Neutrophils Are Dysregulated in Patients with Hereditary Angioedema Types I and II in a Symptom-Free Period

Grymova, Tereza; Vlková, Marcela; Souček, Přemysl; Hakl, Roman; Nechvátalová, Jana; Slanina, Peter; Štíchová, Julie; Litzman, Jiří; Freiberger, Tomáš

doi:10.1155/2019/9515628

Cited by 5 publications

(8 citation statements)

References 77 publications

(80 reference statements)

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“…We propose that the higher level of NGs in the symptom-free stage of the patients may contribute to the constant activation of the KKS [ 42 ]. In contrast to previous studies [ 14 , 45 ], we could not find any significant difference in IL-8 levels—one of the best-known chemotactic factors for NGs—between patients and healthy controls. Interestingly, we found that CCL5 and MCP-1 may have an important role in NG recruitment in HAE.…”

Section: Discussioncontrasting

confidence: 99%

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

Kajdácsi

Veszeli

Mező

et al. 2021

Clinic Rev Allerg Immunol

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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.

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Section: Discussioncontrasting

confidence: 99%

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

Kajdácsi

Veszeli

Mező

et al. 2021

Clinic Rev Allerg Immunol

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“…NEAT1 and CD180 were upregulated and surprisingly IL1RN was also upregulated in patients with a severe phenotype compared to patients with a mild one. In our previous work (Grymová et al, 2019), we showed that CXCL8 expression was higher in HAE patients' neutrophils, while its plasma level was decreased. This discrepancy is now easily interpretable if we consider different CXCL8 resources in the plasma.…”

Section: Macrophages In Hae Coursementioning

confidence: 81%

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

et al. 2023

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Hereditary angioedema (HAE) is a rare genetic disorder with variable expressivity even in carriers of the same underlying genetic defect, suggesting other genetic and epigenetic factors participate in modifying HAE severity. Recent knowledge indicates the role of immune cells in several aspects of HAE pathogenesis, which makes monocytes and macrophages candidates to mediate these effects. Here we combined a search for HAE phenotype modifying gene variants with the characterization of selected genes’ mRNA levels in monocyte and macrophages in a symptom-free period. While no such gene variant was found to be associated with a more severe or milder disease, patients revealed a higher number of dysregulated genes and their expression profile was significantly altered, which was typically manifested by changes in individual gene expression or by strengthened or weakened relations in mutually co-expressed gene groups, depending on HAE severity. SERPING1 showed decreased expression in HAE-C1INH patients, but this effect was significant only in patients carrying mutations supposedly activating nonsense-mediated decay. Pro-inflammatory CXC chemokine superfamily members CXCL8, 10 and 11 were downregulated, while other genes such as FCGR1A, or long non-coding RNA NEAT1 were upregulated in patients. Co-expression within some gene groups (such as an NF-kappaB function related group) was strengthened in patients with a severe and/or mild course compared to controls. All these findings show that transcript levels in myeloid cells achieve different activation or depression levels in HAE-C1INH patients than in healthy controls and/or based on disease severity and could participate in determining the HAE phenotype.

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“…Interestingly, CXCL8 and TNF- α levels, both involved in PMN activation and/or released by neutrophils, were also altered in C1-INH-HAE patients during acute phase compared with symptom-free period [ 63 ] (Table 1 ). Grymova and colleagues confirmed PMN activation and dysregulation in C1-INH-HAE type I and II patients [ 64 ]. mRNA expression of 10 genes related to PMN activation (CD274, IL1 β , IL1RN, CXCL8, MMP9, and TLR4) was increased in HAE patients in symptom-free periods compared with healthy donors in addition to increased CD11b, decreased CD16 plasma membrane deposition, and increased relative CD274 + and CD87 + neutrophil counts, but not by increased NE or MPO plasma levels (Table 1 ).…”

Section: Innate Immune Systemmentioning

confidence: 95%

“…mRNA expression of 10 genes related to PMN activation (CD274, IL1 β , IL1RN, CXCL8, MMP9, and TLR4) was increased in HAE patients in symptom-free periods compared with healthy donors in addition to increased CD11b, decreased CD16 plasma membrane deposition, and increased relative CD274 + and CD87 + neutrophil counts, but not by increased NE or MPO plasma levels (Table 1 ). In addition, a co-culture of PMN and T-cells/PBMC showed a suppressive function of patient’ PMN resulted from a decreased CD25 + and IFN- γ + T-cell/PBMC ratio in patients [ 64 ].…”

Section: Innate Immune Systemmentioning

confidence: 99%

Roles of Immune Cells in Hereditary Angioedema

Ferrara

Cristinziano

Petraroli

et al. 2021

Clinic Rev Allerg Immunol

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Hereditary angioedema (HAE) is a rare genetic disease, characterized by recurrent and unexpected potentially life-threatening mucosal swelling. HAE may be further classified into HAE with C1‐inhibitor deficiency (C1‐INH‐HAE) and HAE with normal C1‐INH activity (nlC1‐INH‐HAE), mostly due to mutations leading to increased vascular permeability. Recent evidence implicates also the innate and adaptive immune responses in several aspects of angioedema pathophysiology. Monocytes/macrophages, granulocytes, lymphocytes, and mast cells contribute directly or indirectly to the pathophysiology of angioedema. Immune cells are a source of vasoactive mediators, including bradykinin, histamine, complement components, or vasoactive mediators, whose concentrations or activities are altered in both attacks and remissions of HAE. In turn, through the expression of various receptors, these cells are also activated by a plethora of molecules. Thereby, activated immune cells are the source of molecules in the context of HAE, and on the other hand, increased levels of certain mediators can, in turn, activate immune cells through the engagement of specific surface receptors and contribute to vascular endothelial processes that lead to hyperpemeability and tissue edema. In this review, we summarize recent developments in the putative involvement of the innate and adaptive immune system of angioedema.

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Neutrophils Are Dysregulated in Patients with Hereditary Angioedema Types I and II in a Symptom-Free Period

Cited by 5 publications

References 77 publications

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

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

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

Roles of Immune Cells in Hereditary Angioedema

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