Neutrophils impact on processes preceding the formation of bradykinin, a major swelling mediator in hereditary angioedema (HAE), yet their potential role in HAE pathogenesis has not been sufficiently studied. We assessed the relative mRNA expression of 10 genes related to neutrophil activation using RNA extracted from the peripheral blood neutrophils of 23 HAE patients in a symptom-free period and 39 healthy donors. Increased relative mRNA expression levels of CD274, IL1B, IL1RN, IL8, MMP9, and TLR4, together with a lack in their mutual correlations detected in HAE patients compared to healthy controls, suggested a preactivated state and dysregulation of patients' neutrophils. Patients' neutrophil-alerted state was further supported by increased CD11b, decreased CD16 plasma membrane deposition, and increased relative CD274+ and CD87+ neutrophil counts, but not by increased neutrophil elastase or myeloperoxidase plasma levels. As CD274 mediates inhibitory signals to different immune cells, neutrophils were cocultured with T-cells/PBMC. The decrease in CD25+ and IFN-γ + T-cell/PBMC ratio in patients indicated the patients' neutrophil suppressive functions. In summary, the results showed neutrophils' alerted state and dysregulation at the transcript level in patients with HAE types I and II even in a symptom-free period, which might make them more susceptible to edema formation. Neutrophils' T-cell suppressive capacity in HAE patients needs to be further investigated.

Central European Institute of Technology Masaryk University Brno Czech Republic

Centre for Cardiovascular Surgery and Transplantation Brno Czech Republic

Department of Clinical Immunology and Allergology Faculty of Medicine Masaryk University Brno Czech Republic

St Anne's University Hospital Brno Czech Republic

Zobrazit více v PubMed

Agostoni A., Aygorenpursun E., Binkley K., et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. Journal of Allergy and Clinical Immunology. 2004;114(3):S51–131. doi: 10.1016/j.jaci.2004.06.047. PubMed DOI PMC

Bissler J. J., Aulak K. S., Donaldson V. H., et al. Molecular defects in hereditary angioneurotic edema. Proceedings of the Association of American Physicians. 1997;109(2):164–173. PubMed

Cichon S., Martin L., Hennies H. C., et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. American Journal of Human Genetics. 2006;79(6):1098–1104. doi: 10.1086/509899. PubMed DOI PMC

Winnewisser J., Rossi M., Späth P., Bürgi H. Type I hereditary angio-oedema. Variability of clinical presentation and course within two large kindreds. Journal of Internal Medicine. 1997;241(1):39–46. doi: 10.1046/j.1365-2796.1997.76893000.x. PubMed DOI

Zuraw B. L., Herschbach J. Detection of C1 inhibitor mutations in patients with hereditary angioedema. Journal of Allergy and Clinical Immunology. 2000;105(3):541–546. doi: 10.1067/mai.2000.104780. PubMed DOI

Bork K., Wulff K., Steinmüller-Magin L., et al. Hereditary angioedema with a mutation in the plasminogen gene. Allergy. 2018;73(2):442–450. doi: 10.1111/all.13270. PubMed DOI

Joseph K., Tuscano T. B., Kaplan A. P. Studies of the mechanisms of bradykinin generation in hereditary angioedema plasma. Annals of Allergy, Asthma & Immunology. 2008;101(3):279–286. doi: 10.1016/S1081-1206(10)60493-0. PubMed DOI

Nussberger J., Cugno M., Amstutz C., Cicardi M., Pellacani A., Agostoni A. Plasma bradykinin in angio-oedema. The Lancet. 1998;351(9117):1693–1697. doi: 10.1016/S0140-6736(97)09137-X. PubMed DOI

Bafunno V., Firinu D., D'Apolito M., et al. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. Journal of Allergy and Clinical Immunology. 2018;141(3):1009–1017. doi: 10.1016/j.jaci.2017.05.020. PubMed DOI

Amulic B., Cazalet C., Hayes G. L., Metzler K. D., Zychlinsky A. Neutrophil function: from mechanisms to disease. Annual Review of Immunology. 2012;30(1):459–489. doi: 10.1146/annurev-immunol-020711-074942. PubMed DOI

Mayadas T. N., Cullere X., Lowell C. A. The multifaceted functions of neutrophils. Annual Review of Pathology. 2014;9(1):181–218. doi: 10.1146/annurev-pathol-020712-164023. PubMed DOI PMC

