Pathways of Neutrophil Granulocyte Activation in Hereditary Angioedema with C1 Inhibitor Deficiency

Erika Kajdácsi,Anne Lise Ferrara,Zsófia Jandrasics,Henriette Farkas,Lilian Varga,Blanka Mező,Kinga Viktória Kőhalmi,Nóra Veszeli,László Cervenak

doi:10.1007/s12016-021-08847-4

Abstract

Hereditary angioedema (HAE) with C1-inhibitor deficiency belongs to bradykinin-mediated angioedemas. It is characterized by recurrent subcutaneous and/or submucosal swelling episodes (HAE attacks) and erythema marginatum skin rash as a pre-attack (prodromal) phase. HAE attacks were shown to be accompanied by peripheral blood neutrophilia. We aimed to find molecular mechanisms that may explain the distinct role of neutrophil granulocytes in HAE. Plasma levels of blood cells and factors related to neutrophil activation (cytokines, chemokines, chemotactic factors, enzymes, and neutrophil extracellular trap) were measured in plasma samples obtained from patients during symptom-free periods (n = 77), during prodromal phase (n = 8) and attacks (n = 14), during a spontaneously resolved attack (n = 1), and in healthy controls (n = 79). Higher counts of white blood cells, lymphocytes, and neutrophil granulocytes were found in symptom-free patients compared with controls; these cell counts were elevated further during HAE attacks. The level of chemokine (C–C motif) ligand 5, monocyte chemoattractant protein-1, and myeloperoxidase were also higher in the symptom-free patients than in the controls. Levels of monocyte chemoattractant protein-1, leukotriene B4, neutrophil elastase, and myeloperoxidase were elevated during attacks. During erythema marginatum, white blood cells and monocyte count and levels of interleukin 8 were elevated compared with symptom-free period. Similar changes were detected during the attack follow-up. We conclude that the activation of NGs in symptom-free periods and a further increase observed during attacks suggests that NGs may be involved in the pathomechanism of HAE with C1-INH deficiency.

Highlights

Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare, potentially lifethreatening disorder characterized by recurrent swelling episodes in subcutaneous and/or submucosal tissues, which are often preceded by prodromal symptoms [1, 2]
A further study showed that neutrophil granulocyte count (NGC) is higher in C1-INHHAE patients during symptom-free periods than in healthy controls, and this difference is further emphasized during HAE attacks
The activation of neutrophil granulocytes (NGs) may lead to the formation of neutrophil extracellular traps (NETs) during which NGs release their DNA content and citrullinated histones decorated with the proteins from azurophilic granules (e.g., neutrophil elastase (NE) and MPO), specific granules, tertiary granules, and the cytoplasm to bind pathogens and provide a negatively charged surface for the activation of the kallikrein-kinin system (KKS) and the complement systems [22,23,24,25,26]

Summary

Introduction

Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare, potentially lifethreatening disorder characterized by recurrent swelling episodes in subcutaneous and/or submucosal tissues, which are often preceded by prodromal symptoms [1, 2]. Zotter et al observed that all hematologic values are increased during attacks and the elevation of WBC count is significantly greater (~ 1.5-fold) than expected based on hemoconcentration alone, and it involves the peripheral blood neutrophil granulocytes (NGs) [13]. The activation of NGs may lead to the formation of neutrophil extracellular traps (NETs) during which NGs release their DNA content and citrullinated histones decorated with the proteins from azurophilic granules (e.g., NE and MPO), specific granules, tertiary granules, and the cytoplasm to bind pathogens and provide a negatively charged surface for the activation of the KKS and the complement systems [22,23,24,25,26]

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