诊断和治疗专家共识[J]. 中华临床免疫和变态反应杂志, 2019, 13(1):1-4.DOI:10.3969/j.issn.1673-8705.2019.01.001.
[14]
Proper SP, Lavery WJ, Bernstein JA. Definition and classification of hereditary angioedema[J]. Allergy Asthma Proc, 2020, 41(6):S03-S07.DOI:10.2500/aap.2020.41.200040.
[15]
曹阳, 刘爽, 支玉香. 遗传性血管性水肿发病机制研究进展[J]. 中国医学科学院学报, 2020, 42(5):686-690.DOI:10.3881/j.issn.1000-503X.11407.
[16]
Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema-the 2021 revision and update[J]. Allergy, 2022, 77(7):1961-1990.DOI:10.1111/all.15214.
[17]
Wilkerson RG, Moellman JJ. Hereditary angioedema[J]. Emerg Med Clin North Am, 2022, 40(1):99-118.DOI:10.1016/j.emc.2021.09.002.
[18]
Aygören-Pürsün E, Magerl M, Maetzel A, et al. Epidemiology of bradykinin-mediated angioedema:a systematic investigation of epidemiological studies[J]. Orphanet J Rare Dis, 2018, 13(1):73.DOI:10.1186/s13023-018-0815-5.
[19]
Busse PJ, Christiansen SC. Hereditary angioedema[J]. N Engl J Med, 2020, 382(12):1136-1148.DOI:10.1056/NEJMra1808012.
[20]
Kaplan AP, Joseph K. Complement,kinins,and hereditary angioedema:mechanisms of plasma instability when C1 inhibitor is absent[J]. Clin Rev Allergy Immunol, 2016, 51(2):207-215.DOI:10.1007/s12016-016-8555-6.
[21]
De Maat S, Joseph K, Maas C, et al. Blood clotting and the pathogenesis of types Ⅰ and Ⅱ hereditary angioedema[J]. Clin Rev Allergy Immunol, 2021, 60(3):348-356.DOI:10.1007/s12016-021-08837-6.
[22]
Steiner UC, Keller M, Schmid P, et al. Mutational spectrum of the SERPING1 gene in Swiss patients with hereditary angioedema[J]. Clin Exp Immunol, 2017, 188(3):430-436.DOI:10.1111/cei.12941.
[23]
Ponard D, Gaboriaud C, Charignon D, et al. SERPING1 mutation update:mutation spectrum and C1 Inhibitor phenotypes[J]. Hum Mutat, 2020, 41(1):38-57.DOI:10.1002/humu.23917.
[24]
Kaplan AP, Joseph K. Pathogenesis of hereditary angioedema:the role of the bradykinin-forming cascade[J]. Immunol Allergy Clin North Am, 2017, 37(3):513-525.DOI:10.1016/j.iac.2017.04.001.
[25]
Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA medical advisory board 2020 guidelines for the management of hereditary angioedema[J]. J Allergy Clin Immunol Pract, 2021, 9(1):132-150.e133.DOI:10.1016/j.jaip.2020.08.046.
[26]
Levi M, Cohn DM, Zeerleder S. Hereditary angioedema:linking complement regulation to the coagulation system[J]. Res Pract Thromb Haemost, 2019, 3(1):38-43.DOI:10.1002/rth2.12175.
[27]
Cicardi M, Zuraw BL. Angioedema due to bradykinin dysregulation[J]. J Allergy Clin Immunol Pract, 2018, 6(4):1132-1141.DOI:10.1016/j.jaip.2018.04.022.
[28]
Lopez Lera A. Pathophysiology and underlying mechanisms in hereditary angioedema[J]. Balkan Med J, 2021, 38(2):82-88.DOI:10.4274/balkanmedj.galenos.2020.2020.10.166.
[29]
Margaglione M, D’apolito M, Santocroce R, et al. Hereditary angioedema:looking for bradykinin production and triggers of vascular permeability[J]. Clin Exp Allergy, 2019, 49(11):1395-1402.DOI:10.1111/cea.13506.
[30]
Bossi F, Fischetti F, Regoli D, et al. Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency[J]. J Allergy Clin Immunol, 2009, 124(6):1303-1310.e1304.DOI:10.1016/j.jaci.2009.08.007.
[31]
Longhurst H, Cicardi M, Craig T, et al. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor[J]. N Engl J Med, 2017, 376(12):1131-1140.DOI:10.1056/NEJMoa1613627.
[32]
Zuraw BL, Cicardi M, Longhurst HJ, et al. Phase Ⅱ study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate[J]. Allergy, 2015, 70(10):1319-1328.DOI:10.1111/all.12658.