Timár C. I., Lőrincz A. M., Ligeti E. Changing world of neutrophils. Pflügers Archiv. 2013;465(11):1521–1533. doi: 10.1007/s00424-013-1285-1. PubMed DOI

Nauseef W. M., Borregaard N. Neutrophils at work. Nature Immunology. 2014;15(7):602–611. doi: 10.1038/ni.2921. PubMed DOI

Henderson L. M., Figueroa C. D., Müller-Esterl W., Bhoola K. D. Assembly of contact-phase factors on the surface of the human neutrophil membrane. Blood. 1994;84(2):474–482. PubMed

Araújo R. C., Kettritz R., Fichtner I., Paiva A. C., Pesquero J. B., Bader M. Altered neutrophil homeostasis in kinin B1 receptor-deficient mice. Biological Chemistry. 2001;382(1):91–95. doi: 10.1515/BC.2001.014. PubMed DOI

Wachtfogel Y. T., Pixley R. A., Kucich U., et al. Purified plasma factor XIIa aggregates human neutrophils and causes degranulation. Blood. 1986;67(6):1731–1737. PubMed

Veszeli N., Csuka D., Zotter Z., et al. Neutrophil activation during attacks in patients with hereditary angioedema due to C1-inhibitor deficiency. Orphanet Journal of Rare Diseases. 2015;10(1):p. 156. doi: 10.1186/s13023-015-0374-y. PubMed DOI PMC

Bowers N. L., Helton E. S., Huijbregts R. P. H., Goepfert P. A., Heath S. L., Hel Z. Immune suppression by neutrophils in HIV-1 infection: role of PD-L1/PD-1 pathway. PLoS Pathogens. 2014;10(3, article e1003993) doi: 10.1371/journal.ppat.1003993. PubMed DOI PMC

Cohen N., Sharon A., Golik A., Zaidenstein R., Modai D. Hereditary angioneurotic edema with severe hypovolemic shock. Journal of Clinical Gastroenterology. 1993;16(3):237–239. doi: 10.1097/00004836-199304000-00016. PubMed DOI

Owen C. A., Campbell M. A., Sannes P. L., Boukedes S. S., Campbell E. J. Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases. The Journal of Cell Biology. 1995;131(3):775–789. doi: 10.1083/jcb.131.3.775. PubMed DOI PMC

Edwards S. W., Nurcombe H. L., Hart C. A. Oxidative inactivation of myeloperoxidase released from human neutrophils. The Biochemical Journal. 1987;245(3):925–928. doi: 10.1042/bj2450925. PubMed DOI PMC

Leliefeld P. H. C., Koenderman L., Pillay J. How neutrophils shape adaptive immune responses. Frontiers in Immunology. 2015;6:p. 471. doi: 10.3389/fimmu.2015.00471. PubMed DOI PMC

Pillay J., Kamp V. M., van Hoffen E., et al. A subset of neutrophils in human systemic inflammation inhibits T cell responses through Mac-1. The Journal of Clinical Investigation. 2012;122(1):327–336. doi: 10.1172/JCI57990. PubMed DOI PMC

Arcoleo F., Salemi M., La Porta A., et al. Upregulation of cytokines and IL-17 in patients with hereditary angioedema. Clinical Chemistry and Laboratory Medicine. 2014;52(5):e91–e93. doi: 10.1515/cclm-2013-1008. PubMed DOI

Demirtürk M., Gelincik A., Çınar S., et al. Increased eNOS levels in hereditary angioedema. International Immunopharmacology. 2014;20(1):264–268. doi: 10.1016/j.intimp.2014.03.007. PubMed DOI

López-Lera A., Cabo F. S., Garrido S., Dopazo A., López-Trascasa M. Disease-modifying factors in hereditary angioedema: an RNA expression-based screening. Orphanet Journal of Rare Diseases. 2013;8(1):p. 77. doi: 10.1186/1750-1172-8-77. PubMed DOI PMC

Van den Steen P. E., Proost P., Wuyts A., Van Damme J., Opdenakker G. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4, and GRO-α and leaves RANTES and MCP-2 intact. Blood. 2000;96(8):2673–2681. PubMed

Ito A., Mukaiyama A., Itoh Y., et al. Degradation of interleukin 1β by matrix metalloproteinases. Journal of Biological Chemistry. 1996;271(25):14657–14660. doi: 10.1074/jbc.271.25.14657. PubMed DOI

