Hereditary angioedema (HAE) is a rare autosomic-dominant disorder characterized by a deficiency of C1 esterase inhibitor which causes episodic swellings of subcutaneous tissues, bowel walls and upper airways that are disabling and potentially life-threatening. We evaluated n = 17 patients with confirmed HAE diagnosis during attack and remission state and n = 19 healthy subjects. The samples were tested for a panel of IL (Interleukin)-17-type cytokines (IL-1β, IL-6, IL-10, granulocyte–macrophage colony stimulating factor (GM-CSF), IL-17, IL-21, IL-22, IL-23) and transforming growth factor-beta (TGF-β) subtypes. Data indicate that there are variations of cytokine levels in HAE subjects comparing the condition during the crisis respect to the value in the remission phase, in particular type 17 signature cytokines are increased, whereas IL-23 is unmodified and TGF-β3 is significantly reduced. When comparing healthy and HAE subjects in the remission state, we found a significant difference for IL-17, GM-CSF, IL-21, TGF-β1 and TGF-β2 cytokines. These results confirm and extend our previous findings indicating that in HAE there is operating an inflammatory activation process, which involves also T helper 17 (Th17) cytokines and TGF-β isoforms, associated with localized angioedema attacks and characterized by elevated bradykinin levels.
This is a preview of subscription content, log in to check access.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
Informed consent was obtained from all individual participants included in the study.
Agostoni A, Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Med (Baltimore). 1992;71(4):206–15.CrossRefGoogle Scholar
Kusuma A, Relan A, Knulst AC, et al. Clinical impact of peripheral attacks in hereditary angioedema patients. Am J Med. 2012;125:937.e17–24.CrossRefGoogle Scholar
Hofman ZLM, Relan A, Hack CE. Hereditary Angioedema attacks: local swelling at multiple sites. Clin Rev Allergy Immunol. 2016;50:34–40.CrossRefPubMedGoogle Scholar
Prematta MG, Kemp JG, Gibbs JG, Mende C, Rhoads C, Craig TJ. Fequency, timing, and type of prodromal symptoms associated with ereditary angioedema attacks. Allergy Asthma Proc. 2009;30:506–11.CrossRefPubMedGoogle Scholar
Magerl M, Doumoulakis G, Kalkounou I, et al. Characterization of prodromal symptoms in a large population of patiets with hereditary angioedema. Clin Exp Dermatol. 2014;39:298–303.CrossRefPubMedGoogle Scholar
Cillari E, Misiano G, Aricò M, et al. Modification of peripheral blood T-lymphocyte surface receptors and Langerhans cell numbers in hereditary angioedema. Am J Clin Pathol. 1986;85(3):305–11.CrossRefPubMedGoogle Scholar
Gluszko P, Undas A, Amenta S, Szczeklik A, Schmaier AH. Administration of gamma interferon in human subjects decreases plasminogen activation and fibrinolysis without influencing C1 inhibitor. J Lab Clin Med. 1994;123(2):232–40.PubMedGoogle Scholar
Arcoleo F, Salemi M, La Porta A, et al. Upregulation of cytokines and IL-17 in patients with hereditary angioedema. Clin Chem Lab Med. 2014;52(5):e91–3.CrossRefPubMedGoogle Scholar
Salemi M, Mandalà V, Muggeo V, et al. Growth factors and IL-17 in hereditary angioedema. Clin Exp Med. 2016;16(2):213–8.CrossRefPubMedGoogle Scholar
Hofman ZLM, 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;138:359–66.CrossRefPubMedGoogle Scholar
Berrettini M, Lammle B, White T, 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;68:455–61.PubMedGoogle Scholar
Cua DJ, Tato CM. Innate IL-17 producing cells: the sentinels of the immune system. Nat Rev Immunol. 2010;10:479–89.CrossRefPubMedGoogle Scholar