[33]
Zuraw BL, Christiansen SC. HAE pathophysiology and underlying mechanisms[J]. Clin Rev Allergy Immunol, 2016, 51(2):216-229.DOI:10.1007/s12016-016-8561-8.
[34]
Haslund D, Ryo LB, Seidelin Majidi S, et al. Dominant-negative SERPING1 variants cause intracellular retention of C1 inhibitor in hereditary angioedema[J]. J Clin Invest, 2019, 129(1):388-405.DOI:10.1172/JCI98869.
[35]
Conigliaro P, Triggianese P, Ballanti E, et al. Complement,infection,and autoimmunity[J]. Curr Opin Rheumatol, 2019, 31(5):532-541.DOI:10.1097/bor.0000000000000633.
[36]
Cugno M, Zanichelli A, Bellatorre AG, et al. Plasma biomarkers of acute attacks in patients with angioedema due to C1-inhibitor deficiency[J]. Allergy, 2009, 64(2):254-257.DOI:10.1111/j.1398-9995.2008.01859.x.
[37]
Grover SP, Kawano T, Wan J, et al. C1 inhibitor deficiency enhances contact pathway-mediated activation of coagulation and venous thrombosis[J]. Blood, 2023, 141(19):2390-2401.DOI:10.1182/blood.2022018849.
[38]
Gailani D. Hereditary angioedema and thrombosis[J]. Blood, 2023, 141(19):2295-2297.DOI:10.1182/blood.2023019861.
[39]
Bork K, Wulff K, Witzke G, et al. Treatment for hereditary angioedema with normal C1-INH and specific mutations in the F12 gene (HAE-FXII)[J]. Allergy, 2017, 72(2):320-324.DOI:10.1111/all.13076.
[40]
Bork K, Wulff K, Witzke G, et al. Treatment of patients with hereditary angioedema with the c.988A>G (p.Lys330Glu) variant in the plasminogen gene[J]. Orphanet J Rare Dis, 2020, 15(1):52.DOI:10.1186/s13023-020-1334-8.
[41]
Serrano C, Guilarte M, Tella R, et al. Oestrogen-dependent hereditary angio-oedema with normal C1 inhibitor:description of six new cases and review of pathogenic mechanisms and treatment[J]. Allergy, 2008, 63(6):735-741.DOI:10.1111/j.1398-9995.2007.01579.x.
[42]
Miranda AR, Ue AP, Sabbag DV, et al. Hereditary angioedema type Ⅲ (estrogen-dependent) report of three cases and literature review[J]. An Bras Dermatol, 2013, 88(4):578-584.DOI:10.1590/abd1806-4841.20131818.
[43]
Bork K, Machnig T, Wulff K, et al. Clinical features of genetically characterized types of hereditary angioedema with normal C1 inhibitor:a systematic review of qualitative evidence[J]. Orphanet J Rare Dis, 2020, 15(1):289.DOI:10.1186/s13023-020-01570-x.
[44]
Bork K, Wulff K, Hardt J, et al. Characterization of a partial exon 9/intron 9 deletion in the coagulation factor Ⅻ gene (F12) detected in two Turkish families with hereditary angioedema and normal C1 inhibitor[J]. Haemophilia, 2014, 20(5):e372-e375.DOI:10.1111/hae.12519.
[45]
Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor Ⅻ (Hageman factor) causes hereditary angioedema type Ⅲ[J]. Am J Hum Genet, 2006, 79(6):1098-1104.DOI:10.1086/509899.
[46]
Hashimura C, Kiyohara C, Fukushi JI, et al. Clinical and genetic features of hereditary angioedema with and without C1-inhibitor (C1-INH) deficiency in Japan[J]. Allergy, 2021, 76(11):3529-3534.DOI:10.1111/all.15034.
[47]
Miyata T, Horiuchi T. Biochemistry,molecular genetics,and clinical aspects of hereditary angioedema with and without C1 inhibitor deficiency[J]. Allergol Int, 2023, 72(3):375-384.DOI:10.1016/j.alit.2023.04.004.
[48]
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[J]. Blood, 2019, 133(10):1152-1163.DOI:10.1182/blood-2018-06-860270.
[49]
Björkqvist J, De Maat S, Lewandrowski U, et al. Defective glycosylation of coagulation factor Ⅻ underlies hereditary angioedema type Ⅲ[J]. J Clin Invest, 2015, 125(8):3132-3146.DOI:10.1172/jci77139.
[50]
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]. J Allergy Clin Immunol, 2016, 138(5):1414-1423.e1419.DOI:10.1016/j.jaci.2016.02.021.