Schönbeck U., Mach F., Libby P. Generation of biologically active IL-1β by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1β processing. The Journal of Immunology. 1998;161(7):3340–3346. PubMed

McIntyre K. W., Stepan G. J., Kolinsky K. D., et al. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. The Journal of Experimental Medicine. 1991;173(4):931–939. doi: 10.1084/jem.173.4.931. PubMed DOI PMC

Liebler J. M., Kunkel S. L., Burdick M. D., Standiford T. J., Rolfe M. W., Strieter R. M. Production of IL-8 and monocyte chemotactic peptide-1 by peripheral blood monocytes. Disparate responses to phytohemagglutinin and lipopolysaccharide. The Journal of Immunology. 1994;152(1):241–249. PubMed

Schröder J. M., Christophers E. Secretion of novel and homologous neutrophil-activating peptides by LPS-stimulated human endothelial cells. The Journal of Immunology. 1989;142(1):244–251. PubMed

Soell M., Diab M., Haan-Archipoff G., et al. Capsular polysaccharide types 5 and 8 of Staphylococcus aureus bind specifically to human epithelial (KB) cells, endothelial cells, and monocytes and induce release of cytokines. Infection and Immunity. 1995;63(4):1380–1386. PubMed PMC

Marie C., Fitting C., Cheval C., et al. Presence of high levels of leukocyte-associated interleukin-8 upon cell activation and in patients with sepsis syndrome. Infection and Immunity. 1997;65(3):865–871. PubMed PMC

Bazzoni F., Cassatella M. A., Rossi F., Ceska M., Dewald B., Baggiolini M. Phagocytosing neutrophils produce and release high amounts of the neutrophil-activating peptide 1/interleukin 8. The Journal of Experimental Medicine. 1991;173(3):771–774. doi: 10.1084/jem.173.3.771. PubMed DOI PMC

Cassatella M. A. Neutrophil-derived proteins: selling cytokines by the pound. Advances in Immunology. 1999;73:369–509. doi: 10.1016/S0065-2776(08)60791-9. PubMed DOI

Kearley J., Barker J. E., Robinson D. S., Lloyd C. M. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. The Journal of Experimental Medicine. 2005;202(11):1539–1547. doi: 10.1084/jem.20051166. PubMed DOI PMC

Marie C., Muret J., Fitting C., Losser M. R., Payen D., Cavaillon J. M. Reduced ex vivo interleukin-8 production by neutrophils in septic and nonseptic systemic inflammatory response syndrome. Blood. 1998;91(9):3439–3446. PubMed

Renckens R., Weijer S., de Vos A. F., et al. Inhibition of plasmin activity by tranexamic acid does not influence inflammatory pathways during human endotoxemia. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24(3):483–488. doi: 10.1161/01.ATV.0000118280.95422.48. PubMed DOI

Hanson A. J., Quinn M. T. Effect of fibrin sealant composition on human neutrophil chemotaxis. Journal of Biomedical Materials Research. 2002;61(3):474–481. doi: 10.1002/jbm.10196. PubMed DOI

Li Y., Xie H., Deng Z., et al. Tranexamic acid ameliorates rosacea symptoms through regulating immune response and angiogenesis. International Immunopharmacology. 2019;67:326–334. doi: 10.1016/j.intimp.2018.12.031. PubMed DOI

Matsuse H., Yanagihara K., Mukae H., Tanaka K., Nakazato M., Kohno S. Association of plasma neutrophil elastase levels with other inflammatory mediators and clinical features in adult patients with moderate and severe pneumonia. Respiratory Medicine. 2007;101(7):1521–1528. doi: 10.1016/j.rmed.2007.01.001. PubMed DOI

Tagami T., Kushimoto S., Tosa R., et al. Plasma neutrophil elastase correlates with pulmonary vascular permeability: a prospective observational study in patients with pneumonia. Respirology. 2011;16(6):953–958. doi: 10.1111/j.1440-1843.2011.01997.x. PubMed DOI

Ciećko-Michalska I., Wierzbicka-Tutka I., Szczepanek M., et al. TGF-β1 and granulocyte elastase in the evaluation of activity of inflammatory bowel disease. A pilot study. Postȩpy Higieny i Medycyny Doświadczalnej. 2014;68:66–72. doi: 10.5604/17322693.1086361. PubMed DOI

