Response to: ‘Correspondence on ‘Critical role of neutrophil extracellular traps (NETs) in patients with Behcet’s disease’’ by Chen et al

ObjectivesBehçet’s disease (BD) is a chronic systemic vasculitis. Thrombosis is a frequent and life-threatening complication. The pathogenesis of BD is poorly understood and evidence supporting a role for primed neutrophils in BD-associated thrombotic risk is scant. To respond to inflammatory insults, neutrophils release web-like structures, known as neutrophil extracellular traps (NETs), which are prothrombotic. We evaluated the role of NETs and markers of NETs in BD.MethodsBlood samples were collected from patients with BD, according to the International Study Group Criteria for Behçet's disease, and healthy donors (HD). NET components, including cell-free DNA (CfDNA) and neutrophil enzymes myeloperoxidase (MPO), were assessed in serum or in purified neutrophils from patients with BD and HD.ResultsPatients with active BD had elevated serum cfDNA levels and MPO-DNA complexes compared with patients with inactive BD and to HD. In addition, levels of cfDNA and MPO-DNA complexes were significantly higher in patients with BD with vascular involvement compared with those without vascular symptoms. Purified neutrophils from patients with BD exhibited spontaneous NETosis compared with HD. Thrombin generation in BD plasma was significantly increased and positively correlated with the levels of MPO-DNA complexes and cfDNA. Importantly, DNAse treatment significantly decreased thrombin generation in BD plasma but not in HD plasma. In addition, biopsy materials obtained from patients with BD showed NETs production in areas of vasculitic inflammation and thrombosis.ConclusionsOur data show that NETs and markers of NETS levels are elevated in patients with BD and contribute to the procoagulant state. Targeting NETs may represent a potential therapeutic target for the reduction or prevention of BD-associated thrombotic risk.

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FRI0003 ELEVATED HISTONE H4 IN NEUTROPHIL EXTRACELLULAR TRAPS PROMOTES MACROPHAGE ACTIVATION IN BEHÇET’S DISEASE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2097 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 572.1-573

Author(s):

L. LI ◽

X. Yu ◽

J. Liu ◽

H. Chen ◽

W. Zheng

Keyword(s):

Behçet’S Disease ◽

Macrophage Activation ◽

Behcet’S Disease ◽

Behçet's Disease ◽

Neutrophil Extracellular Traps ◽

Histone H4 ◽

Behcet's Disease ◽

Extracellular Traps ◽

Tnf Α

Background:Neutrophil-released neutrophil extracellular traps (NETs) are upregulated and promote autoinflammation and thrombosis in Behçet’s disease (BD), a multi-system inflammatory disease with unknown etiology1,2. However, whether NETs promote macrophage activation in BD remains unclear.Objectives:To investigate the potential role of NETs in promoting aberrant macrophage activation in BD.Methods:We quantified NETs by measuring dsDNA using ELISA and immunofluorescence. Macrophages were stimulated with BD- and healthy controls (HC)-derived NETs, and IL-8 and TNF-α production were measured by ELISA. NETs-stimulated macrophages were incubated with naive CD4+T cells, and Th1 cell differentiation was examined on day 7 by flow cytometry. Histones H1, H2A, H2B, H3, H4, S100A8 and neutrophil elastase in NETs were analyzed by western blot. Macrophages were stimulated with anti-Histone 4 antibody-treated NETs, and IL-8 production was measured by ELISA.Results:Circulating NETs (2336±534 ng/ml vs. 1472±549 ng/ml,P=0.0008) and neutrophil-derived NETs (909.2±485.2 ng/ml vs. 582.4±199.2 ng/ml,P=0.0108) were significantly higher in BD patients compared with those in HC. BD NETs stimulated macrophages to produce a higher level of IL-8 (17±4 ng/ml vs. 13±4 ng/ml,P=0.0474) and TNF-α (166±61 pg/ml vs. 102±48 pg/ml,P=0.0132) than HC NETs. Moreover, BD NETs promoted macrophages to facilitate Th1 differentiation than HC NETs (33±10% vs. 24±7%,P=0.0398). Western blot analysis revealed more Histone H4 (289076 (144365, 544038) IOD values vs. 42121 (6958, 129625) IOD values,P=0.0286), but not Histones H1, H2A, H2B, H3, S100A8 or neutrophil elastase in BD NETs compared to HC NETs. Importantly, neutralizing Histone H4 abrogated the BD NETs-stimulated IL-8 overproduction by macrophages (9.99±2.07 ng/ml vs. 13.95±2.91 ng/ml,P=0.021).Conclusion:BD NETs promoted macrophages activation, which might be mediated by a higher level of Histone H4.References:[1]Safi R., Kallas R., Bardawil T., et al. Neutrophils contribute to vasculitis by increased release of neutrophil extracellular traps in Behçet’s disease. J. Dermatol. Sci. 2018;92:143–150.[2]Le Joncour a, Martos r, Loyau s, et al. Critical role of neutrophil extracellular traps (NETs) in patients with Behcet’s disease. Ann Rheum Dis 2019;78:1274–1282.Disclosure of Interests:None declared