[51]
Kaplan AP, Austen KF. A prealbumin activator of prekallikrein.II.Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin[J]. J Exp Med, 1971, 133(4):696-712.DOI:10.1084/jem.133.4.696.
[52]
Bork K, Wulff K, Steinmüller-Magin L, et al. Hereditary angioedema with a mutation in the plasminogen gene[J]. Allergy, 2018, 73(2):442-450.DOI:10.1111/all.13270.
[53]
Dewald G. A missense mutation in the plasminogen gene,within the plasminogen kringle 3 domain,in hereditary angioedema with normal C1 inhibitor[J]. Biochem Biophys Res Commun, 2018, 498(1):193-198.DOI:10.1016/j.bbrc.2017.12.060.
[54]
Veronez CL, Csuka D, Sheikh FR, et al. The expanding spectrum of mutations in hereditary angioedema[J]. J Allergy Clin Immunol Pract, 2021, 9(6):2229-2234.DOI:10.1016/j.jaip.2021.03.008.
[55]
Law RH, Caradoc-Davies T, Cowieson N, et al. The X-ray crystal structure of full-length human plasminogen[J]. Cell Rep, 2012, 1(3):185-190.DOI:10.1016/j.celrep.2012.02.012.
[56]
Shamanaev A, Dickeson SK, Ivanov I, et al. Mechanisms involved in hereditary angioedema with normal C1-inhibitor activity[J]. Front Physiol, 2023, 14:1146834.DOI:10.3389/fphys.2023.1146834.
[57]
Kaplan AP. Hereditary angioedema:investigational therapies and future research[J]. Allergy Asthma Proc, 2020, 41(1):S51-S54.DOI:10.2500/aap.2020.41.200056.
[58]
Dickeson SK, Kumar S, Sun MF, et al. A mechanism for hereditary angioedema caused by a lysine 311-to-glutamic acid substitution in plasminogen[J]. Blood, 2022, 139(18):2816-2829.DOI:10.1182/blood.2021012945.
[59]
Wang K, Geiger H, Mcmahon A. Tranexamic acid for ACE inhibitor induced angioedema[J]. Am J Emerg Med, 2021, 43:292.e295-292.e297.DOI:10.1016/j.ajem.2020.10.029.
[60]
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]. J Allergy Clin Immunol, 2018, 141(3):1009-1017.DOI:10.1016/j.jaci.2017.05.020.
[61]
Ariano A, D’apolito M, Bova M, et al. A myoferlin gain-of-function variant associates with a new type of hereditary angioedema[J]. Allergy, 2020, 75(11):2989-2992.DOI:10.1111/all.14454.
[62]
Baffert F, Le T, Thurston G, et al. Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules[J]. Am J Physiol Heart Circ Physiol, 2006, 290(1):H107-H118.DOI:10.1152/ajpheart.00542.2005.
[63]
D’apolito M, Santacroce R, Colia AL, et al. Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema[J]. Clin Exp Allergy, 2019, 49(5):626-635.DOI:10.1111/cea.13349.
[64]
Zuraw BL. Hereditary angioedema with normal C1 inhibitor:four types and counting[J]. J Allergy Clin Immunol, 2018, 141(3):884-885.DOI:10.1016/j.jaci.2018.01.015.
[65]
Loules G, Parsopoulou F, Zamanakou M, et al. Deciphering the genetics of primary angioedema with normal levels of C1 inhibitor[J]. J Clin Med, 2020, 9(11):3402.DOI:10.3390/jcm9113402.
[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[J]. Allergy, 2019, 74(12):2479-2481.DOI:10.1111/all.13869.
[67]
Bernatchez PN, Acevedo L, Fernandez-Hernando C, et al. Myoferlin regulates vascular endothelial growth factor receptor-2 stability and function[J]. J Biol Chem, 2007, 282(42):30745-30753.DOI:10.1074/jbc.M704798200.
[68]
Bork K, Wulff K, Möhl BS, et al. Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation[J]. J Allergy Clin Immunol, 2021, 148(4):1041-1048.DOI:10.1016/j.jaci.2021.01.011.
[69]
Chopra P, Joshi A, Wu J, et al. The 3-O-sulfation of heparan sulfate modulates protein binding and lyase degradation[J]. Proc Natl Acad Sci U S A, 2021, 118(3):e2012935118.DOI:10.1073/pnas.2012935118.
[70]
Mochizuki H, Futatsumori H, Suzuki E, et al. A quantitative method to detect non-antithrombin-binding 3-O-sulfated units in heparan sulfate[J]. J Biol Chem, 2021, 296:100115.DOI:10.1074/jbc.RA120.015864.
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