Loading…
Phenotypical and Functional Characterization of Neutrophils in Two Pyrin-Associated Auto-inflammatory Diseases
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 characteris...
Saved in:
Published in: | Journal of clinical immunology 2021-07, Vol.41 (5), p.1072-1084 |
---|---|
Main Authors: | , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | 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. |
---|---|
ISSN: | 0271-9142 1573-2592 |
DOI: | 10.1007/s10875-021-01008-4 |