Gouni-Berthold I., Baumeister B., Wegel E., Berthold H. K., Vetter H., Schmidt C. Neutrophil-elastase in chronic inflammatory bowel disease: a marker of disease activity? Hepato-Gastroenterology. 1999;46(28):2315–2320. PubMed

Lee S.-A., Wang P.-H., Chiou H.-L., Chou M.-C., Tsai H.-T., Yang S.-F. Markedly elevated plasma myeloperoxidase protein in patients with pelvic inflammatory disease who have A allele myeloperoxidase gene polymorphism. Fertility and Sterility. 2010;93(4):1260–1266. doi: 10.1016/j.fertnstert.2008.11.024. PubMed DOI

Fernandes R. M. S. N., da Silva N. P., Sato E. I. Increased myeloperoxidase plasma levels in rheumatoid arthritis. Rheumatology International. 2012;32(6):1605–1609. doi: 10.1007/s00296-011-1810-5. PubMed DOI

Glasser L., Fiederlein R. L. Functional differentiation of normal human neutrophils. Blood. 1987;69(3):937–944. PubMed

Neeli I., Khan S. N., Radic M. Histone deimination as a response to inflammatory stimuli in neutrophils. The Journal of Immunology. 2008;180(3):1895–1902. doi: 10.4049/jimmunol.180.3.1895. PubMed DOI

Behnen M., Leschczyk C., Möller S., et al. Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcγRIIIB and Mac-1. The Journal of Immunology. 2014;193(4):1954–1965. doi: 10.4049/jimmunol.1400478. PubMed DOI

Hayashi F., Means T. K., Luster A. D. Toll-like receptors stimulate human neutrophil function. Blood. 2003;102(7):2660–2669. doi: 10.1182/blood-2003-04-1078. PubMed DOI

Sabroe I., Prince L. R., Jones E. C., et al. Selective roles for Toll-like receptor (TLR)2 and TLR4 in the regulation of neutrophil activation and life span. The Journal of Immunology. 2003;170(10):5268–5275. doi: 10.4049/jimmunol.170.10.5268. PubMed DOI

Andreasen P. A., Kjøller L., Christensen L., Duffy M. J. The urokinase-type plasminogen activator system in cancer metastasis: a review. International Journal of Cancer. 1997;72(1):1–22. doi: 10.1002/(SICI)1097-0215(19970703)72:1<1::AID-IJC1>3.0.CO;2-Z. PubMed DOI

Kaplan A. P., Austen K. F. A prealbumin activator of prekallikrein. II. Derivation of activators of prekallikrein from active Hageman factor by digestion with plasmin. The Journal of Experimental Medicine. 1971;133(4):696–712. doi: 10.1084/jem.133.4.696. PubMed DOI PMC

Fields T., Ghebrehiwet B., Kaplan A. P. Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of “spontaneous” formation of bradykinin. Journal of Allergy and Clinical Immunology. 1983;72(1):54–60. doi: 10.1016/0091-6749(83)90052-0. PubMed DOI

Nussberger J., Cugno M., Cicardi M., Agostoni A. Local bradykinin generation in hereditary angioedema. Journal of Allergy and Clinical Immunology. 1999;104(6):1321–1322. doi: 10.1016/S0091-6749(99)70030-8. PubMed DOI

Brown E. W., Ravindran S., Patston P. A. The reaction between plasmin and C1-inhibitor results in plasmin inhibition by the serpin mechanism. Blood Coagulation & Fibrinolysis. 2002;13(8):711–714. doi: 10.1097/00001721-200212000-00007. PubMed DOI

Bork K., Wulff K., Meinke P., Wagner N., Hardt J., Witzke G. A novel mutation in the coagulation factor 12 gene in subjects with hereditary angioedema and normal C1-inhibitor. Clinical Immunology. 2011;141(1):31–35. doi: 10.1016/j.clim.2011.07.002. PubMed DOI

Dewald G., Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochemical and Biophysical Research Communications. 2006;343(4):1286–1289. doi: 10.1016/j.bbrc.2006.03.092. PubMed DOI

Kiss N., Barabás E., Várnai K., et al. Novel duplication in the F12 gene in a patient with recurrent angioedema. Clinical Immunology. 2013;149(1):142–145. doi: 10.1016/j.clim.2013.08.001. PubMed DOI

