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01-07-2021 | Colchicine | Original Article

Phenotypical and Functional Characterization of Neutrophils in Two Pyrin-Associated Auto-inflammatory Diseases

Authors: Bert Malengier-Devlies, Mieke Metzemaekers, Mieke Gouwy, Erika Van Nieuwenhove, Albrecht Betrains, Maaike Cockx, Lotte Vanbrabant, Noëmie Pörtner, Jurgen Vercauteren, Lien De Somer, Sofie Struyf, Steven Vanderschueren, Ellen De Langhe, Paul Proost, Patrick Matthys, Carine Wouters

Published in: Journal of Clinical Immunology | Issue 5/2021

Abstract

Purpose

Familial Mediterranean Fever (FMF) and Pyrin-Associated Autoinflammation with Neutrophilic Dermatosis (PAAND) are clinically distinct autoinflammatory disorders caused by mutations in the pyrin-encoding gene MEFV. We investigated the transcriptional, phenotypical, and functional characteristics of patient neutrophils to explore their potential role in FMF and PAAND pathophysiology.

Methods

RNA sequencing was performed to discover transcriptional aberrancies. The phenotypical features, degranulation properties, and phagocytic capacity of neutrophils were assessed by flow cytometry. Production of reactive oxygen species (ROS), myeloperoxidase (MPO) release, and chemotactic responses were investigated via chemiluminescence, ELISA, and Boyden chamber assays, respectively.

Results

Neutrophils from PAAND and FMF patients showed a partially overlapping, activated gene expression profile with increased expression of S100A8, S100A9, S100A12, IL-4R, CD48, F5, MMP9, and NFKB. Increased MMP9 and S100A8/A9 expression levels were accompanied by high plasma concentrations of the encoded proteins. Phenotypical analysis revealed that neutrophils from FMF patients exhibited an immature character with downregulation of chemoattractant receptors CXCR2, C5aR, and BLTR1 and increased expression of Toll-like receptor 4 (TLR4) and TLR9. PAAND neutrophils displayed an increased random, but reduced CXCL8-induced migration. A tendency for enhanced random migration was observed for FMF neutrophils. PAAND neutrophils showed a moderately but significantly enhanced phagocytic activity as opposed to neutrophils from FMF patients. Neutrophils from both patient groups showed increased MPO release and ROS production.

Conclusions

Neutrophils from patients with FMF and PAAND, carrying different mutations in the MEFV gene, share a pro-inflammatory phenotype yet demonstrate diverse features, underscoring the distinction between both diseases.

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Title: Phenotypical and Functional Characterization of Neutrophils in Two Pyrin-Associated Auto-inflammatory Diseases
Authors: Bert Malengier-Devlies
Mieke Metzemaekers
Mieke Gouwy
Erika Van Nieuwenhove
Albrecht Betrains
Maaike Cockx
Lotte Vanbrabant
Noëmie Pörtner
Jurgen Vercauteren
Lien De Somer
Sofie Struyf
Steven Vanderschueren
Ellen De Langhe
Paul Proost
Patrick Matthys
Carine Wouters
Publication date: 01-07-2021
Publisher: Springer US
Keywords: Colchicine
Familial Mediterranean Fever
Published in: Journal of Clinical Immunology / Issue 5/2021
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-021-01008-4

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Phenotypical and Functional Characterization of Neutrophils in Two Pyrin-Associated Auto-inflammatory Diseases

Abstract

Purpose

Methods

Results

Conclusions

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