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Neutrophils contribute to vasculitis by increased release of neutrophil extracellular traps in Behçet's disease

Journal of Dermatological Science ◽

10.1016/j.jdermsci.2018.08.010 ◽

2018 ◽

Vol 92 (2) ◽

pp. 143-150 ◽

Cited By ~ 17

Author(s):

Rémi Safi ◽

Romy Kallas ◽

Tara Bardawil ◽

Carl Joe Mehanna ◽

Ossama Abbas ◽

...

Keyword(s):

Behçet’S Disease ◽

Behcet’S Disease ◽

Behçet's Disease ◽

Neutrophil Extracellular Traps ◽

Behcet's Disease ◽

Extracellular Traps

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Role of miR-146a rs2910164 and UTS2 rs228648 Genetic Variants in Behçet’s Disease

Immunological Investigations ◽

10.1080/08820139.2021.1883647 ◽

2021 ◽

pp. 1-10

Author(s):

Asmaa Kamal ◽

Fatema T Elgengehy ◽

Zahraa Elawady ◽

Nahla A. Fawzy ◽

Ola El Sisi

Keyword(s):

Behçet’S Disease ◽

Genetic Variants ◽

Behcet’S Disease ◽

Behçet's Disease ◽

Behcet's Disease

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French recommendations for the management of Behçet’s disease

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01620-4 ◽

2021 ◽

Vol 16 (S1) ◽

Author(s):

Isabelle Kone-Paut ◽

◽

Stéphane Barete ◽

Bahram Bodaghi ◽

Kumaran Deiva ◽

...

Keyword(s):

Behçet’S Disease ◽

Behcet’S Disease ◽

Behçet's Disease ◽

Initial Assessment ◽

Diagnostic Process ◽

Behcet's Disease ◽

Therapeutic Modalities ◽

Clinical Presentations ◽

Key Points

AbstractBehçet’s disease (BD) is a systemic variable vessel vasculitis that involves the skin, mucosa, joints, eyes, arteries, veins, nervous system and gastrointestinal system, presenting with remissions and exacerbations. It is a multifactorial disease, and several triggering factors including oral cavity infections and viruses may induce inflammatory attacks in genetically susceptible individuals. BD vasculitis involves different vessel types and sizes of the vascular tree with mixed-cellular perivascular infiltrates and is often complicated by recurrent thrombosis, particularly in the venous compartment. Several new therapeutic modalities with different mechanisms of action have been studied in patients with BD. A substantial amount of new data have been published on the management of BD, especially with biologics, over the last years. These important therapeutic advances in BD have led us to propose French recommendations for the management of Behçet’s disease [Protocole National de Diagnostic et de Soins de la maladie de Behçet (PNDS)]. These recommendations are divided into two parts: (1) the diagnostic process and initial assessment; (2) the therapeutic management. Thirty key points summarize the essence of the recommendations. We highlighted the main differential diagnosis of BD according to the type of clinical involvement; the role of genetics is also discussed, and we indicate the clinical presentations that must lead to the search for a genetic cause.

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