Evidence of membranolytic targeting and intracellular citrullination in neutrophils isolated from patients with rheumatoid arthritis.
Humans
Neutrophils
/ metabolism
Arthritis, Rheumatoid
/ metabolism
Citrullination
Protein-Arginine Deiminase Type 4
/ metabolism
Anti-Citrullinated Protein Antibodies
/ metabolism
Perforin
/ metabolism
Female
Male
Middle Aged
Autoantibodies
/ immunology
Protein-Arginine Deiminases
/ metabolism
Adult
Felty Syndrome
/ metabolism
Extracellular Traps
/ metabolism
Citrulline
/ metabolism
Aged
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
05 Jul 2024
05 Jul 2024
Historique:
received:
12
03
2024
accepted:
02
07
2024
medline:
6
7
2024
pubmed:
6
7
2024
entrez:
5
7
2024
Statut:
epublish
Résumé
Anti-citrullinated protein autoantibodies (ACPA) are diagnostic for rheumatoid arthritis (RA). The antigens recognized by these autoantibodies are produced by protein arginine deiminases (PADs), particularly PAD4. However, it remains unknown why and how PAD4 causes this aberrant citrullination in RA. Here, we report that poly-perforin pores are present on freshly isolated neutrophils from RA patients, but not on healthy donor neutrophils. Neutrophils with perforin pores also contained intracellular citrullinated proteins in the region adjacent to the pores. This response was replicated in vitro by treating neutrophils with purified perforin, which generated intense dots of anti-perforin immunofluorescence, calcium influx, and intracellular citrullination. Extensive neutrophil killing in Felty's syndrome, an aggressive form of RA, correlated with particularly high ACPA, and PAD4 autoantibodies. In contrast, other forms of death, including NETosis, apoptosis, and pyroptosis, produced minimal citrullination. We conclude that neutrophil targeting by perforin leading to intracellular citrullination takes place in patients with RA.
Identifiants
pubmed: 38969707
doi: 10.1038/s41598-024-66516-w
pii: 10.1038/s41598-024-66516-w
doi:
Substances chimiques
Protein-Arginine Deiminase Type 4
EC 3.5.3.15
Anti-Citrullinated Protein Antibodies
0
Perforin
126465-35-8
PADI4 protein, human
EC 3.5.3.15
Autoantibodies
0
Protein-Arginine Deiminases
EC 3.5.3.15
Citrulline
29VT07BGDA
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
15511Subventions
Organisme : NIH HHS
ID : K08 AR082939
Pays : United States
Organisme : NIH HHS
ID : R21 AR075134
Pays : United States
Organisme : NIH HHS
ID : R01 AR074939
Pays : United States
Organisme : NIH HHS
ID : R01 AR081654
Pays : United States
Informations de copyright
© 2024. The Author(s).
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