Zuniga LA, Jain R, Haines C, Cua DJ. Th17 cell development: from the cradle to the grave. Immunol Rev. 2013;252:78–88.CrossRefPubMedGoogle Scholar
Marks BR, Nowyhed HN, Choi JY, et al. Thymic self-reactivity selects natural interleukin 17-producing cells thet can regulate peripheral inflammation. Nat Immunol. 2009;10:1125–32.CrossRefPubMedPubMedCentralGoogle Scholar
Acosta-Rodriguez EV, Rivino L, Geginat J, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8(6):639–46.CrossRefPubMedGoogle Scholar
McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol. 2007;8(12):1390–7.CrossRefPubMedGoogle Scholar
Liang SC, Tan XY, Luxenberg DP, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med. 2006;203:2271–9.CrossRefPubMedPubMedCentralGoogle Scholar
Alam MS, Maekawa Y, Kitamura A, et al. Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc Natl Acad Sci USA. 2010;107:5943–8.CrossRefPubMedPubMedCentralGoogle Scholar
Zheng Y, Danilenko DM, Valdez P. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature. 2007;445:648–51.CrossRefPubMedGoogle Scholar
McGeachy MJ, Bak-Jensen KS, Chen Y, et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10by T cells and restrain Th17 cell-mediated pathology. Nat Immunol. 2007;8:1390–7.CrossRefPubMedGoogle Scholar
Esplugues E, Huber S, Gagliani N, et al. Control of Th17cells occurs in the small intestine. Nature. 2011;465:514–8.CrossRefGoogle Scholar
McGeachy MJ, Chen Y, Tato CM, et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17—producing effector T helper cells in vivo. Nat Immunol. 2009;10:314–24.CrossRefPubMedPubMedCentralGoogle Scholar
Chen Y, Langrish CL, McKenzie B, et al. Anti IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. J Clin Investig. 2006;116:1317–26.CrossRefPubMedPubMedCentralGoogle Scholar
Chackerian AA, Chen SJ, Brodie SJ, et al. Neutralization or absence of interleukin 23 pathway does not compromise immunity to mycobacterial infection. Infect Immun. 2006;74:6092–9.CrossRefPubMedPubMedCentralGoogle Scholar
Lieberman LA, Cardillo F, Owyang AM, et al. IL 23 provides a limited meccanism of resistance to acute toxoplasmosis in the absence of IL-12. J Immunol. 2004;173:1887–93.CrossRefPubMedGoogle Scholar
Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006;212:28–50.CrossRefPubMedGoogle Scholar
Leipe J, Grunke M, Dechant C, et al. Role of Th17 cells in human autoimmune arthritis. Arthr Rheumatol. 2010;62(10):2876–85.CrossRefGoogle Scholar
Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+ CD25- naive T cells to CD4+ CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198(12):1875–86.CrossRefPubMedPubMedCentralGoogle Scholar
Bas M, Adams V, Suvorava T, Niehues T, Hoffmann TK, Kojda G. Nonallergic angioedema: role of bradykinin. Allergy. 2007;10:842–56.CrossRefGoogle Scholar
Pan ZK, Zuraw BL, Lung CC, Prossnitz ER, Browning DD, Ye RD. Bradykinin stimulates NF-kappaB activation and interleukin 1-beta gene expression in cultured human fibroblasts. J Clin Investig. 1996;98:2042–9.CrossRefPubMedPubMedCentralGoogle Scholar
Brovkovych V, Zhang Y, Brovkovych S, Minshall RD, Skidgel RA. A novel pathway for receptor-mediated post-translational activation of inducible nitric oxide synthase. J Cell Mol Med. 2011;15:258–69.CrossRefPubMedGoogle Scholar
Uzawa A, Mori M, Taniguchi J, Kuwabara S. Modulation of kallikrein/kinin system by the angiotensin-converting enzyme inhibitor alleviates experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2014;178:245–52.CrossRefPubMedPubMedCentralGoogle Scholar