Evidence of membranolytic targeting and intracellular citrullination in neutrophils isolated from patients with rheumatoid arthritis.

Autor: Moadab F; Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican Street, Room E507, Seattle, WA, 99108, USA., Wang X; Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican Street, Room E507, Seattle, WA, 99108, USA., Le E; Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican Street, Room E507, Seattle, WA, 99108, USA., Gazitt T; Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican Street, Room E507, Seattle, WA, 99108, USA., Najjar R; Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican Street, Room E507, Seattle, WA, 99108, USA., Nelson JL; Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican Street, Room E507, Seattle, WA, 99108, USA., Joshua V; Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Malmström V; Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Elkon K; Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican Street, Room E507, Seattle, WA, 99108, USA., Grönwall C; Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden., Mustelin T; Division of Rheumatology, Department of Medicine, University of Washington, 750 Republican Street, Room E507, Seattle, WA, 99108, USA. tomas2@uw.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jul 05; Vol. 14 (1), pp. 15511. Date of Electronic Publication: 2024 Jul 05.
DOI: 10.1038/s41598-024-66516-w
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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