Liu D., Cai S., Gu X., Scafidi J., Wu X., Davis A. E. C1 inhibitor prevents endotoxin shock via a direct interaction with lipopolysaccharide. The Journal of Immunology. 2003;171(5):2594–2601. doi: 10.4049/jimmunol.171.5.2594. PubMed DOI

Davis A., III, Lu F., Mejia P. C1 inhibitor, a multi-functional serine protease inhibitor. Thrombosis and Haemostasis. 2010;104(11):886–893. doi: 10.1160/TH10-01-0073. PubMed DOI

Dorresteijn M. J., Visser T., Cox L. A. E., et al. C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia. Critical Care Medicine. 2010;38(11):2139–2145. doi: 10.1097/CCM.0b013e3181f17be4. PubMed DOI

Liu D., Lu F., Qin G., Fernandes S. M., Li J., Davis A. E. C1 inhibitor-mediated protection from sepsis. The Journal of Immunology. 2007;179(6):3966–3972. doi: 10.4049/jimmunol.179.6.3966. PubMed DOI

Gabrilovich D. I., Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology. 2009;9(3):162–174. doi: 10.1038/nri2506. PubMed DOI PMC

Mantovani A., Cassatella M. A., Costantini C., Jaillon S. Neutrophils in the activation and regulation of innate and adaptive immunity. Nature Reviews Immunology. 2011;11(8):519–531. doi: 10.1038/nri3024. PubMed DOI

Honda D., Ohsawa I., Sato N., et al. Diminished capacity of opsonization and immune complex solubilization, and detection of anti-C1q antibodies in sera from patients with hereditary angioedema. Allergology International. 2017;66(4):603–609. doi: 10.1016/j.alit.2017.03.008. PubMed DOI

Kessel A., Peri R., Perricone R., et al. The autoreactivity of B cells in hereditary angioedema due to C1 inhibitor deficiency. Clinical and Experimental Immunology. 2012;167(3):422–428. doi: 10.1111/j.1365-2249.2011.04527.x. PubMed DOI PMC

Nielsen E. W., Gran J. T., Straume B., Mellbye O. J., Johansen H. T., Mollnes T. E. Hereditary angio-oedema: new clinical observations and autoimmune screening, complement and kallikrein-kinin analyses. Journal of Internal Medicine. 1996;239(2):119–130. doi: 10.1046/j.1365-2796.1996.418764000.x. PubMed DOI

Farkas H., Csuka D., Gács J., et al. Lack of increased prevalence of immunoregulatory disorders in hereditary angioedema due to C1-inhibitor deficiency. Clinical Immunology. 2011;141(1):58–66. doi: 10.1016/j.clim.2011.05.004. PubMed DOI

Agostoni A., Cicardi M. Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 patients. Medicine. 1992;71(4):206–215. doi: 10.1097/00005792-199207000-00003. PubMed DOI

Muhlemann M. F., Macrae K. D., Smith A. M., et al. Hereditary angioedema and thyroid autoimmunity. Journal of Clinical Pathology. 1987;40(5):518–523. doi: 10.1136/jcp.40.5.518. PubMed DOI PMC

Sanchez A. M., Yang Y. The role of natural regulatory T cells in infection. Immunologic Research. 2011;49(1-3):124–134. doi: 10.1007/s12026-010-8176-8. PubMed DOI PMC

Visy B., Füst G., Bygum A., et al. Helicobacter pylori infection as a triggering factor of attacks in patients with hereditary angioedema. Helicobacter. 2007;12(3):251–257. doi: 10.1111/j.1523-5378.2007.00501.x. PubMed DOI

Zotter Z., Veszeli N., Kőhalmi K. V., et al. Bacteriuria increases the risk of edematous attacks in hereditary angioedema with C1-inhibitor deficiency. Allergy. 2016;71(12):1791–1793. doi: 10.1111/all.13034. PubMed DOI

Cedzyński M., Madaliński K., Gregorek H., et al. Possible disease-modifying factors: the mannan-binding lectin pathway and infections in hereditary angioedema of children and adults. Archivum Immunologiae et Therapiae Experimentalis. 2008;56(1):69–75. doi: 10.1007/s00005-008-0004-7. PubMed DOI PMC

Myeloid lineage cells evince distinct steady-state level of certain gene groups in dependence on hereditary angioedema severity

SERPING1 Variants and C1-INH Biological Function: A Close Relationship With C1-INH-HAE